{ "bcoid": "GLY_000594", "title": "Human Pathways (Reactome)", "description": "", "filename": "human_protein_pathways_reactome.csv", "filetype": "csv", "categories": { "species": "Homo sapiens", "molecule": "Protein", "tags": "Reactome Pathway", "file_type": "csv", "status": "Reviewed", "scope": "internal" }, "minitable": { "content": [ [ "R-HSA-970119...", "Defective HD..." ], [ "R-HSA-971720...", "Sensory perc..." ] ], "headers": [ "pathway_id...", "pathway_name..." ], "colwidth": [ "40%", "20%" ] }, "sampledata": { "type": "table", "data": [ [ { "type": "string", "label": "pathway_id" }, { "type": "string", "label": "pathway_name" }, { "type": "string", "label": "pathway_summary" }, { "type": "string", "label": "reaction_id_list" } ], [ "R-HSA-9701192", "Defective HDR through Homologous Recombination (HRR) due to BRCA1 loss-of-function", "In addition to its role in DNA double-strand break (DSB) signaling, BRCA1 plays an important role in homologous recombination repair (HRR) of DSBs by directly promoting recruitment of PALB2 and indirectly BRCA2 to DSB repair sites. In addition, BRCA1 increases the speed and processivity of DNA end resection which consists of 5\u2032\u20133\u2032 nucleolytic degradation of DSBs (Cruz-Garcia et al. 2014). The direct BRCA1 interaction with PALB2 helps to fine-tune the localization of BRCA2 and RAD51 at DSBs (Zhang et al. 2009, Sy et al. 2009). PALB2 simultaneously interacts with RAD51, BRCA2 and RAD51AP1 (Modesti et al. 2007, Wiese et al. 2007, Buisson et al. 2010, Dray et al. 2010). PALB2 and RAD51AP1 synergistically stimulate RAD51 recombinase activity, thus enhancing RAD51-mediated strand exchange (branch migration) and promoting the formation of D-loop structures (synaptic complex assembly). A D-loop structure is formed when complementary duplex DNA (sister chromatid arm) is progressively invaded by the RAD51 nucleoprotein filament, with base pairing of the invading ssDNA and the complementary sister chromatid DNA strand (Sung et al. 2003).

The N-terminal region of BRCA1 contains the RING domain (residues 7-98), required for the heterodimerization of BRCA1 with BARD1. BRCA1:BARD1 heterodimer has E3 ubiquitin ligase activity which is important for DNA repair (Drost et al. 2011). Several missense mutations within the RING domain have been linked to increased risks of developing breast/ovarian cancers (Bouwman et al. 2013; Starita et al. 2018). BRCA1 mutant proteins impaired in BARD1 binding are annotated in the pathway \\Defective DNA double strand break response due to BRCA1 loss of function\\.

The C-terminal region of BRCA1 which contains two coiled coil domains (residues 1397-1424) and two BRCT domains (residues 1642-1736 for BRCT 1; residues 1756-1855 for BRCT 2) is involved in PALB2 binding, with the second coiled coil domain being essential (Sy et al. 2009). Several cancer-associated BRCA1 missense mutants that affect the C-terminal region were shown to have reduced ability to bind PALB2 (Sy et al. 2009). In addition, many nonsense and frameshift mutations in BRCA1 reported in cancer result in truncated proteins that lack the PALB2-binding domain.", "R-HSA-9701199" ], [ "R-HSA-9717207", "Sensory perception of sweet, bitter, and umami (glutamate) taste", "Taste receptors for bitter compounds, sweet compounds, and umami compounds (L-glutamate in humans, several amino acids in mice) are G protein-coupled receptors located in type II taste bud cells that signal through a common downstream pathway (reviewed in Margolskee 2002, Kinnamon 2009, Kurihara 2015, Roper and Chauhari et al. 2017, Kinnamon and Finger 2019, Servant et al. 2020). Umami (\\savoury\\, L-glutamate) taste receptors are heterodimers of the plasma membrane proteins TAS1R1 and TAS1R3. TAS1R1:TAS1R3 heterodimers also bind 5' nucleotides such as 5' IMP which synergistically augment umami taste. The glutamate receptors GRM1 (mGluR1) and GRM4 (mGluR4) act in an alternative pathway for sensing glutamate in taste cells (reviewed in Chaudhari et al. 2009). Sweet taste receptors are heterodimers of the plasma membrane proteins TAS1R2 and TAS1R3 (reviewed in Yang et al. 2021). The glucose transporters SGLT1 and GLUT4 are expressed in type II taste cells and may provide an alternative pathway for sensing glucose (reviewed in von Molitor et al. 2020). Bitter receptors are a large family of monomeric plasma membrane proteins, the TAS2R proteins.
TAS1R-containing sweet and umami receptors and TAS2R bitter receptors are each physically associated with a particular heterotrimeric G protein complex, the gustducin complex, containing GNAT3 (gustducin), GNB1 or GNB3, and GNG13. Upon binding an agonist ligand, the receptor activates the alpha subunit, GNAT3, to exchange GDP for GTP, which results in a conformational change in GNAT3 that causes the receptor-gustducin complex to dissociate, yielding GNAT3:GTP, GNB1,3:GNG13, and the receptor:ligand. The GNB1,3:GNG13 complex binds and activates Phospholipase C beta-2 (PLCB2), which then hydrolyzes phosphoinositol 4,5-bisphosphate (PI(4,5)P2) to yield diacylglycerol and inositol 1,4,5-trisphosphate (I(1,4,5)P3). I(1,4,5)P3 binds and activates the calcium channel IP3-gated Ca-channel type 3 (ITPR3) and ITPR3 then releases calcium ions from the endoplasmic reticulum into the cytosol. The increased cytosolic calcium activates the TRPM5 cation channels, which then transport sodium ions along the concentration gradient from the extracellular region to the cytosol (reviewed in Aroke et al. 2020). The depolarization activates SCN2A, SCN3A, and SCN9A channels, which transport further sodium ions from the extracellular region to the cytosol. The depolarization of the plasma membrane opens CALHM1:CALHM3 channels, which transport ATP, a neurotransmitter in the olfactory system, from the cytosol to the extracellular region.
Taste receptors were initially discovered in taste buds of the tongue and have now been found in several other tissues including nasal epithelium (Barnham et al. 2015, inferred from rodent homologs in Tizzano et al. 2011), the respiratory system, pancreatic islet cells, sperm (Governini et al. 2020), leukocytes (Malki et al. 2015), and enteroendocrine cells of the gut (inferred from rat and mouse homologs in Wu et al. 2002).", "R-HSA-9717374,R-HSA-9717382,R-HSA-9717396,R-HSA-9717214,R-HSA-9717215,R-HSA-9717182,R-HSA-9717193,R-HSA-9717202,R-HSA-9717205,R-HSA-9717206,R-HSA-9728697,R-HSA-9728723,R-HSA-9728729,R-HSA-9737035,R-HSA-9737046,R-HSA-9717395,R-HSA-9717383,R-HSA-9728747,R-HSA-9728748,R-HSA-9728752,R-HSA-9717392" ], [ "R-HSA-3108232", "SUMO E3 ligases SUMOylate target proteins", "SUMO proteins are conjugated to lysine residues of target proteins via an isopeptide bond with the C-terminal glycine of SUMO (reviewed in Zhao 2007, Gareau and Lima 2010, Hannoun et al. 2010, Citro and Chiocca 2013, Yang and Chiang 2013). Proteomic analyses indicate that SUMO is conjugated to hundreds of proteins and most targets of SUMOylation are nuclear (Vertegal et al. 2006, Bruderer et al. 2011, Tatham et al. 2011, Da Silva et al. 2012, Becker et al. 2013). Within the nucleus SUMOylation targets include transcription factors (TFs), transcription cofactors (TCs), intracellular (nuclear) receptors, RNA binding proteins, RNA splicing proteins, polyadenylation proteins, chromatin organization proteins, DNA replication proteins, DNA methylation proteins, DNA damage response and repair proteins, immune response proteins, SUMOylation proteins, and ubiquitinylation proteins. Mitochondrial fission proteins are SUMOylated at the mitochondrial outer membrane.
UBE2I (UBC9), the E2 activating enzyme of the SUMO pathway, is itself also a SUMO E3 ligase. Most SUMOylation reactions will proceed with only the substrate protein and the UBE2I:SUMO thioester conjugate. The rates of some reactions are further enhanced by the action of other E3 ligases such as RANBP2. These E3 ligases catalyze SUMO transfer to substrate by one of two basic mechanisms: they interact with both the substrate and UBE2I:SUMO thus bringing them into proximity or they enhance the release of SUMO from UBE2I to the substrate.
In the cell SUMO1 is mainly concentrated at the nuclear membrane and in nuclear bodies. Most SUMO1 is conjugated to RANGAP1 near the nuclear pore. SUMO2 is at least partially cytosolic and SUMO3 is located mainly in nuclear bodies. Most SUMO2 and SUMO3 is unconjugated in unstressed cells and becomes conjugated to target proteins in response to stress (Golebiowski et al. 2009). Especially notable is the requirement for recruitment of SUMO to sites of DNA damage where conjugation to targets seems to coordinate the repair process (Flotho and Melchior 2013).
Several effects of SUMOylation have been described: steric interference with protein-protein interactions, interference with other post-translational modifications such as ubiquitinylation and phosphorylation, and recruitment of proteins that possess a SUMO-interacting motif (SIM) (reviewed in Zhao 2007, Flotho and Melchior 2013, Jentsch and Psakhye 2013, Yang and Chiang 2013). In most cases SUMOylation inhibits the activity of the target protein.
The SUMOylation reactions included in this module have met two criteria: They have been verified by assays of individual proteins (as opposed to mass proteomic assays) and the effect of SUMOylation on the function of the target protein has been tested.", "R-HSA-3000449" ], [ "R-HSA-9652169", "Signaling by MAP2K mutants", "Activating mutations in MAP2K1 and MAP2K2, the genes encoding MEK1 and MEK2, have been identified at low frequency in a variety of cancers as well as in germline diseases such as Noonan syndrome, cardiofaciocutaneous syndromes and other RASopathies (reviewed in Samatar and Poulikakos, 2014; Bezniakow et al, 2014; Rauen, 2013).", "R-HSA-9652165" ], [ "R-HSA-9652817", "Signaling by MAPK mutants", "Mutations in ERK proteins (MAPK1 and MAPK2) are rare, with mutations reported in ~8% of cervical cancers and 1.5% of head and neck squamous cell carcinomas (Ojesina et al, 2014; Cancer Genome Atlas, 2015; reviewed in Najafi et al, 2019). MAPK proteins with activating mutations are often still dependent on upstream phosphorylation by MAP2K proteins, but support sustained downstream signaling by virtue of being resistant to inactivating dephosphorylations (reviewed in Samatar and Poulikakos, 2014; Liu et al, 2018).", "R-HSA-9652816" ], [ "R-HSA-9673163", "Oleoyl-phe metabolism", "Extracellular PM20D1 (N-fatty-acyl-amino acid synthase/hydrolase PM20D1) catalyzes the reversible condensation of L-phenylalanine (L-phe) and oleate ((9Z)-octadecenoate) to form oleoyl-phe (N-(9Z-octadecenoyl)-L-phenylalanine) and water. In addition to the condensation of phe with oleate ((9Z)-octadecenoate) annotated here, purified human PM20D1 protein in vitro can catalyze the condensation of leucine and isoleucine with oleate and with other long-chain unsaturated fatty acids including arachidonate, with lower efficiencies. Although the reverse (hydrolysis) direction of this reaction is thermodynamically favored, expression of PM20D1 protein in mice or in cultured cells was associated with elevated levels of oleoyl-phe in serum and culture media, respectively. Treatment of cultured mouse brown adipose tissue adipocytes and of isolated mitochondria with oleoyl-phe induced uncoupled respiration independently of UCP1 (uncoupling protein 1). Photolabeling studies of isolated mitochondria identified the ADP/ATP symporters SLC25A4 and SLC25A5 as possible targets of oleoyl-phe. Consistent with these observations, expression of PM20D1 and elevated blood levels of oleoyl-phe in mice were associated with increased energy expenditure and improved glucose homeostasis. These results suggest a physiological role for PM20D1 and its condensation reaction product in thermogenesis and raise the possibility that oleoyl-phe and related molecules might have a clinical role in treatment of obesity (Long et al. 2016).", "R-HSA-9673053,R-HSA-9673054" ], [ "R-HSA-9673768", "Signaling by membrane-tethered fusions of PDGFRA or PDGFRB", "In addition to activating missensse and in-frame deletion mutations, PDGFRA and PDGFRB are also subject to low frequency gene fusion events arising from chromosomal rearrangements. To date there are about 35 identified PDGFRA or B fusion partners, with PDGFRB being the more common partner (reviewed in Appiah-Kubi et al, 2017). Although some of the PDGF fusions proteins are cytosolic by virtue of removal of the PDGFR transmembrane region (TMD), a number of fusions retain the TMD and are linked to the plasma membrane (Hidalgo-Curtis et al, 2010; Ozawa et al, 2010; Curtis et al, 2007; Medves et al, 2010; reviewed in Appiah-Kubi et al, 2017). The most common transmembrane fusion partner of PDGFRA and PDGFRB is ETV6 (also known as TEL1), a transcriptional repressor with known ability to homodimerize (Curtis et al, 2007; Golub et al, 1994; Andrae et al, 2008; reviewed in de Braekeleer et al, 2012; Wang et al, 2016; Appiah-Kubi et al, 2017). ", "R-HSA-9673760,R-HSA-9673761" ], [ "R-HSA-9683610", "Maturation of nucleoprotein", "Nucleoprotein, the most abundant viral protein expressed during infection, is found in the cytosol and plasma membrane. After phosphorylation and sumoylation it trimerizes and is moved to the Golgi, the virion budding site (Li et al, 2005; Surjit et al, 2005).", "R-HSA-9686061,R-HSA-9683687,R-HSA-9683664,R-HSA-9687724" ], [ "R-HSA-1059683", "Interleukin-6 signaling", "Interleukin-6 (IL-6) is a pleiotropic cytokine with roles in processes including immune regulation, hematopoiesis, inflammation, oncogenesis, metabolic control and sleep. It is the founding member of a family of IL-6-related cytokines such as IL-11, IL-27 leukemia inhibitory factor (LIF), cilliary neurotrophic factor (CNTF) and oncostatin M.

The IL-6 receptor (IL6R) consists of an alpha subunit that specifically binds IL-6 and a beta subunit, IL6RB or gp130, which is the signaling component of all the receptors for cytokines related to IL-6. IL6R alpha exists in transmembrane and soluble forms. The transmembrane form is mainly expressed by hepatocytes, neutrophils, monocytes/macrophages, and some lymphocytes. Soluble forms of IL6R (sIL6R) are also expressed by these cells. Two major mechanisms for the production of sIL6R have been proposed. Alternative splicing generates a transcript lacking the transmembrane domain by using splicing donor and acceptor sites that flank the transmembrane domain coding region. This also introduces a frameshift leading to the incorporation of 10 additional amino acids at the C terminus of sIL6R.A second mechanism for the generation of sIL6R is the proteolytic cleavage or 'shedding' of membrane-bound IL-6R. Two proteases ADAM10 and ADAM17 are thought to contribute to this (Briso et al. 2008). sIL6R can bind IL6 and stimulate cells that express gp130 but not IL6R alpha, a process that is termed trans-signaling. This explains why many cells, including hematopoietic progenitor cells, neuronal cells, endothelial cells, smooth muscle cells, and embryonic stem cells, do not respond to IL6 alone, but show a remarkable response to IL6/sIL6R. It is clear that the trans-signaling pathway is responsible for the pro-inflammatory activities of IL-6 whereas the membrane bound receptor governs regenerative and anti-inflammatory IL-6 activities

IL6R signal transduction is mediated by two pathways:the JAK-STAT (Janus family tyrosine kinase-signal transducer and activator of transcription) pathway and the Ras-MAPK (mitogen-activated protein kinase) pathway. Negative regulators of IL-6 signaling include SOCS (suppressor of cytokine signals) and SHP2. Within the last few years different antibodies have been developed to inhibit IL-6 activity, and the first such antibodies have been introduced into the clinic for the treatment of inflammatory diseases (Kopf et al. 2010). ", "R-HSA-1067640,R-HSA-1067646,R-HSA-1067651,R-HSA-1067659,R-HSA-1067667,R-HSA-1067676,R-HSA-1067688,R-HSA-1112510,R-HSA-1112514,R-HSA-1112538,R-HSA-1112565,R-HSA-1112587,R-HSA-1112602,R-HSA-1112604,R-HSA-1112690,R-HSA-1112703,R-HSA-1112708,R-HSA-1112727,R-HSA-1112755,R-HSA-9681294" ], [ "R-HSA-109704", "PI3K Cascade", "The PI3K (Phosphatidlyinositol-3-kinase) - AKT signaling pathway stimulates cell growth and survival.", "R-HSA-109699,R-HSA-9607224" ], [ "R-HSA-111458", "Formation of apoptosome", "The apoptosome is a cytoplasmic protein complex of two major components \u2011 the adapter protein apoptotic protease activating factor 1 (APAF1) and the protease caspase\u20119 (CASP9) which interact with each other through their caspase recruitment domains (CARD) (Qin et al. 1999; Yuan S et al. 2010; Yuan S & Akey CW 2013). The function of the apoptosome is to assemble a multimeric complex between APAF1 and procaspase-9 CARDs to facilitate CASP9 activation (Jiang X and Wang X 2000; Srinivasrula SM et al. 2001; Shiozaki EN et al. 2002). The apoptosome is assembled upon APAF1 interaction with cytochrome c (CYCS), which is released from the mitochondrial intermembrane space during apoptosis (Zou H et al. 1997; Yuan S et al. 2013; Shakeri R et al. 2017). CYCS\u2011bound APAF1 undergoes ATP-mediated conformational changes and in the presence of CARD of CASP9 oligomerizes into a heptameric complex, which activates procaspase 9 (Zou H et al. 1997; Bratton SB et al. 2010; Acehan D et al. 2002; Yu X et al. 2005; Yuan S et al. 2010; Su TW et al. 2017). In the apoptosome, recruitment of caspase-9 may occur before oligomerization in the CARD disk, which presumably brings the caspase domain into proximity for their dimerization and activation (Su TW et al. 2017; Hu Q et al. 2014; Cheng TC et al. 2016). Once activated, CASP9 activates downstream effector caspases\u20113 and \u20117. The activated effector caspases then cleave various cellular proteins.

