ID GREM1_HUMAN Reviewed; 184 AA. AC O60565; Q52LV3; Q8N914; Q8N936; DT 12-APR-2005, integrated into UniProtKB/Swiss-Prot. DT 01-AUG-1998, sequence version 1. DT 13-FEB-2019, entry version 148. DE RecName: Full=Gremlin-1; DE AltName: Full=Cell proliferation-inducing gene 2 protein; DE AltName: Full=Cysteine knot superfamily 1, BMP antagonist 1; DE AltName: Full=DAN domain family member 2; DE AltName: Full=Down-regulated in Mos-transformed cells protein; DE AltName: Full=Increased in high glucose protein 2 {ECO:0000303|PubMed:10744662}; DE Short=IHG-2 {ECO:0000303|PubMed:10744662}; DE Flags: Precursor; GN Name=GREM1; Synonyms=CKTSF1B1, DAND2, DRM; ORFNames=PIG2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=9660951; DOI=10.1016/S1097-2765(00)80067-2; RA Hsu D.R., Economides A.N., Wang X., Eimon P.M., Harland R.M.; RT "The Xenopus dorsalizing factor Gremlin identifies a novel family of RT secreted proteins that antagonize BMP activities."; RL Mol. Cell 1:673-683(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND INDUCTION. RX PubMed=10744662; DOI=10.1074/jbc.275.14.9901; RA McMahon R., Murphy M., Clarkson M., Taal M., Mackenzie H.S., RA Godson C., Martin F., Brady H.R.; RT "IHG-2, a mesangial cell gene induced by high glucose, is human RT gremlin. Regulation by extracellular glucose concentration, cyclic RT mechanical strain, and transforming growth factor-beta1."; RL J. Biol. Chem. 275:9901-9904(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND RP INDUCTION. RC TISSUE=Small intestine; RX PubMed=10894942; RA Topol L.Z., Modi W.S., Koochekpour S., Blair D.G.; RT "DRM/GREMLIN (CKTSF1B1) maps to human chromosome 15 and is highly RT expressed in adult and fetal brain."; RL Cytogenet. Cell Genet. 89:79-84(2000). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Tate G., Mitsuya T.; RT "Human Gremlin homologue."; RL Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Kim J.W.; RT "Identification of a human cell proliferation gene."; RL Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Chondrocyte; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Liver; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP PROTEIN SEQUENCE OF 25-39. RX PubMed=15340161; DOI=10.1110/ps.04682504; RA Zhang Z., Henzel W.J.; RT "Signal peptide prediction based on analysis of experimentally RT verified cleavage sites."; RL Protein Sci. 13:2819-2824(2004). RN [9] RP TISSUE SPECIFICITY, AND INVOLVEMENT IN HMPS1. RX PubMed=22561515; DOI=10.1038/ng.2263; RA Jaeger E., Leedham S., Lewis A., Segditsas S., Becker M., RA Cuadrado P.R., Davis H., Kaur K., Heinimann K., Howarth K., East J., RA Taylor J., Thomas H., Tomlinson I.; RT "Hereditary mixed polyposis syndrome is caused by a 40-kb upstream RT duplication that leads to increased and ectopic expression of the BMP RT antagonist GREM1."; RL Nat. Genet. 44:699-703(2012). RN [10] {ECO:0000244|PDB:5AEJ} RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 72-184, FUNCTION, SUBUNIT, RP INTERACTION WITH BMP2, AND DISULFIDE BONDS. RX PubMed=27036124; DOI=10.1042/BCJ20160254; RA Kisonaite M., Wang X., Hyvonen M.; RT "Structure of Gremlin-1 and analysis of its interaction with BMP-2."; RL Biochem. J. 473:1593-1604(2016). CC -!- FUNCTION: Cytokine that may play an important role during CC carcinogenesis and metanephric kidney organogenesis, as a BMP CC antagonist required for early limb outgrowth and patterning in CC maintaining the FGF4-SHH feedback loop. Down-regulates the BMP4 CC signaling in a dose-dependent manner (By similarity). Antagonist CC of BMP2; inhibits BMP2-mediated differentiation of osteoblasts (in CC vitro) (PubMed:27036124). Acts as inhibitor of monocyte CC chemotaxis. Can inhibit the growth or viability of normal cells CC but not transformed cells when is overexpressed (By similarity). CC {ECO:0000250|UniProtKB:O35793, ECO:0000250|UniProtKB:O70326, CC ECO:0000269|PubMed:27036124}. CC -!- SUBUNIT: Homodimer; can also form homooligomers (PubMed:27036124). CC Interacts with BMP2; can form higher oligomers with BMP2 CC (PubMed:27036124). Interacts with SLIT1 and SLIT2 in a CC glycosylation-dependent manner (By similarity). CC {ECO:0000250|UniProtKB:O35793, ECO:0000269|PubMed:27036124}. CC -!- INTERACTION: CC P35968:KDR; NbExp=4; IntAct=EBI-944395, EBI-1005487; CC Q04917:YWHAH; NbExp=5; IntAct=EBI-944395, EBI-306940; CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=O60565-1; Sequence=Displayed; CC Name=2; CC IsoId=O60565-2; Sequence=VSP_013321; CC Note=No experimental confirmation available.; CC -!- TISSUE SPECIFICITY: Highly expressed in small intestine, fetal CC brain and colon. Expression is restricted to intestinal CC subepithelial myofibroblasts (ISEMFs) at the crypt base. In CC subjects with HMPS1, by contrast, GREM1 is expressed, not only in CC basal ISEMFs, but also at very high levels in epithelial cells CC (predominantly colonocytes), with expression extending most of the CC way up the sides of the crypt. Weakly expressed in brain, ovary, CC prostate, pancreas and skeletal muscle. In brain found in the CC region localized around the internal capsule in the large CC subcortical nuclei, including caudate, putamen, substantia nigra, CC thalamus and subthalamus. Predominantly expressed in normal cells CC including neurons, astrocytes and fibroblasts. CC {ECO:0000269|PubMed:10894942, ECO:0000269|PubMed:22561515}. CC -!- INDUCTION: By high glucose through TGFB1-mediated pathways in CC mesangial cell. Down-regulated in tumor cell lines. CC {ECO:0000269|PubMed:10744662, ECO:0000269|PubMed:10894942}. CC -!- DISEASE: Polyposis syndrome, mixed hereditary 1 (HMPS1) CC [MIM:601228]: A disease characterized by apparent autosomal CC dominant inheritance of multiple types of colorectal polyp, with CC colorectal carcinoma occurring in a high proportion of affected CC individuals. Patients can develop polyps of multiple and mixed CC morphologies, including serrated lesions, Peutz-Jeghers polyps, CC juvenile polyps, conventional adenomas and colorectal carcinoma in CC the absence of any identifiable extra-colonic features. CC {ECO:0000269|PubMed:22561515}. Note=The disease is caused by CC mutations affecting the gene represented in this entry. HMPS1 is CC caused by a duplication spanning the 3' end of the SCG5 gene and a CC region upstream of the GREM1 locus. This duplication is associated CC with increased allele-specific GREM1 expression that may cause CC reduced bone morphogenetic protein (BMP) pathway activity. This CC mechanism also underlies tumorigenesis in juvenile polyposis of CC the large bowel (PubMed:22561515). {ECO:0000269|PubMed:22561515}. CC -!- SIMILARITY: Belongs to the DAN family. {ECO:0000305}. CC ----------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC ----------------------------------------------------------------------- DR EMBL; AF045800; AAC39725.1; -; mRNA. DR EMBL; AF110137; AAF06677.1; -; mRNA. DR EMBL; AF154054; AAG23891.1; -; mRNA. DR EMBL; AB032372; BAA84462.1; -; Genomic_DNA. DR EMBL; AY232290; AAP69985.1; -; mRNA. DR EMBL; AK095890; BAC04643.1; -; mRNA. DR EMBL; BC069525; AAH69525.1; -; mRNA. DR EMBL; BC093778; AAH93778.1; -; mRNA. DR EMBL; BC101611; AAI01612.1; -; mRNA. DR CCDS; CCDS10029.1; -. [O60565-1] DR CCDS; CCDS53927.1; -. [O60565-2] DR RefSeq; NP_001178252.1; NM_001191323.1. [O60565-2] DR RefSeq; NP_037504.1; NM_013372.6. [O60565-1] DR UniGene; Hs.40098; -. DR PDB; 5AEJ; X-ray; 1.90 A; A/B/C/D=72-184. DR