Different models have been proposed to explain CASP9 activation: the \u201cproximity\u2011driven dimerization model\u201d and the \u201cinduced conformation model\u201d. The first models states that upon binding to heptameric APAF1, monomers of procaspase\u20119 are brought into close proximity at a high concentration (Acehan et al. 2002; Renatus et al. 2001). This induces dimerization which is sufficient for CASP9 activation whereas autoprocessing within the apoptosome complex merely stabilizes CASP9 dimer (Boatright KM et al. 2003; Pop C et al. 2006). The \u201cinduced conformation model\u201d is based on the observation that CASP9 has a much higher level of catalytic activity when it's bound to the apoptosome. The model suggests that a conformational change occurs at the active site of CASP9 upon binding to APAF1 thus inducing CASP9 homodimerization and stabilizing it in the catalytically active conformation (Shiozaki EN et al. 2002). CASP9 activation may also involve formation of a multimeric CARD:CARD assembly between APAF1 and procaspase\u20119 (Hu Q et al. 2014).
", "R-HSA-114254,R-HSA-114256,R-HSA-114259,R-HSA-114284,R-HSA-9627056" ], [ "R-HSA-111459", "Activation of caspases through apoptosome-mediated cleavage", "Procaspase-3 and 7 are cleaved by the apoptosome.", "R-HSA-114252,R-HSA-114261" ], [ "R-HSA-111463", "SMAC (DIABLO) binds to IAPs ", "Second mitochondria\u2011derived activator of caspases protein (SMAC, also known as direct IAP binding protein with low pI or DIABLO) in its dimeric form interacts and antagonizes X\u2011linked inhibitor of apoptosis protein (XIAP) by concurrently targeting both BIR2 and BIR3 domains of XIAP (Chai J et al. 2000; Liu Z et sl. 2000; Burke SP & Smith JB 2010). XIAP inhibits apoptosis by binding to and inhibiting the effectors caspase\u20113 and \u20117 and an initiator caspase\u20119 (Deveraux QL et al. 1997; Paulsen M et al. 2008). During apoptosis, SMAC (DIABLO) is released from the mitochondria (Du C et al. 2000). In the cytosol, SMAC binds to XIAP displacing it from caspase:XIAP complexes liberating the active caspases (Wu G et al. 2000; Abhari BA & Davoodi J 2008).", "R-HSA-114306,R-HSA-114307,R-HSA-114354,R-HSA-114361,R-HSA-9627350" ], [ "R-HSA-111464", "SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes ", "Second mitochondria derived activator of caspase/direct inhibitor of apoptosis binding protein with low pI (SMAC, also known as DIABLO) regulates XIAP function and potentiates caspase-3, -7 and -9 activity by disrupting the interaction of caspases with XIAP. Residues 56-59 of SMAC (DIABLO) are homologous to the amino-terminal motif that is used by caspase-9 (CASP9) to bind to the BIR3 domain of XIAP. SMAC (DIABLO) competes with CASP9 for binding to BIR3 domain of XIAP promoting the release of XIAP from the CASP9:apoptosome complex (Srinivasula SM et al. 2001; Salvesen et al. 2002). The binding of SMAC to the BIR2 and BIR3 regions of XIAP creates a steric hindrance that is essential for preventing binding of XIAP linker region with effector caspases CASP3 and CASP7 thus achieving neutralization of XIAP inhibition. The strong affinity for XIAP allows SMAC (DIABLO) to displace caspase-3, -7 from the XIAP:caspase complexes (Wu G et al. 2000; Chai J et al. 2001; Huang Y et al. 2003; Abhari BA & Davoodi J 2008).", "R-HSA-114392,R-HSA-114419,R-HSA-114440" ], [ "R-HSA-112043", "PLC beta mediated events", "The phospholipase C (PLC) family of enzymes is both diverse and complex. The isoforms beta, gamma and delta (each have subtypes) make up the members of this family. PLC hydrolyzes phosphatidylinositol bisphosphate (PIP2) into two second messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 mobilizes intracellular calcium stores while DAG activates protein kinase C isoforms which are involved in regulatory functions.", "R-HSA-111870,R-HSA-111879,R-HSA-112037,R-HSA-169680,R-HSA-169683" ], [ "R-HSA-112308", "Presynaptic depolarization and calcium channel opening", "Action potentials occur in electrically excitable cells such as neurons, muscles, and endocrine cells. They are initiated by transient opening of voltage dependent sodium channels, causing a rapid, large depolarization of membrane potentials that spread along the axon membrane.
\n\nThe action potential travels down the axon and reaches the presynaptic terminal depolarizing the membrane in the pre synaptic terminal. The depolarization causes the voltage gated Ca2+ channels to open allowing the influx of Ca2+ that signals the release of neurotransmitter into the synaptic cleft.", "R-HSA-210420" ], [ "R-HSA-112311", "Neurotransmitter clearance", "Neurotransmitter released in the synaptic cleft binds to specific receptors on the post-synaptic cell and the excess of the neurotransmitter is cleared to prevent over activation of the post-synaptic cell. The neurotransmitter is cleared by either re-uptake by the pre-synaptic neuron, diffusion in the perisynaptic area, uptake by astrocytes surrounding the synaptic cleft or enzymatic degradation of the neurotransmitter.", "R-HSA-372519,R-HSA-374919,R-HSA-9634834" ], [ "R-HSA-112314", "Neurotransmitter receptors and postsynaptic signal transmission", "The neurotransmitter in the synaptic cleft released by the pre-synaptic neuron binds specific receptors located on the post-synaptic terminal. These receptors are either ion channels or G protein coupled receptors that function to transmit the signals from the post-synaptic membrane to the cell body.", "R-HSA-9648983,R-HSA-9649108,R-HSA-975311,R-HSA-975389,R-HSA-9673173" ], [ "R-HSA-112382", "Formation of RNA Pol II elongation complex ", "TFIIS is a transcription factor involved in different phases of transcription, occurring in a major ubiquitous form and other tissue specific forms. TFIIS stimulates RNA Pol II complex out of elongation arrest.
Other transcription factors like ELL, Elongin family members and TFIIF interact directly with elongating Pol II and increase its elongation rate. These factors have been observed to act on naked DNA templates by suppressing transient pausing by the enzyme at all or most steps of nucleotide addition. In Drosophila, ELL is found at a large number of transcriptionally active sites on polytene chromosomes. In general, ELL is suspected to have more unidentified functions.
Elongin is a heterotrimeric protein complex that stimulates the overall rate of elongation. In addition, Elongin may act as an E3 Ubiquitin ligase. Ubiquitylation of RNA Pol II occurs rapidly after genotoxic assault by UV light or chemicals, and results in degradation by proteasome. The FACT complex appears to promote elongation by facilitating passage of polymerase through chromatin.
All these factors contribute to the formation of a processive elongation complex centered around the RNA Pol II complex positioned on the DNA:RNA hybrid. This enables the RNA Pol II elongation complex to function as a platform that coordinates mRNA processing and export (Reviewed by Shilatifard et al., 2003).", "R-HSA-112379,R-HSA-112381" ], [ "R-HSA-112399", "IRS-mediated signalling", "Release of phospho-IRS from the insulin receptor triggers a cascade of signalling events via PI3K, SOS, RAF and the MAP kinases.", "R-HSA-74737" ], [ "R-HSA-113418", "Formation of the Early Elongation Complex", "Transcription elongation by RNA polymerase II (RNAPII) is controlled by a number of trans-acting transcription elongation factors as well as by cis-acting elements. Transcription elongation is a rate-limiting step for proper mRNA production in which the phosphorylation of Pol II CTD is a crucial biochemical event. The role of CTD phosphorylation in transcription by Pol II is greatly impaired by protein kinase inhibitors such as 5,6-dichloro-1- ribofuranosylbenzimidazole (DRB), which block CTD phosphorylation and induce arrest of elongating Pol II. DRB-sensitive activation Pol II CTD during elongation has enabled the isolation of two sets of factors -Negative Elongation Factors (NELF) and DRB sensitivity inducing factor (DSIF). P-Tefb is a DRB-sensitive, cyclin-dependent CTD kinase composed of Cdk9 that carries out Serine-2 phosphorylation of Pol II CTD during elongation.
The mechanism by which DSIF, NELF and P-TEFb act together in Pol II-regulated elongation is yet to be fully understood. Various biochemical evidences point to a model in which DSIF and NELF negatively regulate elongation through interactions with polymerase containing a hypophosphorylated CTD. Subsequent phosphorylation of the Pol II CTD by P-Tefb might promote elongation by inhibiting interactions of DSIF and NELF with the elongation complex.
", "R-HSA-112383,R-HSA-113402,R-HSA-113407" ], [ "R-HSA-114516", "Disinhibition of SNARE formation", "The SNARE (SNAp REceptor) family of proteins are critical components of the machinery required for membrane fusion (S\u00f6llner et al. 1993, Wu et al. 2017). SNAREs can be grouped into three broad subfamilies: synaptosomal-associated proteins (SNAPs), vesicle-associated membrane proteins (VAMPs) and syntaxins. SNAPs contain two SNARE motifs and lack transmembrane domains, instead they are anchored to the membrane by thioester-linked acyl groups (Hong 2005). VAMPS or R-SNAREs have two subfamilies: short VAMPs or brevins and long VAMPs or longins. Syntaxins are evolutionarily less-well conserved, but except STX11 are transmembrane proteins (Hong 2005). Several SNARE proteins including Syntaxin-2 (STX2), STX4, STX11 and Vesicle-associated membrane protein 8 (VAMP8) are thought to be involved in platelet granule secretion (Golebiewska et al. 2013).", "R-HSA-114683,R-HSA-114684" ], [ "R-HSA-114604", "GPVI-mediated activation cascade", "The GPVI receptor is a complex of the GPVI protein with Fc epsilon R1 gamma (FcR). The Src family kinases Fyn and Lyn constitutively associate with the GPVI-FcR complex in platelets and initiate platelet activation through phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) in the FcR gamma chain, leading to binding and activation of the tyrosine kinase Syk. Downstream of Syk, a series of adapter molecules and effectors lead to platelet activation.

The GPVI receptor signaling cascade is similar to that of T- and B-cell immune receptors, involving the formation of a signalosome composed of adapter and effector proteins. At the core of the T-cell receptor signalosome is the transmembrane adapter LAT and two cytosolic adapters SLP-76 and Gads. While LAT is essential for signalling to PLCgamma1 downstream of the T-cell receptor, the absence of LAT in platelets only impairs the activation of PLCgamma2, the response to collagen and GPVI receptor ligands remains sufficient to elicit a full aggregation response. In contrast, GPVI signalling is almost entirely abolished in the absence of SLP-76.", "R-HSA-114600,R-HSA-114689,R-HSA-139842,R-HSA-2316429,R-HSA-429449,R-HSA-429497,R-HSA-430158,R-HSA-434633,R-HSA-434637,R-HSA-434836,R-HSA-437118,R-HSA-437162,R-HSA-437192,R-HSA-437195,R-HSA-437932,R-HSA-437936,R-HSA-442273,R-HSA-442291,R-HSA-442314,R-HSA-453183,R-HSA-453200,R-HSA-5684169,R-HSA-5684801,R-HSA-5684806,R-HSA-5684836" ], [ "R-HSA-114608", "Platelet degranulation ", "Platelets function as exocytotic cells, secreting a plethora of effector molecules at sites of vascular injury. Platelets contain a number of distinguishable storage granules including alpha granules, dense granules and lysosomes. On activation platelets release a variety of proteins, largely from storage granules but also as the result of apparent cell lysis. These act in an autocrine or paracrine fashion to modulate cell signaling.


Alpha granules contain mainly polypeptides such as fibrinogen, von Willebrand factor, growth factors and protease inhibitors that that supplement thrombin generation at the site of injury. Dense granules contain small molecules, particularly adenosine diphosphate (ADP), adenosine triphosphate (ATP), serotonin and calcium, all recruit platelets to the site of injury. \n\nThe molecular mechanism which facilitates granule release involves soluble NSF attachment protein receptors (SNAREs), which assemble into complexes to form a universal membrane fusion apparatus. Although all cells use SNAREs for membrane fusion, different cells possess different SNARE isoforms. Platelets and chromaffin cells use many of the same chaperone proteins to regulate SNARE-mediated secretion (Fitch-Tewfik & Flaumenhaft 2013).", "R-HSA-350745,R-HSA-351323,R-HSA-351341,R-HSA-429157,R-HSA-481007,R-HSA-481009,R-HSA-481010,R-HSA-481044,R-HSA-482770,R-HSA-482772,R-HSA-482775" ], [ "R-HSA-1169091", "Activation of NF-kappaB in B cells", "DAG and calcium activate protein kinase C beta (PKC-beta, Kochs et al. 1991) which phosphorylates CARMA1 and other proteins (Sommer et al. 2005). Phosphorylated CARMA1 recruits BCL10 and MALT1 to form the CBM complex (Sommer et al. 2005, Tanner et al. 2007) which, in turn, recruits the kinase TAK1 and the IKK complex (Sommer et al. 2005, Shinohara et al. 2005 using chicken cells). TAK1 phosphorylates the IKK-beta subunit, activating it (Wang et al. 2001). The IKK complex then phosphorylates IkB complexed with NF-kappaB dimers in the cytosol (Zandi et al. 1998, Burke et al. 1999, Heilker et al. 1999), resulting in the degradation of IkB (Miyamoto et al. 1994, Traenckner et al. 1994, Alkalay et al. 1995, DiDonato et al. 1995, Li et al. 1995, Lin et al. 1995, Scherer et al. 1995, Chen et al. 1995). NF-kappaB dimers are thereby released and are translocated to the nucleus where they activate transcription (Baeuerle and Baltimore 1988, Blank et al. 1991, Ghosh et al. 2008, Fagerlund et al. 2008).", "R-HSA-1168373,R-HSA-1168633,R-HSA-1168635,R-HSA-1168637,R-HSA-1168638,R-HSA-1168640,R-HSA-1168641,R-HSA-1168642,R-HSA-1168643,R-HSA-1168644" ], [ "R-HSA-1169408", "ISG15 antiviral mechanism", "Interferon-stimulated gene 15 (ISG15) is a member of the ubiquitin-like (Ubl) family. It is strongly induced upon exposure to type I Interferons (IFNs), viruses, bacterial LPS, and other stresses. Once released the mature ISG15 conjugates with an array of target proteins, a process termed ISGylation. ISGylation utilizes a mechanism similar to ubiquitination, requiring a three-step enzymatic cascade. UBE1L is the ISG15 E1 activating enzyme which specifically activates ISG15 at the expense of ATP. ISG15 is then transfered from E1 to the E2 conjugating enzyme UBCH8 and then to the target protein with the aid of an ISG15 E3 ligase, such as HERC5 and EFP. Hundreds of target proteins for ISGylation have been identified. Several proteins that are part of antiviral signaling pathways, such as RIG-I, MDA5, Mx1, PKR, filamin B, STAT1, IRF3 and JAK1, have been identified as targets for ISGylation. ISG15 also conjugates some viral proteins, inhibiting viral budding and release. ISGylation appears to act either by disrupting the activity of a target protein and/or by altering its localization within the cell.", "R-HSA-1169307,R-HSA-1169394,R-HSA-1169395,R-HSA-1169397,R-HSA-1169398,R-HSA-1169399,R-HSA-1169402,R-HSA-1169403,R-HSA-1169404,R-HSA-1169405,R-HSA-1169406,R-HSA-1176059,R-HSA-1678841,R-HSA-1678842,R-HSA-1678843,R-HSA-936462" ], [ "R-HSA-1181150", "Signaling by NODAL", "Signaling by NODAL is essential for patterning of the axes of the embryo and formation of mesoderm and endoderm (reviewed in Schier 2009, Shen 2007). The NODAL proprotein is secreted and cleaved extracellularly to yield mature NODAL. Mature NODAL homodimerizes and can also form heterodimers with LEFTY1, LEFTY2, or CERBERUS, which negatively regulate NODAL signaling. NODAL also forms heterodimers with GDF1, which increases NODAL activity. NODAL dimers bind the NODAL receptor comprising a type I Activin receptor (ACVR1B or ACVR1C), a type II Activin receptor (ACVR2A or ACVR2B), and an EGF-CFC coreceptor (CRIPTO or CRYPTIC). After binding NODAL, the type II activin receptor phosphorylates the type I activin receptor which then phosphorylates SMAD2 and SMAD3 (R-SMADs). Phosphorylated SMAD2 and SMAD3 form hetero-oligomeric complexes with SMAD4 (CO-SMAD) and transit from the cytosol to the nucleus. Within the nucleus the SMAD complexes interact with transcription factors such as FOXH1 to activate transcription of target genes.", "R-HSA-170847,R-HSA-173488,R-HSA-1181152,R-HSA-1181155,R-HSA-1181156,R-HSA-1181355,R-HSA-1225894,R-HSA-1225919,R-HSA-1535903" ], [ "R-HSA-1221632", "Meiotic synapsis", "Meiotic synapsis is the stable physical pairing of homologous chromosomes that begins in leptonema of prophase I and lasts until anaphase of prophase I. First, short segments of axial elements form along chromosomes. Telomeres then cluster at a region of the inner nuclear membrane and axial elements extend and fuse along the length of the chromosomes. Subsequent to the initiation of recombination transverse filaments of SYCP1 link axial/lateral elements to a central element containing SYCE1 and SYCE2, thus forming the synaptonemal complex (reviewed in Yang and Wang 2009).
Unsynapsed regions are silenced during pachynema by recruitment of BRCA1 and ATR, which phosphorylates histone H2AX (reviewed in Inagaki et al. 2010).", "R-HSA-912389,R-HSA-912408,R-HSA-912450,R-HSA-912467,R-HSA-912470,R-HSA-912505" ], [ "R-HSA-1222556", "ROS and RNS production in phagocytes", "The first line of defense against infectious agents involves an active recruitment of phagocytes to the site of infection. Recruited cells include polymorhonuclear (PMN) leukocytes (i.e., neutrophils) and monocytes/macrophages, which function together as innate immunity sentinels (Underhill DM & Ozinsky A 2002; Stuart LM & Ezekowitz RA 2005; Flannagan RS et al. 2012). Dendritic cells are also present, serving as important players in antigen presentation for ensuing adaptive responses (Savina A & Amigorena S 2007). These cell types are able to bind and engulf invading microbes into a membrane-enclosed vacuole - the phagosome, in a process termed phagocytosis. Phagocytosis can be defined as the receptor-mediated engulfment of particles greater than 0.5 micron in diameter. It is initiated by the cross-linking of host cell membrane receptors following engagement with their cognate ligands on the target surface (Underhill DM & Ozinsky A 2002; Stuart LM & Ezekowitz RA 2005; Flannagan RS et al. 2012). When engulfed by phagocytes, microorganisms are exposed to a number of host defense microbicidal events within the resulting phagosome. These include the production of reactive oxygen and nitrogen species (ROS and RNS, RONS) by specialized enzymes (Fang FC et al. 2004; Kohchi C et al. 2009; Gostner JM et al. 2013; Vatansever F et al. 2013). NADPH oxidase (NOX) complex consume oxygen to produce superoxide radical anion (O2.-) and hydrogen peroxide (H2O2) (Robinson et al. 2004). Induced NO synthase (iNOS) is involved in the production of NO, which is the primary source of all RNS in biological systems (Evans TG et al. 1996). The phagocyte NADPH oxidase and iNOS are expressed in both PMN and mononuclear phagocytes and both cell types have the capacity for phagosomal burst activity. However, the magnitude of ROS generation in neutrophils far exceeds that observed in macrophages (VanderVen BC et al. 2009). Macrophages are thought to produce considerably more RNS than neutrophils (Fang FC et al. 2004; Nathan & Shiloh 2000).

The presence of RONS characterized by a relatively low reactivity, such as H2O2, O2\u02d9\u2212 or NO, has no deleterious effect on biological environment (Attia SM 2010; Weidinger A & and Kozlov AV 2015). Their activity is controlled by endogenous antioxidants (both enzymatic and non-enzymatic) that are induced by oxidative stress. However the relatively low reactive species can initiate a cascade of reactions to generate more damaging \u201csecondary\u201d species such as hydroxyl radical (\u2022OH), singlet oxygen or peroxinitrite (Robinson JM 2008; Fang FC et al. 2004). These \\secondary\\ RONS are extremely toxic causing irreversible damage to all classes of biomolecules (Weidinger A & and Kozlov AV 2015; Fang FC et al. 2004; Kohchi C et al. 2009; Gostner JM et al. 2013; Vatansever F et al. 2013).

Although macrophages and neutrophils use similar mechanisms for the internalization of targets, there are differences in how they perform phagocytosis and in the final outcome of the process (Tapper H & Grinstein S 1997; Vierira OV et al. 2002). Once formed, the phagosome undergoes an extensive maturation process whereby it develops into a microbicidal organelle able to eliminate the invading pathogen. Maturation involves re-modeling both the membrane of the phagosome and its luminal contents (Vierira OV et al. 2002). In macrophages, phagosome formation and maturation follows a series of strictly coordinated membrane fission/fusion events between the phagosome and compartments of the endo/lysosomal network gradually transforming the nascent phagosome into a phagolysosome, a degradative organelle endowed with potent microbicidal properties (Zimmerli S et al. 1996; Vierira OV et al. 2002). Neutrophils instead contain a large number of preformed granules such as azurophilic and specific granules that can rapidly fuse with phagosomes delivering antimicrobial substances (Karlsson A & Dahlgren C 2002; Naucler C et al. 2002; Nordenfelt P and Tapper H 2011). Phagosomal pH dynamics may also contribute to the maturation process by regulating membrane traffic events. The microbicidal activity of macrophages is characterized by progressive acidification of the lumen (down to pH 4\u20135) by the proton pumping vATPase. A low pH is a prerequisite for optimal enzymatic activity of most late endosomal/lysosomal hydrolases reported in macrophages. Neutrophil phagosome pH regulation differs significantly from what is observed in macrophages (Nordenfelt P and Tapper H 2011; Winterbourn CC et al. 2016). The massive activation of the oxidative burst is thought to result in early alkalization of neutrophil phagosomes which is linked to proton consumption during the generation of hydrogen peroxide (Segal AW et al. 1981; Levine AP et al. 2015). Other studies showed that neutrophil phagosome maintained neutral pH values before the pH gradually decreased (Jankowski A et al. 2002). Neutrophil phagosomes also exhibited a high proton leak, which was initiated upon activation of the NADPH oxidase, and this activation counteracted phagosomal acidification (Jankowski A et al. 2002).

The Reactome module describes ROS and RNS production by phagocytic cells. The module includes cell-type specific events, for example, myeloperoxidase (MPO)-mediated production of hypochlorous acid in neutrophils. It also highlights differences between phagosomal pH dynamics in neutrophils and macrophages. The module describes microbicidal activity of selective RONS such as hydroxyl radical or peroxynitrite. However, detection of any of these species in the phagosomal environment is subject to many uncertainties (N\u00fcsse O 2011; Erard M et al. 2018). The mechanisms by which reactive oxygen/nitrogen species kill pathogens in phagocytic immune cells are still not fully understood. ", "R-HSA-435171,R-HSA-1222516,R-HSA-418436,R-HSA-6788999,R-HSA-6789092" ], [ "R-HSA-1227986", "Signaling by ERBB2", "ERBB2, also known as HER2 or NEU, is a receptor tyrosine kinase (RTK) belonging to the EGFR family. ERBB2 possesses an extracellular domain that does not bind any known ligand, contrary to other EGFR family members, a single transmembrane domain, and an intracellular domain consisting of an active kinase and a C-tail with multiple tyrosine phosphorylation sites. Inactive ERBB2 is associated with a chaperone heat shock protein 90 (HSP90) and its co-chaperone CDC37 (Xu et al. 2001, Citri et al. 2004, Xu et al. 2005). In addition, ERBB2 is associated with ERBB2IP (also known as ERBIN or LAP2), a protein responsible for proper localization of ERBB2. In epithelial cells, ERBB2IP restricts expression of ERBB2 to basolateral plasma membrane regions (Borg et al. 2000).

\nERBB2 becomes activated by forming a heterodimer with another ligand-activated EGFR family member, either EGFR, ERBB3 or ERBB4, which is accompanied by dissociation of chaperoning proteins HSP90 and CDC37 (Citri et al. 2004), as well as ERBB2IP (Borg et al. 2000) from ERBB2. ERBB2 heterodimers function to promote cell proliferation, cell survival and differentiation, depending on the cellular context. ERBB2 can also be activated by homodimerization when it is overexpressed, in cancer for example.

\nIn cells expressing both ERBB2 and EGFR, EGF stimulation of EGFR leads to formation of both ERBB2:EGFR heterodimers (Wada et al. 1990, Karunagaran et al. 1996) and EGFR homodimers. Heterodimers of ERBB2 and EGFR trans-autophosphorylate on twelve tyrosine residues, six in the C-tail of EGFR and six in the C-tail of ERBB2 - Y1023, Y1139, Y1196, Y1221, Y1222 and Y1248 (Margolis et al. 1989, Hazan et al. 1990,Walton et al. 1990, Helin et al. 1991, Ricci et al. 1995, Pinkas-Kramarski 1996). Phosphorylated tyrosine residues in the C-tail of EGFR and ERBB2 serve as docking sites for downstream signaling molecules. Three key signaling pathways activated by ERBB2:EGFR heterodimers are RAF/MAP kinase cascade, PI3K-induced AKT signaling, and signaling by phospholipase C gamma (PLCG1). Downregulation of EGFR signaling is mediated by ubiquitin ligase CBL, and is shown under Signaling by EGFR.

\nIn cells expressing ERBB2 and ERBB3, ERBB3 activated by neuregulin NRG1 or NRG2 binding (Tzahar et al. 1994) forms a heterodimer with ERBB2 (Pinkas-Kramarski et al. 1996, Citri et al. 2004). ERBB3 is the only EGFR family member with no kinase activity, and can only function in heterodimers, with ERBB2 being its preferred heterodimerization partner. After heterodimerization, ERBB2 phosphorylates ten tyrosine residues in the C-tail of ERBB3, Y1054, Y1197, Y1199, Y1222, Y1224, Y1260, Y1262, Y1276, Y1289 and Y1328 (Prigent et al. 1994, Pinkas-Kramarski et al. 1996, Vijapurkar et al. 2003, Li et al. 2007) that subsequently serve as docking sites for downstream signaling molecules, resulting in activation of PI3K-induced AKT signaling and RAF/MAP kinase cascade. Signaling by ERBB3 is downregulated by the action of RNF41 ubiquitin ligase, also known as NRDP1.

\nIn cells expressing ERBB2 and ERBB4, ligand stimulated ERBB4 can either homodimerize or form heterodimers with ERBB2 (Li et al. 2007), resulting in trans-autophosphorylation of ERBB2 and ERBB4 on C-tail tyrosine residues that will subsequently serve as docking sites for downstream signaling molecules, leading to activation of RAF/MAP kinase cascade and, in the case of ERBB4 CYT1 isoforms, PI3K-induced AKT signaling (Hazan et al. 1990, Cohen et al. 1996, Li et al. 2007, Kaushansky et al. 2008). Signaling by ERBB4 is downregulated by the action of WWP1 and ITCH ubiquitin ligases, and is shown under Signaling by ERBB4.", "R-HSA-1247497,R-HSA-1963581,R-HSA-1963582,R-HSA-1963586,R-HSA-1963589" ], [ "R-HSA-1234176", "Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha", "HIF-alpha subunits, comprising HIF1A (Bruick and McKnight 2001, Ivan et al. 2001, Jaakkola et al. 2001), HIF2A (Percy et al. 2008, Furlow et al. 2009), and HIF3A (Maynard et al. 2003), are hydroxylated at proline residues by the prolyl hydroxylases PHD1 (EGLN2), PHD2 (EGLN1), and PHD3 (EGLN3) (Bruick and McKnight 2001, Berra et al. 2003, Hirsila et al. 2003, Metzen et al. 2003, Tuckerman et al. 2004, Appelhoff et al. 2004, Fedulova et al. 2007, Tian et al. 2011). The reaction requires molecular oxygen as a substrate and so it is inhibited by hypoxia. PHD2 (EGLN1) is predominantly cytosolic (Metzen et al. 2003) and is the key determinant in the regulation of HIF-alpha subunits by oxygen (Berra et al. 2003).
HIF-alpha subunits hydroxylated at proline residues are bound by VHL, an E3 ubiquitin ligase in a complex containing ElonginB, Elongin C, CUL2, and RBX1. VHL ubiquitinates HIF-alpha, resulting in destruction of HIF-alpha by proteolysis. Hypoxia inhibits proline hydroxylation and interaction with VHL, stabilizing HIF-alpha, which transits to the nucleus and activates gene expression.", "R-HSA-1234159,R-HSA-1234163,R-HSA-1234165,R-HSA-1234166,R-HSA-1234169,R-HSA-1234172,R-HSA-1234173,R-HSA-1234175,R-HSA-1234177,R-HSA-1234179,R-HSA-1234181,R-HSA-1234183" ], [ "R-HSA-1236394", "Signaling by ERBB4", "ERBB4, also known as HER4, belongs to the ERBB family of receptors, which also includes ERBB1 (EGFR/HER1), ERBB2 (HER2/NEU) and ERBB3 (HER3). Similar to EGFR, ERBB4 has an extracellular ligand binding domain, a single transmembrane domain and a cytoplasmic domain which contains an active tyrosine kinase and a C-tail with multiple phosphorylation sites. At least three and possibly four splicing isoforms of ERBB4 exist that differ in their C-tail and/or the extracellular juxtamembrane regions: ERBB4 JM-A CYT1, ERBB4 JM-A CYT2 and ERBB4 JM-B CYT1 (the existence of ERBB4 JM-B CYT2 has not been confirmed).

ERBB4 becomes activated by binding one of its seven ligands, three of which, HB-EGF, epiregulin EPR and betacellulin BTC, are EGF-like (Elenius et al. 1997, Riese et al. 1998), while four, NRG1, NRG2, NRG3 and NRG4, belong to the related neuregulin family (Tzahar et al. 1994, Carraway et al. 1997, Zhang et al. 1997, Hayes et al. 2007). Upon ligand binding, ERBB4 forms homodimers (Sweeney et al. 2000) or it heterodimerizes with ERBB2 (Li et al. 2007). Dimers of ERBB4 undergo trans-autophosphorylation on tyrosine residues in the C-tail (Cohen et al. 1996, Kaushansky et al. 2008, Hazan et al. 1990, Li et al. 2007), triggering downstream signaling cascades. The pathway Signaling by ERBB4 only shows signaling by ERBB4 homodimers. Signaling by heterodimers of ERBB4 and ERBB2 is shown in the pathway Signaling by ERBB2. Ligand-stimulated ERBB4 is also able to form heterodimers with ligand-stimulated EGFR (Cohen et al. 1996) and ligand-stimulated ERBB3 (Riese et al. 1995). Dimers of ERBB4 with EGFR and dimers of ERBB4 with ERBB3 were demonstrated in mouse cell lines in which human ERBB4 and EGFR or ERBB3 were exogenously expressed. These heterodimers undergo trans-autophosphorylation. The promiscuous heteromerization of ERBBs adds combinatorial diversity to ERBB signaling processes. As ERBB4 binds more ligands than other ERBBs, but has restricted expression, ERBB4 expression channels responses to ERBB ligands. The signaling capabilities of the four receptors have been compared (Schulze et al. 2005).

As for other receptor tyrosine kinases, ERBB4 signaling effectors are largely dictated through binding of effector proteins to ERBB4 peptides that are phosphorylated upon ligand binding. All splicing isoforms of ERBB4 possess two tyrosine residues in the C-tail that serve as docking sites for SHC1 (Kaushansky et al. 2008, Pinkas-Kramarski et al. 1996, Cohen et al. 1996). Once bound to ERBB4, SHC1 becomes phosphorylated on tyrosine residues by the tyrosine kinase activity of ERBB4, which enables it to recruit the complex of GRB2 and SOS1, resulting in the guanyl-nucleotide exchange on RAS and activation of RAF and MAP kinase cascade (Kainulainen et al. 2000).