PDBsum; 5AEJ; -. DR ProteinModelPortal; O60565; -. DR SMR; O60565; -. DR IntAct; O60565; 8. DR MINT; O60565; -. DR STRING; 9606.ENSP00000300177; -. DR iPTMnet; O60565; -. DR PhosphoSitePlus; O60565; -. DR BioMuta; GREM1; -. DR jPOST; O60565; -. DR MaxQB; O60565; -. DR PaxDb; O60565; -. DR PeptideAtlas; O60565; -. DR PRIDE; O60565; -. DR ProteomicsDB; 49469; -. DR ProteomicsDB; 49470; -. [O60565-2] DR DNASU; 26585; -. DR Ensembl; ENST00000560830; ENSP00000453141; ENSG00000166923. [O60565-2] DR Ensembl; ENST00000622074; ENSP00000478319; ENSG00000166923. [O60565-1] DR Ensembl; ENST00000632478; ENSP00000488158; ENSG00000282046. [O60565-2] DR Ensembl; ENST00000632802; ENSP00000488588; ENSG00000282046. [O60565-1] DR GeneID; 26585; -. DR KEGG; hsa:26585; -. DR UCSC; uc001zhe.3; human. [O60565-1] DR CTD; 26585; -. DR DisGeNET; 26585; -. DR EuPathDB; HostDB:ENSG00000166923.10; -. DR GeneCards; GREM1; -. DR HGNC; HGNC:2001; GREM1. DR HPA; HPA007526; -. DR MalaCards; GREM1; -. DR MIM; 601228; phenotype. DR MIM; 603054; gene. DR neXtProt; NX_O60565; -. DR OpenTargets; ENSG00000166923; -. DR Orphanet; 157794; Hereditary mixed polyposis syndrome. DR PharmGKB; PA26537; -. DR eggNOG; ENOG410IG3Z; Eukaryota. DR eggNOG; ENOG4111HEF; LUCA. DR GeneTree; ENSGT00940000154209; -. DR HOGENOM; HOG000237358; -. DR HOVERGEN; HBG051837; -. DR InParanoid; O60565; -. DR OMA; RVKECRC; -. DR OrthoDB; 1270652at2759; -. DR PhylomeDB; O60565; -. DR TreeFam; TF106445; -. DR ChiTaRS; GREM1; human. DR GenomeRNAi; 26585; -. DR PRO; PR:O60565; -. DR Proteomes; UP000005640; Chromosome 15. DR Bgee; ENSG00000166923; Expressed in 174 organ(s), highest expression level in mucosa of stomach. DR ExpressionAtlas; O60565; baseline and differential. DR Genevisible; O60565; HS. DR GO; GO:0009986; C:cell surface; IEA:Ensembl. DR GO; GO:0062023; C:collagen-containing extracellular matrix; HDA:BHF-UCL. DR GO; GO:0005615; C:extracellular space; NAS:BHF-UCL. DR GO; GO:0036122; F:BMP binding; IDA:UniProtKB. DR GO; GO:0005125; F:cytokine activity; IEA:UniProtKB-KW. DR GO; GO:0016015; F:morphogen activity; ISS:BHF-UCL. DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB. DR GO; GO:0048018; F:receptor ligand activity; ISS:BHF-UCL. DR GO; GO:0030297; F:transmembrane receptor protein tyrosine kinase activator activity; ISS:BHF-UCL. DR GO; GO:0043184; F:vascular endothelial growth factor receptor 2 binding; ISS:BHF-UCL. DR GO; GO:0006915; P:apoptotic process; IEA:Ensembl. DR GO; GO:0001658; P:branching involved in ureteric bud morphogenesis; IEA:Ensembl. DR GO; GO:0002042; P:cell migration involved in sprouting angiogenesis; ISS:BHF-UCL. DR GO; GO:0000902; P:cell morphogenesis; IDA:BHF-UCL. DR GO; GO:0007267; P:cell-cell signaling; IEA:Ensembl. DR GO; GO:0030199; P:collagen fibril organization; IMP:BHF-UCL. DR GO; GO:0048263; P:determination of dorsal identity; IMP:BHF-UCL. DR GO; GO:0030326; P:embryonic limb morphogenesis; IEA:Ensembl. DR GO; GO:0060173; P:limb development; IMP:AgBase. DR GO; GO:0003337; P:mesenchymal to epithelial transition involved in metanephros morphogenesis; IEA:Ensembl. DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:AgBase. DR GO; GO:0030514; P:negative regulation of BMP signaling pathway; IDA:BHF-UCL. DR GO; GO:0030502; P:negative regulation of bone mineralization; IMP:BHF-UCL. DR GO; GO:1900158; P:negative regulation of bone mineralization involved in bone maturation; IMP:BHF-UCL. DR GO; GO:0046851; P:negative regulation of bone remodeling; IMP:BHF-UCL. DR GO; GO:1900155; P:negative regulation of bone trabecula formation; IMP:BHF-UCL. DR GO; GO:0090191; P:negative regulation of branching involved in ureteric bud