The CYT1 isoforms of ERBB4 also possess a C-tail tyrosine residue that, upon trans-autophosphorylation, serves as a docking site for the p85 alpha subunit of PI3K (Kaushansky et al. 2008, Cohen et al. 1996), leading to assembly of an active PI3K complex that converts PIP2 to PIP3 and activates AKT signaling (Kainulainen et al. 2000).

Besides signaling as a conventional transmembrane receptor kinase, ERBB4 differs from other ERBBs in that JM-A isoforms signal through efficient release of a soluble intracellular domain. Ligand activated homodimers of ERBB4 JM-A isoforms (ERBB4 JM-A CYT1 and ERBB4 JM-A CYT2) undergo proteolytic cleavage by ADAM17 (TACE) in the juxtamembrane region, resulting in shedding of the extracellular domain and formation of an 80 kDa membrane bound ERBB4 fragment known as ERBB4 m80 (Rio et al. 2000, Cheng et al. 2003). ERBB4 m80 undergoes further proteolytic cleavage, mediated by the gamma-secretase complex, which releases the soluble 80 kDa ERBB4 intracellular domain, known as ERBB4 s80 or E4ICD, into the cytosol (Ni et al. 2001). ERBB4 s80 is able to translocate to the nucleus, promote nuclear translocation of various transcription factors, and act as a transcription co-factor. For example, in mammary cells, ERBB4 binds SH2 transcription factor STAT5A. ERBB4 s80 shuttles STAT5A to the nucleus, and actsa as a STAT5A co-factor in binding to and promoting transcription from the beta-casein (CSN2) promoter, and may be involved in the regulation of other lactation-related genes (Jones et al. 1999, Williams et al. 2004, Muraoka-Cook et al. 2008). ERBB4 s80 binds activated estrogen receptor in the nucleus and acts as a transcriptional co-factor in promoting transcription of some estrogen-regulated genes, including progesterone receptor gene NR3C3 and CXCL12 (SDF1) (Zhu et al. 2006). In neuronal precursors, ERBB4 s80 binds the complex of TAB and NCOR1, helps to move the complex into the nucleus, and is a co-factor of TAB:NCOR1-mediated inhibition of expression of astrocyte differentiation genes GFAP and S100B (Sardi et al. 2006).

The C-tail of ERBB4 possesses several WW-domain binding motifs (three in CYT1 isoform and two in CYT2 isoform), which enable interaction of ERBB4 with WW-domain containing proteins. ERBB4 s80, through WW-domain binding motifs, interacts with YAP1 transcription factor, a known proto-oncogene, and is a co-regulator of YAP1-mediated transcription in association with TEAD transcription factors (Komuro et al. 2003, Omerovic et al. 2004). Hence, the WW binding motif couples ERBB4 to the major effector arm of the HIPPO signaling pathway. The tumor suppressor WWOX, another WW-domain containing protein, competes with YAP1 in binding to ERBB4 s80 and prevents translocation of ERBB4 s80 to the nucleus (Aqeilan et al. 2005).

WW-domain binding motifs in the C-tail of ERBB4 play an important role in the downregulation of ERBB4 receptor signaling, enabling the interaction of intact ERBB4, ERBB4 m80 and ERBB4 s80 with NEDD4 family of E3 ubiquitin ligases WWP1 and ITCH. The interaction of WWP1 and ITCH with intact ERBB4 is independent of receptor activation and autophosphorylation. Binding of WWP1 and ITCH ubiquitin ligases leads to ubiquitination of ERBB4 and its cleavage products, and subsequent degradation through both proteasomal and lysosomal routes (Omerovic et al. 2007, Feng et al. 2009). In addition, the s80 cleavage product of ERBB4 JM-A CYT-1 isoform is the target of NEDD4 ubiquitin ligase. NEDD4 binds ERBB4 JM-A CYT-1 s80 (ERBB4jmAcyt1s80) through its PIK3R1 interaction site and mediates ERBB4jmAcyt1s80 ubiquitination, thereby decreasing the amount of ERBB4jmAcyt1s80 that reaches the nucleus (Zeng et al. 2009).

ERBB4 also binds the E3 ubiquitin ligase MDM2, and inhibitor of p53 (Arasada et al. 2005). Other proteins that bind to ERBB4 intracellular domain have been identified by co-immunoprecipitation and mass spectrometry (Gilmore-Hebert et al., 2010), and include transcriptional co-repressor TRIM28/KAP1, which promotes chromatin compaction. DNA damage signaling through ATM releases TRIM28-associated heterochromatinization. Interactions of ERBB4 with TRIM28 and MDM2 may be important for integration of growth factor responses and DNA damage responses.

In human breast cancer cell lines, ERBB4 activation enhances anchorage-independent colony formation in soft agar but inhibits cell growth in a monolayer culture. Different ERBB4 ligands induce different gene expression changes in breast cancer cell lines. Some of the genes induced in response to ERBB4 signaling in breast cancer cell lines are RAB2, EPS15R and GATA4. It is not known if these gene are direct transcriptional targets of ERBB4 (Amin et al. 2004).

Transcriptome and ChIP-seq comparisons of full-length and intracellular domain isoforms in isogenic MCF10A mammary cell background have revealed the diversification of ERBB4 signaling engendered by alternative splicing and cleavage (Wali et al., 2014). ERBB4 broadly affected protease expression, cholesterol biosynthesis, HIF1-alpha signaling, and HIPPO signaling pathways, and other pathways were differentially activated by CYT1 and CYT2 isoforms. For example, CYT1 promoted expression of transcription factors TWIST1 and SNAIL1 that promote epithelial-mesenchymal transition. HIF1-alpha and HIPPO signaling are mediated, respectively, by binding of ERBB4 to HIF1-alpha and to YAP (Paatero et al., 2012, Komuro et al., 2003). ERBB4 increases activity of the transcription factor SREBF2, resulting in increased expression of SREBF2-target genes involved in cholesterol biosynthesis. The mechanism is not known and may involve facilitation of SREBF2 cleavage through ERBB4-mediated PI3K signaling (Haskins et al. 2016).

In some contexts, ERBB4 promotes growth suppression or apoptosis (Penington et al., 2002). Activation of ERBB4 in breast cancer cell lines leads to JNK dependent increase in BRCA1 mRNA level and mitotic cell cycle delay, but the exact mechanism has not been elucidated (Muraoka Cook et al. 2006). The nature of growth responses may be connected with the spliced isoforms expressed. In comparisons of CYT1 vs CYT2 (full-length and ICD) expression in mammary cells, CYT1 was a weaker growth inducer, associated with attenuated MAPK signaling relative to CYT2 (Wali et al., 2014). ERBB4 s80 is also able to translocate to the mitochondrial matrix, presumably when its nuclear translocation is inhibited. Once in the mitochondrion, the BH3 domain of ERBB4, characteristic of BCL2 family members, may enable it to act as a pro apoptotic factor (Naresh et al. 2006).

ERBB4 plays important roles in the developing and adult nervous system. Erbb4 deficiency in somatostatin-expressing neurons of the thalamic reticular nucleus alters behaviors dependent on sensory selection (Ahrens et al. 2015). NRG1-activated ERBB4 signaling enhances AMPA receptor responses through PKC-dependent AMPA receptor exocytosis. This results in an increased excitatory input to parvalbumin-expressing inhibitory neurons in the visual cortex and regulates visual cortical plasticity (Sun et al. 2016). NRG1-activated ERBB4 signaling is involved in GABAergic activity in amygdala which mediates fear conditioning (fear memory) (Lu et al. 2014). Conditional Erbb4 deletion from fast-spiking interneurons, chandelier and basket cells of the cerebral cortex leads to synaptic defects associated with increased locomotor activity and abnormal emotional, social and cognitive function that can be linked to some of the schizophrenia features. The level of GAD1 (GAD67) protein is reduced in the cortex of conditional Erbb4 mutants. GAD1 is a GABA synthesizing enzyme. Cortical mRNA levels of GAD67 are consistently decreased in schizophrenia (Del Pino et al. 2014). Erbb4 is expressed in the GABAergic neurons of the bed nucleus stria terminalis, a part of the extended amygdala. Inhibition of NRG1-triggered ERBB4 signaling induces anxiety-like behavior, which depends on GABAergic neurotransmission. NRG1-ERBB4 signaling stimulates presynaptic GABA release, but the exact mechanism is not known (Geng et al. 2016). NRG1 protects cortical interneurons against ischemic brain injury through ERBB4-mediated increase in GABAergic transmission (Guan et al. 2015). NRG2-activated ERBB4 can reduce the duration of GABAergic transmission by binding to GABA receptors at the postsynaptic membrane via their GABRA1 subunit and promoting endocytosis of GABA receptors (Mitchell et al. 2013). NRG1 promotes synchronization of prefrontal cortex interneurons in an ERBB4 dependent manner (Hou et al. 2014). NRG1-ERBB4 signaling protects neurons from the cell death induced by a mutant form of the amyloid precursor protein (APP) (Woo et al. 2012).

Clinical relevance of ERBB4 has been identified in several contexts. In cancer, putative and validated gain-of-function mutations or gene amplification that may be drivers have been identified at modest frequencies, and may also contribute to resistance to EGFR and ERBB2-targeted therapies. This is noteworthy as ERBB4 kinase activity is inhibited by pan-ERBB tyrosine kinase inhibitors, including lapatinib, which is approved by the US FDA. The reduced prevalence relative to EGFR and ERBB2 in cancer may reflect more restricted expression of ERBB4, or differential signaling, as specific ERBB4 isoforms have been linked to growth inhibition or apoptosis in experimental systems. ERBB2/ERBB4 heterodimers protect cardiomyocytes, so reduced activity of ERBB4 in patients treated with the ERBB2-targeted therapeutic antibody trastuzumab may contribute to the cardiotoxicity of this agent when used in combination with (cardiotoxic) anthracyclines.

With the importance of ERBB4 in developing and adult nervous system, NRG1 and/or ERBB4 polymorphisms, splicing aberrations and mutations have been linked to nervous system disorders including schizophrenia and amyotrophic lateral sclerosis, although these findings are not yet definitive.", "R-HSA-9612639,R-HSA-9612593,R-HSA-1236398,R-HSA-1250220,R-HSA-1250315,R-HSA-1977958,R-HSA-1977959" ], [ "R-HSA-1236974", "ER-Phagosome pathway", "The other TAP-dependent cross-presentation mechanism in phagocytes is the endoplasmic reticulum (ER)-phagosome model. Desjardins proposed that ER is recruited to the cell surface, where it fuses with the plasma membrane, underneath phagocytic cups, to supply membrane for the formation of nascent phagosomes (Gagnon et al. 2002). Three independent studies simultaneously showed that ER contributes to the vast majority of phagosome membrane (Guermonprez et al. 2003, Houde et al. 2003, Ackerman et al. 2003). The composition of early phagosome membrane contains ER-resident proteins, the components required for cross-presentation. This model is similar to the phagosome-to-cytosol model in that Ag is translocated to cytosol for proteasomal degradation, but differs in that antigenic peptides are translocated back into the phagosome (instead of ER) for peptide:MHC-I complexes. ER fusion with phagosome introduces molecules that are involved in Ag transport to cytosol (Sec61) and proteasome-generated peptides back into the phagosome (TAP) for loading onto MHC-I.
Although the ER-phagosome pathway is controversial, the concept remains attractive as it explains how peptide-receptive MHC-I molecules could intersect with a relatively high concentration of exogenous antigens, presumably a crucial prerequisite for efficient cross-presentation (Basha et al. 2008).", "R-HSA-1236935,R-HSA-1236947,R-HSA-1236949,R-HSA-1236965,R-HSA-1236971,R-HSA-8863858,R-HSA-8863895,R-HSA-8863914,R-HSA-8863973,R-HSA-8951595" ], [ "R-HSA-1236978", "Cross-presentation of soluble exogenous antigens (endosomes)", "Exogenous soluble antigens are cross-presented by dendritic cells, albeit with lower efficiency than for particulate substrates. Soluble antigens destined for cross-presentation are taken up by distinct endocytosis mechanisms which route them into stable early endosomes and then to the cytoplasm for proteasomal degradation and peptide loading.", "R-HSA-1236939,R-HSA-1236940,R-HSA-1236941,R-HSA-1236955,R-HSA-1236970" ], [ "R-HSA-1250196", "SHC1 events in ERBB2 signaling", "All ERBB2 heterodimers, ERBB2:EGFR, ERBB2:ERBB3 and ERBB2:ERBB4, are able to activate RAF/MAP kinase cascade by recruiting SHC1 (Pinkas-Kramarski et al. 1996, Sepp-Lorenzino et al. 1996) to phosphorylated C-tail tyrosine residues in either EGFR (Y1148 and Y1173), ERBB2 (Y1196, Y1221, Y1222 and Y1248), ERBB3 (Y1328) or ERBB4 (Y1188 and Y1242 in JM-A CYT1 isoform, Y1178 and Y1232 in JM-B CYT1 isoform, Y1172 and Y1226 in JM-A CYT2 isoform). SHC1 recruitment is followed by phosphorylation (Segatto et al. 1993, Soler et al. 1994), and the phosphorylated SHC1 recruits GRB2:SOS1 complex (Xie et al. 1995), which leads to SOS1-mediated guanyl-nucleotide exchange on RAS (Xie et al. 1995) and downstream activation of RAF and MAP kinases.", "R-HSA-1250195,R-HSA-1250463,R-HSA-1250486,R-HSA-1963578,R-HSA-8934446,R-HSA-8934465" ], [ "R-HSA-1250342", "PI3K events in ERBB4 signaling", "The CYT1 isoforms of ERBB4 possess a C-tail tyrosine residue that, upon trans-autophosphorylation, serves as a docking site for the p85 alpha subunit of PI3K - PIK3R1 (Kaushansky et al. 2008, Cohen et al. 1996). Binding of PIK3R1 to CYT1 isoforms of ERBB4 is followed by recruitment of the p110 catalytic subunit of PI3K (PIK3CA), leading to assembly of an active PI3K complex that converts PIP2 to PIP3 and activates AKT signaling (Kainulainen et al. 2000).", "R-HSA-1250353,R-HSA-1250370" ], [ "R-HSA-1250347", "SHC1 events in ERBB4 signaling", "All splicing isoforms of ERBB4 possess two tyrosine residues in the C-tail that serve as docking sites for SHC1 (Kaushansky et al. 2008, Pinkas-Kramarski et al. 1996, Cohen et al. 1996). Once bound to ERBB4, SHC1 becomes phosphorylated on tyrosine residues by the tyrosine kinase activity of ERBB4, which enables it to recruit the complex of GRB2 and SOS1, resulting in the guanyl-nucleotide exchange on RAS and activation of RAF and MAP kinase cascade (Kainulainen et al. 2000).", "R-HSA-1250348,R-HSA-1250357,R-HSA-1250380,R-HSA-1250383" ], [ "R-HSA-1251985", "Nuclear signaling by ERBB4", "Besides signaling as a transmembrane receptor, ligand activated homodimers of ERBB4 JM-A isoforms (ERBB4 JM-A CYT1 and ERBB4 JM-A CYT2) undergo proteolytic cleavage by ADAM17 (TACE) in the juxtamembrane region, resulting in shedding of the extracellular domain and formation of an 80 kDa membrane bound ERBB4 fragment known as ERBB4 m80 (Rio et al. 2000, Cheng et al. 2003). ERBB4 m80 undergoes further proteolytic cleavage, mediated by the gamma-secretase complex, which releases the soluble 80 kDa ERBB4 intracellular domain, known as ERBB4 s80 or E4ICD, into the cytosol (Ni et al. 2001). ERBB4 s80 is able to translocate to the nucleus, promote nuclear translocation of various transcription factors, and act as a transcription co-factor. In neuronal precursors, ERBB4 s80 binds the complex of TAB and NCOR1, helps to move the complex into the nucleus, and is a co-factor of TAB:NCOR1-mediated inhibition of expression of astrocyte differentiation genes GFAP and S100B (Sardi et al. 2006). In mammary cells, ERBB4 s80 recruits STAT5A transcription factor in the cytosol, shuttles it to the nucleus, and acts as the STAT5A co-factor in binding to and promoting transcription from the beta-casein (CSN2) promoter, and may be involved in the regulation of other lactation-related genes (Williams et al. 2004, Muraoka-Cook et al. 2008). ERBB4 s80 was also shown to bind activated estrogen receptor in the nucleus and act as its transcriptional co-factor in promoting transcription of some estrogen-regulated genes, such as progesterone receptor gene NR3C3 and CXCL12 i.e. SDF1 (Zhu et al. 2006). ERBB4s80 may inhibit transcription of telomerase reverse transcriptase (TERT) by increasing methylation of the TERT gene promoter through an unknown mechanism (Ishibashi et al. 2012).

The C-tail of ERBB4 possesses several WW-domain binding motifs (three in CYT1 isoform and two in CYT2 isoform), which enable interaction of ERBB4 with WW-domain containing proteins. ERBB4 s80, through WW-domain binding motifs, interacts with YAP1 transcription factor, a known proto-oncogene, and may be a co-regulator of YAP1-mediated transcription (Komuro et al. 2003, Omerovic et al. 2004). The tumor suppressor WWOX, another WW-domain containing protein, competes with YAP1 in binding to ERBB4 s80 and prevents translocation of ERBB4 s80 to the nucleus (Aqeilan et al. 2005). ERBB4 s80 is also able to translocate to the mitochondrial matrix, presumably when its nuclear translocation is inhibited. Once in the mitochondrion, the BH3 domain of ERBB4, characteristic of BCL2 family members, may enable it to act as a pro-apoptotic factor (Naresh et al. 2006).", "R-HSA-9612448,R-HSA-9612671,R-HSA-9612672,R-HSA-1251992,R-HSA-1251997,R-HSA-1252013,R-HSA-1253319,R-HSA-1253321,R-HSA-1253325,R-HSA-1253343,R-HSA-1254248,R-HSA-1254251,R-HSA-1254285,R-HSA-1254290,R-HSA-1254291,R-HSA-8954179,R-HSA-8954182,R-HSA-8954185,R-HSA-8954224,R-HSA-1254386,R-HSA-1254392,R-HSA-8954199,R-HSA-8954207,R-HSA-8954208,R-HSA-9612277,R-HSA-9612445,R-HSA-9612257,R-HSA-9612243" ], [ "R-HSA-1257604", "PIP3 activates AKT signaling", "Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007. ", "R-HSA-198266,R-HSA-198270,R-HSA-198640,R-HSA-2316429,R-HSA-2317314,R-HSA-2317332,R-HSA-114542,R-HSA-198298,R-HSA-2219524,R-HSA-2316434" ], [ "R-HSA-1266695", "Interleukin-7 signaling", "Interleukin-7 (IL7) is produced primarily by T zone fibroblastic reticular cells found in lymphoid organs, and also expressed by non-hematopoietic stromal cells present in other tissues including the skin, intestine and liver. It is an essential survival factor for lymphocytes, playing a key anti-apoptotic role in T-cell development, as well as mediating peripheral T-cell maintenance and proliferation. This dual function is reflected in a dose-response relationship that distinguishes the survival function from the proliferative activity; low doses of IL7 (<1 ng/ml) sustain only survival, higher doses (>1 ng/ml) promote survival and cell cycling (Kittipatarin et al. 2006, Swainson et al. 2007).

The IL7 receptor is a heterodimeric complex of the the common cytokine-receptor gamma chain (IL2RG, CD132, or Gc) and the IL7-receptor alpha chain (IL7R, IL7RA, CD127). Both chains are members of the type 1 cytokine family. Neither chain is unique to the IL7 receptor as IL7R is utilized by the receptor for thymic stromal lymphopoietin (TSLP) while IL2RG is shared with the receptors for IL2, IL4, IL9, IL15 and IL21. IL2RG consists of a single transmembrane region and a 240aa extracellular region that includes a fibronectin type III (FNIII) domain thought to be involved in receptor complex formation. It is expressed on most lymphocyte populations. Null mutations of IL2RG in humans cause X-linked severe combined immunodeficiency (X-SCID), which has a phenotype of severely reduced T-cell and natural killer (NK) cell populations, but normal numbers of B cells. In addition to reduced T- and NK-cell numbers, Il2rg knockout mice also have dramatically reduced B-cell populations suggesting that Il2rg is more critical for B-cell development in mice than in humans. Patients with severe combined immunodeficiency (SCID) phenotype due to IL7R mutations (see Puel & Leonard 2000), or a partial deficiency of IL7R (Roifman et al. 2000) have markedly reduced circulating T cells, but normal levels of peripheral blood B cells and NK cells, similar to the phenotype of IL2RG mutations, highlighting a requirement for IL7 in T cell lymphopoiesis. It has been suggested that IL7 is essential for murine, but not human B cell development, but recent studies indicate that IL7 is essential for human B cell production from adult bone marrow and that IL7-induced expansion of the progenitor B cell compartment is increasingly critical for human B cell production during later stages of development (Parrish et al. 2009).

IL7 has been shown to induce rapid and dose-dependent tyrosine phosphorylation of JAKs 1 and 3, and concomitantly tyrosine phosphorylation and DNA-binding activity of STAT5a/b (Foxwell et al. 1995). IL7R was shown to directly induce the activation of JAKs and STATs by van der Plas et al. (1996). Jak1 and Jak3 knockout mice displayed severely impaired thymic development, further supporting their importance in IL7 signaling (Rodig et al. 1998, Nosaka et al. 1995).

The role of STAT5 in IL7 signaling has been studied largely in mouse models. Tyr449 in the cytoplasmic domain of IL7RA is required for T-cell development in vivo and activation of JAK/STAT5 and PI3k/Akt pathways (Jiang et al. 2004, Pallard et al. 1999). T-cells from an IL7R Y449F knock-in mouse did not activate STAT5 (Osbourne et al. 2007), indicating that IL7 regulates STAT5 activity via this key tyrosine residue. STAT5 seems to enhance proliferation of multiple cell lineages in mouse models but it remains unclear whether STAT5 is required solely for survival signaling or also for the induction of proliferative activity (Kittipatarin & Khaled, 2007).

The model for IL7 receptor signaling is believed to resemble that of other Gc family cytokines, based on detailed studies of the IL2 receptor, where IL2RB binds constitutively to JAK1 while JAK3 is pre-associated uniquely with the IL2RG chain. Extending this model to IL7 suggests a similar series of events: IL7R constitutively associated with JAK1 binds IL7, the resulting trimer recruits IL2RG:JAK3, bringing JAK1 and JAK3 into proximity. The association of both chains of the IL7 receptor orients the cytoplasmic domains of the receptor chains so that their associated kinases (Janus and phosphatidylinositol 3-kinases) can phosphorylate sequence elements on the cytoplasmic domains (Jiang et al. 2005). JAKs have low intrinsic enzymatic activity, but after mutual phosphorylation acquire much higher activity, leading to phosphorylation of the critical Y449 site on IL7R. This site binds STAT5 and possibly other signaling adapters, they in turn become phosphorylated by JAK1 and/or JAK3. Phosphorylated STATs translocate to the nucleus and trigger the transcriptional events of their target genes.

The role of the PI3K/AKT pathway in IL7 signaling is controversial. It is a potential T-cell survival pathway because in many cell types PI3K signaling regulates diverse cellular functions such as cell cycle progression, transcription, and metabolism. The ERK/MAPK pathway does not appear to be involved in IL7 signaling (Crawley et al. 1996).

It is not clear how IL7 influences cell proliferation. In the absence of a proliferative signal such as IL7 or IL3, dependent lymphocytes arrest in the G0/G1 phase of the cell cycle. To exit this phase, cells typically activate specific G1 Cyclin-dependent kinases/cyclins and down regulate cell cycle inhibitors such as Cyclin-dependent kinase inhibitor 1B (Cdkn1b or p27kip1). There is indirect evidence suggesting a possible role for IL7 stimulated activation of PI3K/AKT signaling, obtained from transformed cell lines and thymocytes, but not confirmed by observations using primary T-cells (Kittipatarin & Khaled, 2007). IL7 withdrawal results in G1/S cell cycle arrest and is correlated with loss of cdk2 activity (Geiselhart et al. 2001), both events which are known to be regulated by the dephosphorylating activity of Cdc25A. Expression of a p38 MAPK-resistant Cdc25A mutant in an IL-7-dependent T-cell line as well as in peripheral, primary T-cells was sufficient to sustain cell survival and promote cell cycling for several days in the absence of IL7 (Khaled et al. 2005). Cdkn1b is a member of the CIP/KIP family of cyclin-dependent cell cycle inhibitors (CKIs) that negatively regulates the G1/S transition. In IL7 dependent T-cells, the expression of Cdkn1b was sufficient to cause G1 arrest in the presence of IL7. Withdrawal of IL7 induced the upregulation of Cdkn1b and arrested cells in G1 while siRNA knockout of Cdkn1b enhanced cell cycle progression. However, adoptive transfer of Cdkn1b-deficient lymphocytes into IL7 deficient mice indicated that loss of Cdkn1b could only partially compensate for the IL7 signal needed by T-cells to expand in a lymphopenic environment (Li et al. 2006), so though Cdkn1b may be involved in negative regulation of the cell cycle through an effect on cdk2 activity, its absence is not sufficient to fully induce cell cycling under lymphopenic conditions.", "R-HSA-1264832,R-HSA-1266684,R-HSA-1295516,R-HSA-1295519,R-HSA-1295540,R-HSA-449958,R-HSA-449978,R-HSA-451895,R-HSA-452102,R-HSA-507937,R-HSA-6785165,R-HSA-8865605,R-HSA-8865613,R-HSA-8865626,R-HSA-8865693,R-HSA-8865711,R-HSA-8983003,R-HSA-8983011,R-HSA-8983059,R-HSA-8983061,R-HSA-8983063,R-HSA-8983077,R-HSA-8983078,R-HSA-9012671,R-HSA-9025969,R-HSA-9679028" ], [ "R-HSA-1268020", "Mitochondrial protein import", "A human mitochondrion contains about 1500 proteins, more than 99% of which are encoded in the nucleus, synthesized in the cytosol and imported into the mitochondrion. Proteins are targeted to four locations (outer membrane, intermembrane space, inner membrane, and matrix) and must be sorted accordingly (reviewed in Kutik et al. 2007, Milenkovic et al. 2007, Bolender et al. 2008, Endo and Yamano 2009, Wiedemann and Pfanner 2017, Kang et al. 2018). Newly synthesized proteins are transported from the cytosol across the outer membrane by the TOMM40:TOMM70 complex. Proteins that contain presequences first interact with the TOMM20 subunit of the complex while proteins that contain internal targeting elements first interact with the TOMM70 subunit. After initial interaction the protein is conducted across the outer membrane by TOMM40 subunits. In yeast some proteins such as Aco1, Atp1, Cit1, Idh1, and Atp2 have both presequences that interact with TOM20 and mature regions that interact with TOM70 (Yamamoto et al. 2009).
After passage across the outer membrane, proteins may be targeted to the outer membrane via the SAMM50 complex, to the inner membrane via the TIMM22 or TIMM23 complexes (reviewed in van der Laan et al. 2010), to the matrix via the TIMM23 complex (reviewed in van der Laan et al. 2010), or proteins may fold and remain in the intermembrane space (reviewed in Stojanovski et al. 2008, Deponte and Hell 2009, Sideris and Tokatlidis 2010). Presequences on matrix and inner membrane proteins cause interaction with TIMM23 complexes; internal targeting sequences cause outer membrane proteins to interact with the SAMM50 complex and inner membrane proteins to interact with the TIMM22 complex. While in the intermembrane space hydrophobic proteins are chaperoned by the TIMM8:TIMM13 complex and/or the TIMM9:TIMM10:FXC1 complex.", "R-HSA-1268022,R-HSA-1268025,R-HSA-1299475,R-HSA-1299476,R-HSA-1299478,R-HSA-1299480,R-HSA-1299481,R-HSA-1299482,R-HSA-1299484,R-HSA-1299487,R-HSA-1307802,R-HSA-1307803,R-HSA-1955380,R-HSA-8986181" ], [ "R-HSA-1296041", "Activation of G protein gated Potassium channels", "Activation of Kir 3 channels occurs after binding of G beta gamma subunits of GPCR. Activation of Kir3/GIRK leads to K+ efflux. The dissociation of GPCR into G alpha and G beta gamma subunits is activated by the activation of GABA B receptor by GABA binding.", "R-HSA-1013012,R-HSA-1013013,R-HSA-1013020" ], [ "R-HSA-1299308", "Tandem of pore domain in a weak inwardly rectifying K+ channels (TWIK)", "TWIK channels exhibit very low current and comprise of TWIK1, TWIK2 and KCNK7 members. TWIK current may be low due to rapid recycling of the channels from the plasma membrane.", "R-HSA-1299304" ], [ "R-HSA-1299316", "TWIK-releated acid-sensitive K+ channel (TASK)", "TASK 1 and 3 are closely related both structurally and functionally. TASK1 and TASK3 are activated by extracellular acidification and inhibited by decrease in pH. TASK 1 and Task 3 form functional homodimers and heterodimers, however the biophysical properties of TAS1 and TASK3 heteromers are different form parent subunit properties.", "R-HSA-1299318" ], [ "R-HSA-1300642", "Sperm Motility And Taxes", "A series of receptor signaling pathways potentially govern chemical communication between sperm and egg, chemotactically guiding incoming sperm towards the oocyte. Though several substances are confirmed as sperm chemoattractant, progesterone (P) seems to be the best chemoattractant candidate for human sperm. Ion channels control the sperm ability to fertilize the egg by regulating sperm maturation in the female reproductive tract and by triggering key sperm physiological responses required for successful fertilization such as hyperactivated motility, chemotaxis, and the acrosome reaction. CatSper, a pH regulated, calcium selective ion channel, potassium channel KSper (Slo3), and Hv1, the voltage gated proton channel are involved in regulation of sperm hyperactivated motility. While progesterone, secreted by ovulated cumulus oophorus, may act as a chemoattractant for sperm cells over the short distances, a major determinant of sperm guidance over long distances in the mammalian female reproductive tract is rheotaxis.", "R-HSA-2534359,R-HSA-2534365,R-HSA-2534378,R-HSA-2534388" ], [ "R-HSA-1306955", "GRB7 events in ERBB2 signaling", "Heterodimers of ERBB2 and ERBB3 are able to bind GRB7 (Fiddes et al. 1998) through phosphorylated tyrosine residues in the C-tail of ERBB3 (Y1199 and Y1262) (Fiddes et al. 1998), but the exact downstream signaling of this complex has not been elucidated. GRB7 can recruit SHC1 to the active ERBB2 complex, and contributes to ERBB2 signaling-induced RAS activation, which promotes cellular proliferation, but the exact mechanism has not been elucidated (Pradip et al. 2013). In addition, GRB7 can be phosphorylated by the integrin-activated PTK2 (FAK), leading to VAV2-dependent activation of RAC1 and promotion of cell migration. The exact mechanistic details of GRB7-induced RAC1 activation are not known (Pradip et al. 2013).", "R-HSA-1306953" ], [ "R-HSA-1358803", "Downregulation of ERBB2:ERBB3 signaling", "Level of plasma membrane ERBB3 is regulated by E3 ubiquitin ligase RNF41 (also known as NRDP1), which binds and ubiquitinates both inactive and activated ERBB3, targeting it for degradation (Cao et al. 2007). RNF41 is subject to self-ubiquitination which keeps its levels low when ERBB3 is not stimulated, and preserves ERBB3 expression on the cell surface (Qiu et al. 2002). Self-ubiquitination of RNF41 is reversible, through the action of ubiquitin protease USP8, an enzyme stabilized by AKT-mediated phosphorylation. Therefore, activation of AKT by ERBB2:ERBB3 signaling leads to phosphorylation of USP8 (Cao et al. 2007), which increases level of RNF41 through deubiquitination, and results in degradation of activated ERBB3 (Cao et al. 2007) - a negative feedback loop of ERBB3 signaling. Downregulation of EGFR and ERBB4 signaling is explained in pathways Signaling by EGFR and Signaling by ERBB4.", "R-HSA-1358789,R-HSA-1358790,R-HSA-1358791,R-HSA-1358792,R-HSA-1358795,R-HSA-1358797,R-HSA-1358798,R-HSA-1358801" ], [ "R-HSA-1368071", "NR1D1 (REV-ERBA) represses gene expression", "REV-ERBA binds DNA elements very similar to those bound by the transcription activator RORA. RORAREV-ERBA bound to DNA and heme recruits the corepressors NCoR and HDAC3 to repress transcription. Thus REV-ERBA and RORA appear to compete to repress or activate genes, repectively.", "R-HSA-5663252" ], [ "R-HSA-1368108", "BMAL1:CLOCK,NPAS2 activates circadian gene expression", "As inferred from mouse, BMAL1:CLOCK (ARNTL:CLOCK) and BMAL1:NPAS2 (ARNTL:NPAS2) heterodimers bind to sequence elements (E boxes) in the promoters of target genes and enhance transcription (Gekakis et al. 1998, reviewed in Munoz and Baler 2003).", "R-HSA-1368889,R-HSA-549364,R-HSA-549424,R-HSA-549428,R-HSA-5663105,R-HSA-5663122,R-HSA-5663124,R-HSA-5663127,R-HSA-5663132,R-HSA-5663138,R-HSA-5663156,R-HSA-5663165,R-HSA-5663170,R-HSA-879724,R-HSA-879762,R-HSA-879770,R-HSA-879782,R-HSA-879798,R-HSA-8878679,R-HSA-8878702" ], [ "R-HSA-139915", "Activation of PUMA and translocation to mitochondria", "Puma is transactivated in a p53-dependent manner and by E2F1. Activated Puma is translocated to mitochondria.", "R-HSA-139913,R-HSA-4331340,R-HSA-139914,R-HSA-140221,R-HSA-4331324" ], [ "R-HSA-140342", "Apoptosis induced DNA fragmentation", " DNA fragmentation in response to apoptotic signals is achieved, in part, through the activity of apoptotic nucleases, termed DNA fragmentation factor (DFF) or caspase-activated DNase (CAD) (reviewed in Widlak and Garrard, 2005). In non-apoptotic cells, DFF is a nuclear heterodimer consisting of a 45 kD chaperone and inhibitor subunit (DFF45)/inhibitor of CAD (ICAD-L)] and a 40 kD nuclease subunit (DFF40/CAD)( Liu et al. 1997, 1998; Enari et al. 1998). During apoptosis, activated caspase-3 or -7 cleave DFF45/ICAD releasing active DFF40/CAD nuclease. The activity of DFF is tightly controlled at multiple stages. During translation, DFF45/ICAD, Hsp70, and Hsp40 proteins play a role in insuring the appropriate folding of DFF40 during translation(Sakahira and Nagata, 2002). The nuclease activity of DFF40 is enhanced by the chromosomal proteins histone H1, Topoisomerase II and HMGB1/2(Widlak et al., 2000). In addition, the inhibitors (DFF45/35; ICAD-S/L) are produced in stoichiometric excess (Widlak et al., 2003).", "R-HSA-211186,R-HSA-211190,R-HSA-211191,R-HSA-211193,R-HSA-211206,R-HSA-211207,R-HSA-211219,R-HSA-211224,R-HSA-211239,R-HSA-211247,R-HSA-266204,R-HSA-9029667" ], [ "R-HSA-140534", "Caspase activation via Death Receptors in the presence of ligand", "Caspase-8 is synthesized as zymogen (procaspase-8) and is formed from procaspase-8 as a cleavage product. However, the cleavage itself appears not to be sufficient for the formation of an active caspase-8. Only the coordinated dimerization and cleavage of the zymogen produce efficient activation in vitro and apoptosis in cellular systems [Boatright KM and Salvesen GS 2003; Keller N et al 2010; Oberst A et al 2010].