morphogenesis; IEA:Ensembl. DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IDA:BHF-UCL. DR GO; GO:0030308; P:negative regulation of cell growth; IEA:Ensembl. DR GO; GO:0032331; P:negative regulation of chondrocyte differentiation; IMP:AgBase. DR GO; GO:0090027; P:negative regulation of monocyte chemotaxis; ISS:BHF-UCL. DR GO; GO:0045668; P:negative regulation of osteoblast differentiation; IMP:UniProtKB. DR GO; GO:0033689; P:negative regulation of osteoblast proliferation; IMP:BHF-UCL. DR GO; GO:0090291; P:negative regulation of osteoclast proliferation; IMP:BHF-UCL. DR GO; GO:0060394; P:negative regulation of pathway-restricted SMAD protein phosphorylation; IDA:BHF-UCL. DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IEA:Ensembl. DR GO; GO:0045766; P:positive regulation of angiogenesis; IEA:Ensembl. DR GO; GO:0090190; P:positive regulation of branching involved in ureteric bud morphogenesis; IEA:Ensembl. DR GO; GO:2000727; P:positive regulation of cardiac muscle cell differentiation; ISS:BHF-UCL. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:BHF-UCL. DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IEA:Ensembl. DR GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; IEA:Ensembl. DR GO; GO:1900086; P:positive regulation of peptidyl-tyrosine autophosphorylation; ISS:BHF-UCL. DR GO; GO:0002092; P:positive regulation of receptor internalization; ISS:BHF-UCL. DR GO; GO:2000273; P:positive regulation of signaling receptor activity; ISS:BHF-UCL. DR GO; GO:0051973; P:positive regulation of telomerase activity; IDA:BHF-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:BHF-UCL. DR GO; GO:0003257; P:positive regulation of transcription from RNA polymerase II promoter involved in myocardial precursor cell differentiation; ISS:BHF-UCL. DR GO; GO:0009954; P:proximal/distal pattern formation; IEA:Ensembl. DR GO; GO:0010717; P:regulation of epithelial to mesenchymal transition; IMP:UniProtKB. DR GO; GO:0051893; P:regulation of focal adhesion assembly; IEA:Ensembl. DR GO; GO:0007165; P:signal transduction; ISS:BHF-UCL. DR GO; GO:0060676; P:ureteric bud formation; IEA:Ensembl. DR Gene3D; 2.10.90.10; -; 1. DR InterPro; IPR006207; Cys_knot_C. DR InterPro; IPR029034; Cystine-knot_cytokine. DR InterPro; IPR004133; DAN. DR InterPro; IPR017159; Gremlin-1/2. DR Pfam; PF03045; DAN; 1. DR PIRSF; PIRSF037254; Gremlin_precursor; 1. DR SMART; SM00041; CT; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Complete proteome; Cytokine; KW Direct protein sequencing; Disulfide bond; Glycoprotein; KW Reference proteome; Secreted; Signal. FT SIGNAL 1 24 {ECO:0000269|PubMed:15340161}. FT CHAIN 25 184 Gremlin-1. FT /FTId=PRO_0000006714. FT DOMAIN 94 184 CTCK. FT CARBOHYD 42 42 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT DISULFID 94 144 {ECO:0000244|PDB:5AEJ, FT ECO:0000269|PubMed:27036124}. FT DISULFID 108 158 {ECO:0000244|PDB:5AEJ, FT ECO:0000269|PubMed:27036124}. FT DISULFID 118 176 {ECO:0000244|PDB:5AEJ, FT ECO:0000269|PubMed:27036124}. FT DISULFID 122 178 {ECO:0000244|PDB:5AEJ, FT ECO:0000269|PubMed:27036124}. FT VAR_SEQ 39 79 Missing (in isoform 2). FT {ECO:0000303|PubMed:14702039}. FT /FTId=VSP_013321. FT STRAND 74 76 {ECO:0000244|PDB:5AEJ}. FT HELIX 77 86 {ECO:0000244|PDB:5AEJ}. FT TURN 87 89 {ECO:0000244|PDB:5AEJ}. FT STRAND 93 103 {ECO:0000244|PDB:5AEJ}. FT STRAND 111 131 {ECO:0000244|PDB:5AEJ}. FT STRAND 134 157 {ECO:0000244|PDB:5AEJ}. FT STRAND 161 180 {ECO:0000244|PDB:5AEJ}. FT STRAND 182 184 {ECO:0000244|PDB:5AEJ}. SQ SEQUENCE 184 AA; 20697 MW; 4B588598DE12C47E CRC64; MSRTAYTVGA LLLLLGTLLP AAEGKKKGSQ GAIPPPDKAQ HNDSEQTQSP QQPGSRNRGR GQGRGTAMPG EEVLESSQEA LHVTERKYLK RDWCKTQPLK QTIHEEGCNS RTIINRFCYG QCNSFYIPRH IRKEEGSFQS CSFCKPKKFT TMMVTLNCPE LQPPTKKKRV TRVKQCRCIS IDLD //