The caspase-8 zymogens are present in the cells as inactive monomers, which are recruited to the death-inducing signaling complex (DISC) by homophilic interactions with the DED domain of FADD. The monomeric zymogens undergo dimerization and the subsequent conformational changes at the receptor complex, which results in the formation of catalytically active form of procaspase-8.[Boatright KM et al 2003; Donepudi M et al 2003; Keller N et al 2010; Oberst A et al 2010].", "R-HSA-2562564,R-HSA-139952" ], [ "R-HSA-141430", "Inactivation of APC/C via direct inhibition of the APC/C complex", "In the direct inhibition model, the cytosolic Mitotic Checkpoint Complex, consisting of hBUBR1, hBUB3, Cdc20 and Mad2, directly inhibits APC/C by binding to it.", "R-HSA-141439,R-HSA-141423,R-HSA-141437" ], [ "R-HSA-141444", "Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal", "The signal from unattached kinetochores is amplified through a Mad2 inhibitory signal that is propagated by the binding of Mad1 to the kinetochore, the association of Mad2 with Mad1, the conversion of Mad2 conformation to an inhibitory form through its association with Mad1 and finally the release of the inhibitory form of Mad2 from the kinetochore.", "R-HSA-141409,R-HSA-141422,R-HSA-141431,R-HSA-141439" ], [ "R-HSA-1433557", "Signaling by SCF-KIT", "Stem cell factor (SCF) is a growth factor with membrane bound and soluble forms. It is expressed by fibroblasts and endothelial cells throughout the body, promoting proliferation, migration, survival and differentiation of hematopoetic progenitors, melanocytes and germ cells.(Linnekin 1999, Ronnstrand 2004, Lennartsson and Ronnstrand 2006). The receptor for SCF is KIT, a tyrosine kinase receptor (RTK) closely related to the receptors for platelet derived growth factor receptor, colony stimulating factor 1 (Linnekin 1999) and Flt3 (Rosnet et al. 1991). Four isoforms of c-Kit have been identified in humans. Alternative splicing results in isoforms of KIT differing in the presence or absence of four residues (GNNK) in the extracellular region. This occurs due to the use of an alternate 5' splice donor site. These GNNK+ and GNNK- variants are co-expressed in most tissues; the GNNK- form predominates and was more strongly tyrosine-phosphorylated and more rapidly internalized (Ronnstrand 2004). There are also splice variants that arise from alternative usage of splice acceptor site resulting in the presence or absence of a serine residue (Crosier et al., 1993). Finally, there is an alternative shorter transcript of KIT expressed in postmeiotic germ cells in the testis which encodes a truncated KIT consisting only of the second part of the kinase domain and thus lackig the extracellular and transmembrane domains as well as the first part of the kinase domain (Rossi et al. 1991). Binding of SCF homodimers to KIT results in KIT homodimerization followed by activation of its intrinsic tyrosine kinase activity. KIT stimulation activates a wide array of signalling pathways including MAPK, PI3K and JAK/STAT (Reber et al. 2006, Ronnstrand 2004). Defects of KIT in humans are associated with different genetic diseases and also in several types of cancers like mast cell leukaemia, germ cell tumours, certain subtypes of malignant melanoma and gastrointestinal tumours.", "R-HSA-1433374,R-HSA-1433415,R-HSA-1433418,R-HSA-1433423,R-HSA-1433428,R-HSA-1433451,R-HSA-1433454,R-HSA-1433456,R-HSA-1433471,R-HSA-1433488,R-HSA-1433501,R-HSA-1433514,R-HSA-1433542,R-HSA-1470009,R-HSA-1470010,R-HSA-1470012,R-HSA-1472121,R-HSA-1562641,R-HSA-205205,R-HSA-205231,R-HSA-205234,R-HSA-205238,R-HSA-205262,R-HSA-205286,R-HSA-205289,R-HSA-205321,R-HSA-205328,R-HSA-9669854,R-HSA-9669893,R-HSA-9681375" ], [ "R-HSA-1433559", "Regulation of KIT signaling", "SCF induced proliferation is negatively regulated by various proteins including SHP1, PKC, CBL, SOCS1, SOCS6 and LNK.", "R-HSA-1433410,R-HSA-1433506,R-HSA-1433508,R-HSA-1470011,R-HSA-1562640,R-HSA-205244,R-HSA-205306,R-HSA-205319" ], [ "R-HSA-1433617", "Regulation of signaling by NODAL", "Mature NODAL can form heterodimers with LEFTY1, LEFTY2, or CERBERUS. The heterodimers do not activate the NODAL receptor. LEFTY1 and LEFTY2 also bind CRIPTO and CRYPTIC coreceptors and prevent them from interacting with other components of the NODAL receptor. By these mechanisms LEFTY1, LEFTY2, and CERBERUS negatively regulate NODAL signaling (reviewed in Shen 2007, Schier 2009).", "R-HSA-1181351,R-HSA-1181352,R-HSA-1181354" ], [ "R-HSA-1442490", "Collagen degradation", "Collagen fibril diameter and spatial organisation are dependent on the species, tissue type and stage of development (Parry 1988). The lengths of collagen fibrils in mature tissues are largely unknown but in tendon can be measured in millimetres (Craig et al. 1989). Collagen fibrils isolated from adult bovine corneal stroma had ~350 collagen molecules in transverse section, tapering down to three molecules at the growing tip (Holmes & Kadler 2005).

The classical view of collagenases is that they actively unwind the triple helical chain, a process termed molecular tectonics (Overall 2002, Bode & Maskos 2003), before preferentially cleaving the alpha2 chain followed by the remaining chains (Chung et al. 2004). More recently it has been suggested that collagen fibrils exist in an equilibrium between protected and vulnerable states (Stultz 2002, Nerenberg & Stultz 2008). The prototypical triple-helical structure of collagen does not fit into the active site of collagenase MMPs. In addition the scissile bonds are not solvent-exposed and are therefore inaccessible to the collagenase active site (Chung et al. 2004, Stultz 2002). It was realized that collagen must locally unfold into non-triple helical regions to allow collagenolysis. Observations using circular dichroism and differential scanning calorimetry confirm that there is considerable heterogeneity along collagen fibres (Makareeva et al. 2008) allowing access for MMPs at physiological temperatures (Salsas-Escat et al. 2010).

Collagen fibrils with cut chains are unstable and accessible to proteinases that cannot cleave intact collagen strands (Woessner & Nagase 2000, Somerville et al. 2003). Continued degradation leads to the formation of gelatin (Lovejoy et al. 1999). Degradation of collagen types other than I-III is less well characterized but believed to occur in a similar manner.

Metalloproteinases (MMPs) play a major part in the degradation of several extracellular macromolecules including collagens. MMP1 (Welgus et al. 1981), MMP8 (Hasty et al. 1987), and MMP13 (Knauper et al. 1996), sometimes referred to as collagenases I, II and III respectively, are able to initiate the intrahelical cleavage of the major fibril forming collagens I, II and III at neutral pH, and thus thought to define the rate-limiting step in normal tissue remodeling events. All can cleave additional substrates including other collagen subtypes. Collagenases cut collagen alpha chains at a single conserved Gly-Ile/Leu site approximately 3/4 of the molecule's length from the N-terminus (Fields 1991, Chung et al. 2004). The cleavage site is characterised by the motif G(I/L)(A/L); the G-I/L bond is cleaved. In collagen type I this corresponds to G953-I954 in the Uniprot canonical alpha chain sequences (often given as G775-I776 in literature). It is not clear why only this bond is cleaved, as the motif occurs at several other places in the chain. MMP14, a membrane-associated MMP also known as Membrane-type matrix metalloproteinase 1 (MT-MMP1), is able to cleave collagen types I, II and III (Ohuchi et al. 1997).", "R-HSA-1454757,R-HSA-1454822,R-HSA-1458433,R-HSA-1474196,R-HSA-1474197,R-HSA-1474210,R-HSA-1474213,R-HSA-1564112,R-HSA-1564117,R-HSA-1564120,R-HSA-1564142,R-HSA-1564143,R-HSA-1564164,R-HSA-1564169,R-HSA-1564179,R-HSA-1564184,R-HSA-2167942,R-HSA-2168038,R-HSA-2168046,R-HSA-2168923,R-HSA-2168960,R-HSA-2168982,R-HSA-2172405,R-HSA-2172433,R-HSA-2471621,R-HSA-2471842,R-HSA-2473584,R-HSA-2473594,R-HSA-2473596,R-HSA-2482180,R-HSA-2484882,R-HSA-2485111,R-HSA-2537499,R-HSA-5696408" ], [ "R-HSA-1445148", "Translocation of SLC2A4 (GLUT4) to the plasma membrane", "In adipocytes and myocytes insulin signaling causes intracellular vesicles carrying the GLUT4 (SLC2A4) glucose transporter to translocate to the plasma membrane, allowing the cells to take up glucose from the bloodstream (reviewed in Zaid et al. 2008, Leney and Tavare 2009, Bogan and Kandror 2010, Foley et al. 2011, Hoffman and Elmendorf 2011, Kandror and Pilch 2011, Jaldin-Fincati et al. 2017). In myocytes muscle contraction alone can also cause translocation of GLUT4.
Though the entire pathway leading to GLUT4 translocation has not been elucidated, several steps are known. Insulin activates the kinases AKT1 and AKT2. Muscle contraction activates the kinase AMPK-alpha2 and possibly also AKT. AKT2 and, to a lesser extent, AKT1 phosphorylate the RAB GTPase activators TBC1D1 and TBC1D4, causing them to bind 14-3-3 proteins and lose GTPase activation activity. As a result RAB proteins (probably RAB8A, RAB10, RAB14 and possibly RAB13) accumulate GTP. The connection between RAB:GTP and vesicle translocation is unknown but may involve recruitment and activation of myosins.
Myosins 1C, 2A, 2B, 5A, 5B have all been shown to play a role in translocating GLUT4 vesicles near the periphery of the cell. Following docking at the plasma membrane the vesicles fuse with the plasma membrane in a process that depends on interaction between VAMP2 on the vesicle and SNAP23 and SYNTAXIN-4 at the plasma membrane.", "R-HSA-1445143,R-HSA-1445144,R-HSA-1445149,R-HSA-1449574,R-HSA-1449597,R-HSA-1454689,R-HSA-1454699,R-HSA-1458463,R-HSA-1458485,R-HSA-2255342,R-HSA-2255343,R-HSA-2316347,R-HSA-2316349,R-HSA-2316352,R-HSA-5260201" ], [ "R-HSA-1461957", "Beta defensins", "Humans have 38 beta-defensin genes plus 9-10 pseudogenes (details available on the HGNC website at http://www.genenames.org/genefamilies/DEFB). Many beta-defensins are encoded by recently duplicated genes giving rise to identical transcripts. Nomenclature is confusing and currently in transition. Uniprot recommended names are used throughout this pathway.
Many beta-defensins show expression that correlates with infection (Sahl et al. 2005, Pazgier et al. 2006). All so far characterized beta-defensins, i.e. beta-defensin 1 (hBD1), 4A (hBD2), 103 (hBD3), 104 (hBD4), 106 (hBD6), 118 (hBD18) and 128 (hBD28) have antimicrobial properties (Pazgier et al. 2006). For beta-defensins 4A, 103 and 118 (hBD2, 3, and 18) this has been shown to correlate with membrane permeabilization effects (Antcheva et al. 2004, Sahl et al. 2005, Yenugu et al. 2004). Electrostatic interaction and disruption of microbial membranes is widely believed to the primary mechanism of action for beta-defensins. Two models explain how membrane disruption takes place, the 'pore model' which postulates that beta-defensins form transmembrane pores in a similar manner to alpha-defensins, and the 'carpet model', which suggests that beta-defensins act as detergents. Beta-defensins contain 6 conserved cysteine residues that in beta-defensins 1, 4A and 103 (hBD1-3) are experimentally confirmed to be cross-linked 1-5, 2-4, 3-6. The canonical sequence for beta-defensins is x2-10Cx5-6(G/A)xCX3-4Cx9-13Cx4-7CCxn. Structurally they are similar to alpha-defensins but with much shorter pre-regions. Though dimerization of some beta-defensins has been reported this is not the case for all and it is unclear whether it is required for function. The majority of functional studies have focused on beta-defensin 103 (hBD3), which has the most significant antimicrobial activity at physiological salt concentrations (Harder et al. 2001). Beta-defensin 103 is highly cationic with a net charge of +11 e0. It exhibits broad-spectrum antimicrobial activity against gram-positive bacteria and some gram-negative bacteria (Harder et al. 2001), though some species are highly resistant (Sahly et al. 2003). Sensitivity correlates with lipid composition of the membrane, with more negatively-charged lipids correlating with larger beta-defensin 103-induced changes in membrane capacitance (Bohling et al. 2006). Though membrane disruption is widely believed to be the primary mechanism of action of beta-defensins they have other antimicrobial properties, such as inhibition of cell wall biosynthesis (Sass et al. 2010), and chemoattractant effects (Yang et al. 1999, Niyonsaba et al. 2002, 2004). The chemotactic activity of beta-defensins 1, 4A and 103 (hBD1-3) for memory T cells and immature DCs is mediated through binding to the chemokine receptor CCR6 and probably another unidentified Gi-coupled receptor (Yang et al. 1999, 2000).

Like defensins, the human cathelicidin LL37 peptide is rich in positively-charged residues (Lehrer & Ganz 2002).
Expression of certain beta-defensins can be induced in response to various signals, such as bacteria, pathogen-associated molecular patterns (PAMPs), or proinflammatory cytokines (Ganz 2003, Yang et al. 2004). Like the alpha-defensins, copy number variation has been reported for DEFB4, DEFB103 and DEFB104 with individuals having 2-12 copies per diploid genome. In contrast DEFB1 does not show such variation but exhibits a number of SNPs (Hollox et al. 2003, Linzmier & Ganz 2005).", "R-HSA-1467269,R-HSA-1471322,R-HSA-1471338,R-HSA-1973968,R-HSA-1974676" ], [ "R-HSA-1461973", "Defensins", "The defensins are a family of antimicrobial cationic peptide molecules which in mammals have a characteristic beta-sheet-rich fold and framework of six disulphide-linked cysteines (Selsted & Ouellette 2005, Ganz 2003). Human defensin peptides have two subfamilies, alpha- and beta-defensins, differing in the length of peptide chain between the six cysteines and the order of disulphide bond pairing between them. A third subfamily, the theta defensins, is derived from alpha-defensins prematurely truncated by a stop codon between the third and fourth cysteine residues. The translated products are shortened to nonapeptides, covalently dimerized by disulfide linkages, and cyclized via new peptide bonds between the first and ninth residues. Humans have one pseudogene but no translated representatives of the theta class.
In solution most alpha and beta defensins are monomers but can form dimers and higher order structures.

The primary cellular sources of defensins are neutrophils, epithelial cells and intestinal Paneth cells.Those expressed in neutrophils and the gut are predominantly constitutive, while those in epithelial tissues such as skin are often inducible by proinflammatory stimuli such as LPS or TNF-alpha.

Defensins are translated as precursor polypeptides that include a typical signal peptide or prepiece that is cleaved in the Golgi body, and a propiece, cleaved by differing mechanisms to produce the mature defensin. Mature defensin peptides can be further processed by removal of individual N-terminal residues (Yang et al. 2004). This may be a mechanism to broaden the activity profile of defensins (Ghosh et al. 2002).

Defensins have direct antimicrobial effects and kill a wide range of Gram-positive and negative bacteria, fungi and some viruses. The primary antimicrobial action of defensins is permeabilization of microbial target membranes but several additional mechanisms have been suggested (Brogden 2005, Wilmes et al. 2011). Defensins and related antimicrobial peptides such as cathelicidin bridge the innate and acquired immune responses. In addition to their antimicrobial properties, cathelicidin and several defensins show receptor-mediated chemotactic activity for immune cells such as monocytes, T cells or immature DCs, induce cytokine production by monocytes and epithelial cells, modulate angiogenesis and stimulate wound healing (Yang et al. 1999, 2000, 2004, Rehaume & Hancock 2008, Yeung et al. 2011).", "R-HSA-1462023,R-HSA-1467209" ], [ "R-HSA-1474228", "Degradation of the extracellular matrix", "Matrix metalloproteinases (MMPs), previously referred to as matrixins because of their role in degradation of the extracellular matrix (ECM), are zinc and calcium dependent proteases belonging to the metzincin family. They contain a characteristic zinc-binding motif HEXXHXXGXXH (Stocker & Bode 1995) and a conserved Methionine which forms a Met-turn. Humans have 24 MMP genes giving rise to 23 MMP proteins, as MMP23 is encoded by two identical genes. All MMPs contain an N-terminal secretory signal peptide and a prodomain with a conserved PRCGXPD motif that in the inactive enzyme is localized with the catalytic site, the cysteine acting as a fourth unpaired ligand for the catalytic zinc atom. Activation involves delocalization of the domain containing this cysteine by a conformational change or proteolytic cleavage, a mechanism referred to as the cysteine-switch (Van Wart & Birkedal-Hansen 1990). Most MMPs are secreted but the membrane type MT-MMPs are membrane anchored and some MMPs may act on intracellular proteins. Various domains determine substrate specificity, cell localization and activation (Hadler-Olsen et al. 2011). MMPs are regulated by transcription, cellular location (most are not activated until secreted), activating proteinases that can be other MMPs, and by metalloproteinase inhibitors such as the tissue inhibitors of metalloproteinases (TIMPs). MMPs are best known for their role in the degradation and removal of ECM molecules. In addition, cleavage of the ECM and other cell surface molecules can release ECM-bound growth factors, and a number of non-ECM proteins are substrates of MMPs (Nagase et al. 2006). MMPs can be divided into subgroups based on domain structure and substrate specificity but it is clear that these are somewhat artificial, many MMPs belong to more than one functional group (Vise & Nagase 2003, Somerville et al. 2003).", "R-HSA-375135,R-HSA-1454781,R-HSA-1454791,R-HSA-1454843,R-HSA-1566962,R-HSA-1566979,R-HSA-1566981,R-HSA-1592270,R-HSA-1592310,R-HSA-1592314,R-HSA-2485148,R-HSA-2514772,R-HSA-2514790,R-HSA-2514823,R-HSA-2514831,R-HSA-2533874,R-HSA-2533944,R-HSA-2533950,R-HSA-2533965,R-HSA-2533970,R-HSA-2534160,R-HSA-2534206,R-HSA-2534240,R-HSA-2534248,R-HSA-2534260,R-HSA-3785684,R-HSA-3788061,R-HSA-3788075,R-HSA-3791149,R-HSA-3791155,R-HSA-3791295,R-HSA-3791319,R-HSA-3814820,R-HSA-3827958,R-HSA-3828025,R-HSA-4086205,R-HSA-4224014,R-HSA-8848658,R-HSA-8855825,R-HSA-8940554,R-HSA-8940561,R-HSA-8942302,R-HSA-8943959,R-HSA-8943987" ], [ "R-HSA-1482925", "Acyl chain remodelling of PG", "In the acyl chain remodelling pathway (Lands cycle), phosphatidylglycerol (PG) is hydrolyzed by phopholipases and subsequently reacylated by acyltransferases. These cycles modify the fatty acid composition of glycerophospholipids to generate diverse molecules asymmetrically distributed in the cell membrane. The events occur additionally in the inner mitochondria membranes (IM) as well as in the endoplasmic reticulum (ER) membrane (Ghomashchi et al. 2010, Singer et al. 2002, Cao et al. 2008, Yang et al. 2004, Nie et al. 2010).", "R-HSA-1482539,R-HSA-1482546,R-HSA-1482635,R-HSA-1482689,R-HSA-1482745,R-HSA-1482847,R-HSA-1482900,R-HSA-1482907,R-HSA-1482920,R-HSA-1602368" ], [ "R-HSA-1483148", "Synthesis of PG", "Phosphatidylglycerol (PG) is synthesised at the inner mitochondrial (IM) membrane, phosphatidic acid (PA) and cytidine triphosphate (CTP) are converted into cytidine diphosphate-diacylglycerol (CDP-DAG), which in turn is converted with glycerol-3-phosphate (G3P) into phosphatidylglycerophosphate (PGP) and cytidine monophosphate (CMP). Finally, PGP is dephosphorylated to PG. In addition, PG can be synthesised at the endoplamic reticulum (ER) membrane when phospholipase D transphosphatidylates phosphatidylcholine (PC) with glycerol to displace choline (Cho) and form PG (Piazza & Marmer 2007, Stuhne-Sekalec et al. 1986, Lykidis et al. 1997, Cao & Hatch 1994).", "R-HSA-1482939,R-HSA-1483142,R-HSA-1483165,R-HSA-1483197" ], [ "R-HSA-1483166", "Synthesis of PA", "In the de novo synthesis of phosphatidic acid (PA), lysophosphatidic acid (LPA) is initially formed by the esterification of sn-1 by glycerol 3-phosphate acyltransferase (GPAT) from glycerol 3-phosphate (G3P). Next, LPA is converted to PA by a LPA acyltransferase (AGPAT, also known as LPAAT). In addition to this, PA is also formed when phosphatidylcholine (PC) is hydrolyzed by phospholipases D1 and D2 (PLD1 and 2). PA is involved in acyl chain remodeling via cleavage by phospholipases followed by reacylation by acyltransferases (Ghomashchi et al. 2010, Singer et al. 2002, Prasad et al. 2011, Shindou & Shimizu 2009, Cao et al. 2006).", "R-HSA-1482548,R-HSA-1482604,R-HSA-1482656,R-HSA-1482679,R-HSA-1482695,R-HSA-1483002,R-HSA-1483182,R-HSA-1602446,R-HSA-188467,R-HSA-549112,R-HSA-6786650,R-HSA-6792445,R-HSA-75885,R-HSA-75889,R-HSA-8878654,R-HSA-8878787,R-HSA-8954398" ], [ "R-HSA-1483226", "Synthesis of PI", "Phosphatidylinositol (PI) is synthesized when phosphatidic acid (PA) and cytidine triphosphate (CTP) are converted into cytidine diphosphate-diacylglycerol (CDP-DAG) followed by conversion into PI and cytidine monophosphate (CMP) (Stuhne-Sekalec et al 1986, Lykidis et al. 1997).", "R-HSA-1482976,R-HSA-1483121,R-HSA-8869241" ], [ "R-HSA-156584", "Cytosolic sulfonation of small molecules", "Two groups of sulfotransferease (SULT) enzymes catalyze the transfer of a sulfate group from 3-phosphoadenosine 5-phosphosulfate (PAPS) to a hydroxyl group on an acceptor molecule, yielding a sulfonated acceptor and 3-phosphoadenosine 5-phosphate (PAP). One is localized to the Golgi apparatus and mediates the sulfonation of proteoglycans. The second, annotated here, is cytosolic and mediates the sulfonation of a diverse array of small molecules, increasing their solubilities in water and modifying their physiological functions. There are probably thirteen or more human cytosolic SULT enzymes; eleven of these have been purified and characterized enzymatically, and are annotated here (Blanchard et al. 2004; Gamage et al. 2005). These enzymes appear to be active as dimers. Their substrate specificities are typically broad, and not related in an obvious way to their structures; indeed, apparently orthologous human and rodent SULT enzymes can have different substrate specificities (Glatt 2000), and none has been exhaustively characterized. The substrates listed in the table and annotated here are a sample of the known ones, chosen to indicate the range of activity of these enzymes and to capture some of their known physiologically important targets. Absence of a small molecule - enzyme pair from the table, however, may only mean that it has not yet been studied.", "R-HSA-158468,R-HSA-158849,R-HSA-158860,R-HSA-159358,R-HSA-176474,R-HSA-176517,R-HSA-176521,R-HSA-176585,R-HSA-176588,R-HSA-176604,R-HSA-176606,R-HSA-176631,R-HSA-176646,R-HSA-176664,R-HSA-176669,R-HSA-5695964,R-HSA-8953499,R-HSA-8954262" ], [ "R-HSA-156590", "Glutathione conjugation", "Glutathione S-Transferases (GSTs; EC 2.5.1.18) are another major set of phase II conjugation enzymes. They can be found in the cytosol as well as being microsomal membrane-bound. Cytosolic GSTs are encoded by at least 5 gene families (alpha, mu, pi, theta and zeta GST) whereas membrane-bound enzymes are encoded by single genes. Soluble GSTs are homo- or hetero-dimeric enzymes (approximately 25KDa subunits) which can act on a wide range of endogenous and exogenous electrophiles. GSTs mediate conjugation using glutathione (GSH), a tripeptide synthesized from its precursor amino acids gamma-glutamate, cysteine and glycine. A generalized reaction is

RX + GSH -> HX + GSR

Glutathione conjugates are excreted in bile and converted to cysteine and mercapturic acid conjugates in the intestine and kidneys. GSH is the major, low molecular weight, non-protein thiol synthesized de novo in mammalian cells. As well as taking part in conjugation reactions, GSH also has antioxidant ability and can metabolize endogenous and exogenous compounds. The nucleophilic GSH attacks the electrophilic substrate forming a thioether bond between the cysteine residue of GSH and the electrophile. The result is generally a less reactive and more water-soluble conjugate that can be easily excreted. In some cases, GSTs can activate compounds to reactive species such as certain haloalkanes and haloalkenes. Substrates for GSTs include epoxides, alkenes and compounds with electrophilic carbon, sulfur or nitrogen centres. There are two types of conjugation reaction with glutathione: displacement reactions where glutathione displaces an electron-withdrawing group and addition reactions where glutathione is added to activated double bond structures or strained ring systems.", "R-HSA-176054,R-HSA-176059,R-HSA-3301943,R-HSA-5692232,R-HSA-5693724" ], [ "R-HSA-156827", "L13a-mediated translational silencing of Ceruloplasmin expression", "While circularization of mRNA during translation initiation is thought to contribute to an increase in the efficiency of translation, it also appears to provide a mechanism for translational silencing. This might be achieved by bringing inhibitory 3' UTR-binding proteins into a position in which they interfere either with the function of the translation initiation complex or with the assembly of the ribosome (Mazumder et al 2001). Translational silencing of Ceruloplasmin (Cp) occurs 16 hrs after its induction by INF-gamma (Mazumder et al., 1997). Although the mechanism by which silencing occurs has not yet been determined, this process is mediated by the L13a subunit of the 60s ribosome and thought to require circularization of the Cp mRNA (Sampath et al., 2003; Mazumder et al., 2001; Mazumder et al., 2003). Between 14 and 16 hrs after INF gamma induction, the L13a subunit of the 60s ribosome is phosphorylated and released from the 60s subunit. Phosphorylated L13a then associates with the GAIT element in the 3' UTR of the Cp mRNA inhibiting its translation.", "R-HSA-156823,R-HSA-156826,R-HSA-156832" ], [ "R-HSA-159227", "Transport of the SLBP independent Mature mRNA", "Transport of the SLBP independent Mature mRNA through the nuclear pore.", "R-HSA-111439,R-HSA-158481,R-HSA-158484" ], [ "R-HSA-159230", "Transport of the SLBP Dependant Mature mRNA", "Transport of U7 snRNP and stem-loop binding protein (SLBP) processed mRNA.", "R-HSA-159046,R-HSA-159050,R-HSA-77587" ], [ "R-HSA-159231", "Transport of Mature mRNA Derived from an Intronless Transcript", "Transport of mRNA from the nucleus to the cytoplasm, where it is translated into protein, is highly selective and closely coupled to correct RNA processing.", "R-HSA-158441,R-HSA-158447,R-HSA-77594" ], [ "R-HSA-159236", "Transport of Mature mRNA derived from an Intron-Containing Transcript", "Transport of mRNA from the nucleus to the cytoplasm, where it is translated into protein, is highly selective and closely coupled to correct RNA processing. This coupling is achieved by the nuclear pore complex, which recognizes and transports only completed mRNAs.", "R-HSA-159101,R-HSA-75096,R-HSA-75097,R-HSA-75098" ], [ "R-HSA-159418", "Recycling of bile acids and salts", "Of the 20-40 grams of bile salts released daily by the liver, all but approximately 0.5 grams are reabsorbed from the intestine, returned to the liver, and re-used. This recycling involves a series of transport processes: uptake by enterocytes mediated by ASBT (SLC10A2), traversal of the enterocyte cytosol mediated by ileal bile acid binding protein (I-BABP - FABP6), efflux from enterocytes mediated by MRP3 (ABCC3), travel through the portal blood as a complex with albumin, and uptake by hepatocytes mediated by Na+-taurocholate transporting protein (NTPC - SLC10A1) and, to a lesser extent by organic anion transporting proteins A, C, and 8 (OATPA - SLCO1A2, OATPC - SLCO1B1, and OATP-8 - SLCO1B3). Once returned to the hepatocyte cytosol, bile acids (generated in the intestine by the action of bacteria on secreted bile salts) are activated by conjugation with coenzyme A, then coupled to glycine or taurine, regenerating bile salts for re-export into the bile, mediated by the bile salt export pump, ABCB11 (Kullak-Ublick et al. 2004; Mihalik et al. 2002; Trauner and Boyer 2003). Unmodified bile salts returned to the hepatocyte cytosol can be re-exported by ABCB11 without further modification.
", "R-HSA-159425,R-HSA-159431,R-HSA-193362,R-HSA-194079,R-HSA-194083,R-HSA-194121,R-HSA-194130,R-HSA-194153,R-HSA-194187,R-HSA-5340195,R-HSA-5340251,R-HSA-8873850,R-HSA-9733964,R-HSA-9733969,R-HSA-9733973,R-HSA-9733545,R-HSA-9733960" ], [ "R-HSA-162588", "Budding and maturation of HIV virion", "With the virus components precariously assembled on the inner leaflet of the plasma membrane, the host cell machinery is required for viral budding. The virus takes advantage of the host ESCRT pathway to terminate Gag polymerization and catalyze release. The ESCRT pathway is normally responsible for membrane fission that creates cytoplasm filled vesicular bodies. In this case HIV (and other viruses) take advantage of the ESCRT cellular machinery to facilitate virion budding from the host.", "R-HSA-3139027,R-HSA-3159227,R-HSA-3159232" ], [ "R-HSA-163125", "Post-translational modification: synthesis of GPI-anchored proteins", "Glycosylphosphatidyl inositol (GPI) acts as a membrane anchor for many cell surface proteins. GPI is synthesized in the endoplasmic reticulum. In humans, a single pathway consisting of eleven reactions appears to be responsible for the synthesis of the major GPI species involved in membrane protein anchoring.

As a nascent protein fated to become GPI-anchored moves into the lumen of the endoplasmic reticulum, it is attacked by a transamidase complex that cleaves it near its carboxy terminus and attaches an acylated GPI moiety. The GPI moiety is deacylated, yielding a protein-GPI conjugate that can be efficiently transported to the Golgi apparatus.", "R-HSA-8940388" ], [ "R-HSA-163282", "Mitochondrial transcription initiation", "Human mtDNA is transcribed by a dedicated mitochondrial RNA polymerase (POLRMT), which displays significant sequence similarity to the monomeric RNA polymerases found in bacteriophages. In contrast to the phage T7 RNA polymerase, POLRMT cannot interact with promoter DNA and initiate transcription on its own, but requires the presence of the mitochondrial transcription factor A (TFAM), and either transcription factor B1 (TFB1M) or B2 (TFB2M). The 4 proteins of the basal mitochondrial transcription machinery have been purified in recombinant form and used to reconstitute transcription in vitro with a promoter containing DNA fragment (Falkenberg et al., 2002). Although both TFB1M and TFB2M can support in vitro transcription with POLRMT, TFB2M is at least two orders of magnitude more active than TFB1M and the physiological role of TFB1M in mitochondrial transcription has not yet been completely defined. The TFB1M and TFB2M display primary sequence similarity to a family of rRNA methyltransferases, which dimethylates two adjacent adenosine bases near the 3' end of the small subunit rRNA during ribosome biogenesis (Falkenberg et al., 2002; McCulloch et al., 2002). Human TFB1M is, in fact, a dual function protein, which not only support mitochondrial transcription in vitro, but also acts as a rRNA methyltransferase (Seidel-Rogol et al., 2003). The methyltransferase activity is not required for transcription, since point mutations in conserved methyltransferase motifs of TFB1M revealed that it stimulates transcription in vitro independently of S-adenosylmethionine binding and rRNA methyltransferase activity.", "R-HSA-163296,R-HSA-163310" ], [ "R-HSA-163560", "Triglyceride catabolism", "Triacylglycerol is a major energy store in the body and its hydrolysis to yield fatty acids and glycerol is a tightly regulated part of energy metabolism. A central part in this regulation is played by hormone-sensitive lipase (HSL), a neutral lipase abundant in adipocytes and skeletal and cardiac muscle, but also abundant in ovarian and adrenal tissue, where it mediates cholesterol ester hydrolysis, yielding cholesterol for steroid biosynthesis. The hormones to which it is sensitive include catecholamines (e.g., epinephrine), ACTH, and glucagon, all of which trigger signaling cascades that lead to its phosphorylation and activation, and insulin, which sets off events leading to its dephosphorylation and inactivation (Holm et al. 2000; Kraemer and Shen 2002).

The processes of triacylglycerol and cholesterol ester hydrolysis are also regulated by subcellular compartmentalization: these lipids are packaged in cytosolic particles and the enzymes responsible for their hydrolysis, and perhaps for additional steps in their metabolism, are organized at the surfaces of these particles (e.g., Brasaemle et al. 2004). This organization is dynamic: the inactive form of HSL is not associated with the particles, but is translocated there after being phosphorylated. Conversely, perilipin, a major constituent of the particle surface, appears to block access of enzymes to the lipids within the particle; its phosphorylation allows greater access.

Here, HSL-mediated triacylglycerol hydrolysis is described as a pathway containing twelve reactions. The first six of these involve activation: phosphorylation of HSL, dimerization of HSL, disruption of CGI-58:perilipin complexes at the surfaces of cytosolic lipid particles, phosphorylation of perilipin, association of phosphorylated HSL with FABP, and translocation of HSL from the cytosol to the surfaces of lipid particles. The next four reactions are the hydrolysis reactions themselves: the hydrolysis of cholesterol esters, and the successive removal of three fatty acids from triacylglycerol. The last two reactions, dephosphorylation of perilipin and HSL, negatively regulate the pathway. These events are outlined in the figure below. Inputs (substrates) and outputs (products) of individual reactions are connected by black arrows; blue lines connect output activated enzymes to the other reactions that they catalyze.

Despite the undoubted importance of these reactions in normal human energy metabolism and in the pathology of diseases such as type II diabetes, they have been studied only to a limited extent in human cells and tissues. Most experimental data are derived instead from two rodent model systems: primary adipocytes from rats, and mouse 3T3-L1 cells induced to differentiate into adipocytes.", "R-HSA-163402,R-HSA-163416,R-HSA-163418,R-HSA-163432,R-HSA-163489,R-HSA-163539,R-HSA-163549,R-HSA-163551,R-HSA-163554,R-HSA-163568,R-HSA-163595,R-HSA-163602,R-HSA-188467,R-HSA-5334794,R-HSA-8848338,R-HSA-8848339,R-HSA-8848355" ], [ "R-HSA-163765", "ChREBP activates metabolic gene expression", "ChREBP (Carbohydrate Response Element Binding Protein) is a large multidomain protein containing a nuclear localization signal near its amino terminus, polyproline domains, a basic helix-loop-helix-leucine zipper domain, and a leucine-zipper-like domain (Uyeda et al., 2002). Its dephosphorylation in response to molecular signals associated with the well-fed state allows it to enter the nucleus, interact with MLX protein, and bind to ChRE DNA sequence motifs near Acetyl-CoA carboxylase, Fatty acid synthase, and Pyruvate kinase (L isoform) genes (Ishi et al.2004). This sequence of events is outlined schematically in the picture below (adapted from Kawaguchi et al. (2001) - copyright (2001) National Academy of Sciences, U.S.A.).", "R-HSA-163666,R-HSA-163669,R-HSA-163733,R-HSA-163743,R-HSA-163748,R-HSA-163770" ], [ "R-HSA-165054", "Rev-mediated nuclear export of HIV RNA", "The HIV-1 genome contains 9 genes encoded by a single transcript. In order for the virus to replicate, unspliced, singly-spliced and fully spliced viral mRNA must be exported from the nucleus. The HIV-1 mRNA splice sites are inefficient resulting it the accumulation of a pool of incompletely spliced RNAs (Staffa and Cochrane, 1994). In the early stages of the viral life cycle, or in the absence of the viral Rev protein, completely spliced viral mRNA which encode the regulatory proteins Tat, Nef and Rev are exported from the nucleus while the incompletely spliced structural protein encoding transcripts are held within the nucleus by cellular proteins that normally function in preventing the nuclear export of cellular pre-mRNA. Export of both unspliced and partially spliced mRNA is mediated by the viral protein Rev which is recruited, along with cellular cofactors, to the Rev Response Element (RRE) within the HIV-1 mRNA sequence (Malim et al., 1990; Fischer et al., 1994). The cellular hRIP protein is essential for correct Rev-mediated export of viral RNAs to the cytoplasm (Sanchez-Velar et al., 2004; Yu et al., 2005).", "R-HSA-165028,R-HSA-165034,R-HSA-165043,R-HSA-165047,R-HSA-165055,R-HSA-180687,R-HSA-180739,R-HSA-180885" ], [ "R-HSA-1650814", "Collagen biosynthesis and modifying enzymes", "The biosynthesis of collagen is a multistep process. Collagen propeptides are cotranslationally translocated into the ER lumen. Propeptides undergo a number of post-translational modifications. Proline and lysine residues may be hydroxylated by prolyl 3-, prolyl 4- and lysyl hydroxylases. 4-hydroxyproline is essential for intramolecular hydrogen bonding and stability of the triple helical collagenous domain. In fibril forming collagens approximately 50% of prolines are 4-hydroxylated; the extent of this and of 3-hydroxyproline and lysine hydroxylation varies between tissues and collagen types (Kivirikko et al. 1972, 1992). Hydroxylysine molecules can form cross-links between collagen molecules in fibrils, and are sites for glycosyl- and galactosylation. Collagen peptides all have non-collagenous domains; collagens within the subclasses have common chain structures. These non-collagenous domains have regulatory functions; some are biologically active when cleaved from the main peptide chain. Fibrillar collagens all have a large triple helical domain (COL1) bordered by N and C terminal extensions, called the N and C propeptides, which are cleaved prior to formation of the collagen fibril. The C propeptide, also called the NC1 domain, is highly conserved. It directs chain association during intracellular assembly of the procollagen molecule from three collagen propeptide alpha chains (Hulmes 2002). The N-propeptide has a short linker (NC2) connecting the main triple helix to a short minor one (COL2) and a globular N-terminal region NC3. NC3 domains are variable both in size and the domains they contain.

Collagen propeptides typically undergo a number of post-translational modifications. Proline and lysine residues are hydroxylated by prolyl 3-, prolyl 4- and lysyl hydroxylases. 4-hydroxyproline is essential for intramolecular hydrogen bonding and stability of the triple helical collagenous domain. Prolyl 4-hydroxylase may also have a role in alpha chain association as no association of the C-propeptides of type XII collagen was seen in the presence of prolyl 4-hydroxylase inhibitors (Mazzorana et al. 1993, 1996). In fibril forming collagens approximately 50% of prolines are 4-hydroxylated; the extent of this is species dependent, lower hydroxylation correlating with lower ambient temperature and thermal stability (Cohen-Solal et al. 1986, Notbohm et al. 1992). Similarly the extent of 3-hydroxyproline and lysine hydroxylation varies between tissues and collagen types (Kivirikko et al. 1992). Hydroxylysine molecules can form cross-links between collagen molecules in fibrils, and are sites for glycosyl- and galactosylation.

Collagen molecules fold and assemble through a series of distinct intermediates (Bulleid 1996). Individual collagen polypeptide chains are translocated co-translationally across the membrane of the endoplasmic reticulum (ER). Intra-chain disulfide bonds are formed within the N-propeptide, and hydroxylation of proline and lysine residues occurs within the triple helical domain (Kivirikko et al. 1992). When the peptide chain is fully translocated into the ER lumen the C-propeptide folds, the conformation being stabilized by intra-chain disulfide bonds (Doege and Fessler 1986). Pro alpha-chains associate via the C-propeptides (Byers et al. 1975, Bachinger et al. 1978), or NC2 domains for FACIT family collagens (Boudko et al. 2008) to form an initial trimer which can be stabilized by the formation of inter-chain disulfide bonds (Schofield et al. 1974, Olsen et al. 1976), though these are not a prerequisite for further folding (Bulleid et al. 1996). The triple helix then nucleates and folds in a C- to N- direction. The association of the individual chains and subsequent triple helix formation are distinct steps (Bachinger et al. 1980). The N-propeptides associate and in some cases form inter-chain disulfide bonds (Bruckner et al., 1978). Procollagen is released via carriers into the exracellular space (Canty & Kadler 2005). Fibrillar procollagens undergo removal of the C- and N-propeptides by procollagen C and N proteinases respectively, both Zn2+ dependent metalloproteinases. Propeptide processing is a required step for normal collagen I and III fibril formation, but collagens can retain some or all of their non-collagenous propeptides. Retained collagen type V and XI N-propeptides contribute to the control of fibril growth by sterically limiting lateral molecule addition (Fichard et al. 1995). Processed fibrillar procollagen is termed tropocollagen, which is considered to be the unit of higher order fibrils and fibres. Tropocollagens of the fibril forming collagens I, II, III, V and XI sponteneously aggregate in vitro in a manner that has been compared with crystallization, commencing with a nucleation event followed by subsequent organized aggregation (Silver et al. 1992, Prockop & Fertala 1998). Fibril formation is stabilized by lysyl oxidase catalyzed crosslinks between adjacent molecules (Siegel & Fu 1976).", "R-HSA-1614460,R-HSA-1614461,R-HSA-1650808,R-HSA-1980233,R-HSA-1981104,R-HSA-1981120,R-HSA-1981128,R-HSA-1981157,R-HSA-2002428,R-HSA-2002440,R-HSA-2002460,R-HSA-2022073,R-HSA-2089971,R-HSA-2152276,R-HSA-8948219,R-HSA-8948222,R-HSA-8948224,R-HSA-8948226,R-HSA-8948228,R-HSA-8948230,R-HSA-8948231,R-HSA-8948232,R-HSA-8948234" ], [ "R-HSA-166016", "Toll Like Receptor 4 (TLR4) Cascade", "Toll-like Receptor 4 is a microbe associated molecular pattern receptor well known for it's sensitivity to bacterial lipopolysaccharides (LPS). LPS is assembled within diverse Gram-negative bacteria, many of which are human or plant pathogens. It is a component of the outer membrane of Gram-negative bacteria and consists of lipid A, a core polysaccharide and an O-polysaccharide of variable length (often more than 50 monosaccharide units). LPS is a potent activator of the innate immune response in humans, causing reactions including fever, headache, nausea, diarrhoea, changes in leukocyte and platelet counts, disseminated intravascular coagulation, multiorgan failure, shock and death. All these reactions are induced by cytokines and other endogenous mediators which are produced after interaction of LPS with the humoral and cellular targets of the host. In macrophages and dendritic cells, LPS-mediated activation of TLR4 triggers the biosynthesis of diverse mediators of inflammation, such as TNF-alpha and IL6, and activates the production of co-stimulatory molecules required for the adaptive immune response. In mononuclear and endothelial cells, LPS also stimulates tissue factor production. These events are desirable for clearing local infections, but when these various mediators and clotting factors are overproduced, they can damage small blood vessels and precipitate shock accompanied by disseminated intravascular coagulation and multiple organ failure.", "R-HSA-166015,R-HSA-166041,R-HSA-166168,R-HSA-2201293,R-HSA-2201341,R-HSA-2559439" ], [ "R-HSA-1660499", "Synthesis of PIPs at the plasma membrane", "At the plasma membrane, subsequent phosphorylation of phosphatidylinositol 4-phosphate (PI4P) produces phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) while the actions of various other kinases and phosphatases produces phosphatidylinositol 3-phosphate (PI3P), phosphatidylinositol 5-phosphate (PI5P), phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2), and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) (Zhang et al. 1997, Gurung et al. 2003, Guo et al. 1999, Vanhaesebroeck et al. 1997, Tolias et al. 1998, Schaletzky et al. 2003, Kim et al. 2002, Clarke et al. 2010). Many of the phosphatidylinositol phosphatases that act at the plasma membrane belong to the myotubularin family. Enzymatically inactive myotubularin family members can heterodimerize with catalytically active mytotubularins to regulate their stability, activity and/or substrate specificity (Berger et al. 2006, Zou et al. 2012).", "R-HSA-1675773,R-HSA-1675776,R-HSA-1675780,R-HSA-1675810,R-HSA-1675836,R-HSA-1675949,R-HSA-1675988,R-HSA-1675994,R-HSA-1676048,R-HSA-1676082,R-HSA-1676109,R-HSA-1676134,R-HSA-1676145,R-HSA-1676149,R-HSA-1676164,R-HSA-1676177,R-HSA-1676203,R-HSA-6809254,R-HSA-6809309,R-HSA-6809320,R-HSA-6809325,R-HSA-6809785,R-HSA-6809793,R-HSA-6809944,R-HSA-6809975,R-HSA-8870332,R-HSA-8870489,R-HSA-8870499,R-HSA-8871366,R-HSA-8871370,R-HSA-8871373,R-HSA-8871376,R-HSA-199456" ], [ "R-HSA-1660514", "Synthesis of PIPs at the Golgi membrane", "At the Golgi membrane, phosphatidylinositol 4-phosphate (PI4P) is primarily generated from phosphorylation of phosphatidylinositol (PI). Other phosphoinositides are also generated by the action of various kinases and phosphatases such as: phosphatidylinositol 3-phosphate (PI3P), phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2), phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) (Godi et al. 1999, Minogue et al. 2001, Rohde et al. 2003, Sbrissa et al. 2007, Sbrissa et al. 2008, Domin et al. 2000, Arcaro et al. 2000).", "R-HSA-1675824,R-HSA-1675883,R-HSA-1675921,R-HSA-1675928,R-HSA-1675961,R-HSA-1676005,R-HSA-1676114,R-HSA-1676133,R-HSA-1676152,R-HSA-1676185,R-HSA-1676204" ] ] }, "readme": "Name\n - Human Pathways (Reactome)\n\nVersion\n - 1.11.2\n\nCreated on\n - 2021-10-15T06:14:22.181602\n\nModified on\n - 2022-01-18T12:53:30.227002\n\nCreated by\n - [jeetvora@gwu.edu], Karina Martinez [karinamartinez@gwu.edu], Amanda Bell [amandab2140@gwu.edu], Jonathon Keeney [keeneyjg@gwu.edu], Millicent Quartey [mquartey@email.gwu.edu]\n\nAuthors\n - Not Applicable []\n\nChecksum\n - \n\nUsability Domain\n - \n - REACTOME is an open-source, open access, manually curated and peer-reviewed pathway database. \n\nDescription Domain\n Keywords\n - pathways\n - reactions\n - REACTOME\n\n Pipeline Steps\n - Step-1: The script loads the Reactome Pathways for UniProtKB canonical accessions from the triplestore containing triples from nt file and extracts the data as a csv dataset. \n\nExecution Domain\n Scripts - https://github.com/GW-HIVE/glygen-backend-integration/blob/master/pipeline/integrator/make-protein-dataset.py\n\n\n Software Prerequisites\n Name: Python\n Version: 2.7.5\n URI: https://www.python.org/download/releases/2.7.5/\n\nI/O Domain\n Input Subdomain\n Name: uniprot-proteome-homo-sapiens.nt\n URI: https://data.glygen.org//ln2downloads/ebi/2021_03/uniprot-proteome-homo-sapiens.nt\n Output Subdomain\n Name: human_protein_pathways_reactome.csv\n URI: http://data.glygen.org/ln2data/releases/data/v-1.12.1/reviewed/human_protein_pathways_reactome.csv\n Name: human_protein_pathways_reactome.stat.csv\n URI: http://data.glygen.org/ln2data/releases/data/v-1.12.1/reviewed/human_protein_pathways_reactome.stat.csv", "downloadurl": "/ln2data/releases/data/v-1.12.1/reviewed/human_protein_pathways_reactome.csv" }