ID CYR61_HUMAN Reviewed; 381 AA. AC O00622; O14934; O43775; Q9BZL7; DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot. DT 01-JUL-1997, sequence version 1. DT 13-FEB-2019, entry version 173. DE RecName: Full=Protein CYR61; DE AltName: Full=CCN family member 1; DE AltName: Full=Cysteine-rich angiogenic inducer 61; DE AltName: Full=Insulin-like growth factor-binding protein 10; DE Short=IBP-10; DE Short=IGF-binding protein 10; DE Short=IGFBP-10; DE AltName: Full=Protein GIG1; DE Flags: Precursor; GN Name=CYR61; Synonyms=CCN1, GIG1, IGFBP10; 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]. RX PubMed=9135077; DOI=10.1038/sj.onc.1200986; RA Jay P., Berge-Lefranc J.-L., Marsollier C., Mejean C., Taviaux S., RA Berta P.; RT "The human growth factor-inducible immediate early gene, CYR61, maps RT to chromosome 1p."; RL Oncogene 14:1753-1757(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=9536281; DOI=10.1136/mp.50.6.310; RA Martinerie C., Viegas-Pequignot E., Nguyen V.C., Perbal B.; RT "Chromosomal mapping and expression of the human cyr61 gene in tumour RT cells from the nervous system."; RL Mol. Pathol. 50:310-316(1997). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=10852911; DOI=10.1074/jbc.M003053200; RA Albrecht C., von Der Kammer H., Mayhaus M., Klaudiny J., Schweizer M., RA Nitsch R.M.; RT "Muscarinic acetylcholine receptors induce the expression of the RT immediate early growth regulatory gene CYR61."; RL J. Biol. Chem. 275:28929-28936(2000). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Placenta; RA Kolesnikova T.V., Lau L.F.; RT "Human growth-factor inducible gene product CYR61, complete RT sequence."; RL Submitted (JUN-1997) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [MRNA]. RA Bi A.B., Yu L.; RT "Cloning of HumCyr61 gene expressing down-regulatedly in RT rhabdomyosarcoma."; RL Submitted (NOV-1997) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [MRNA]. RA Schuetze N., Lechner A., Groll C., Koehrle J., Jakob F.; RT "Regulation of hCYR61 by vitamin D, serum and cytokines in fetal human RT osteoblasts."; RL Submitted (JUL-1997) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=11810026; DOI=10.1007/BF02256579; RA Leng E., Malcolm T., Tai G., Estable M., Sadowski I.; RT "Organization and expression of the Cyr61 gene in normal human RT fibroblasts."; RL J. Biomed. Sci. 9:59-67(2002). RN [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT TRP-334. RG NIEHS SNPs program; RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Lung, Placenta, and Skin; 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 [10] RP FUNCTION IN WOUND HEALING. RX PubMed=11584015; DOI=10.1074/jbc.M107666200; RA Chen C.-C., Mo F.-E., Lau L.F.; RT "The angiogenic factor Cyr61 activates a genetic program for wound RT healing in human skin fibroblasts."; RL J. Biol. Chem. 276:47329-47337(2001). RN [11] RP INTERACTION WITH INTEGRIN ALPHA-V/BETA-3. RX PubMed=9446626; DOI=10.1074/jbc.273.5.3090; RA Kireeva M.L., Lam S.C., Lau L.F.; RT "Adhesion of human umbilical vein endothelial cells to the immediate- RT early gene product Cyr61 is mediated through integrin alphavbeta3."; RL J. Biol. Chem. 273:3090-3096(1998). RN [12] RP INTERACTION WITH INTEGRIN ALPHA-IIB/BETA-3. RX PubMed=10446209; DOI=10.1074/jbc.274.34.24321; RA Jedsadayanmata A., Chen C.-C., Kireeva M.L., Lau L.F., Lam S.C.; RT "Activation-dependent adhesion of human platelets to Cyr61 and RT Fisp12/mouse connective tissue growth factor is mediated through RT integrin alpha(IIb)beta(3)."; RL J. Biol. Chem. 274:24321-24327(1999). RN [13] RP INTERACTION WITH INTEGRIN ALPHA-6/BETA-1. RX PubMed=10821835; DOI=10.1074/jbc.M003040200; RA Chen N., Chen C.-C., Lau L.F.; RT "Adhesion of human skin fibroblasts to Cyr61 is mediated through RT integrin alpha 6beta 1 and cell surface heparan sulfate RT proteoglycans."; RL J. Biol. Chem. 275:24953-24961(2000). RN [14] RP INTERACTION WITH INTEGRIN ALPHA-V/BETA-6. RX PubMed=11287419; DOI=10.1074/jbc.M100978200; RA Grzeszkiewicz T.M., Kirschling D.J., Chen N., Lau L.F.; RT "CYR61 stimulates human skin fibroblast migration through Integrin RT alpha vbeta 5 and enhances mitogenesis through integrin alpha vbeta 3, RT independent of its carboxyl-terminal domain."; RL J. Biol. Chem. 276:21943-21950(2001). RN [15] RP PHOSPHORYLATION AT SER-188. RX PubMed=26091039; DOI=10.1016/j.cell.2015.05.028; RA Tagliabracci V.S., Wiley S.E., Guo X., Kinch L.N., Durrant E., Wen J., RA Xiao J., Cui J., Nguyen K.B., Engel J.L., Coon J.J., Grishin N., RA Pinna L.A., Pagliarini D.J., Dixon J.E.; RT "A single kinase generates the majority of the secreted RT phosphoproteome."; RL Cell 161:1619-1632(2015). CC -!- FUNCTION: Promotes cell proliferation, chemotaxis, angiogenesis CC and cell adhesion. Appears to play a role in wound healing by up- CC regulating, in skin fibroblasts, the expression of a number of CC genes involved in angiogenesis, inflammation and matrix remodeling CC including VEGA-A, VEGA-C, MMP1, MMP3, TIMP1, uPA, PAI-1 and CC integrins alpha-3 and alpha-5. CYR61-mediated gene regulation is CC dependent on heparin-binding. Down-regulates the expression of CC alpha-1 and alpha-2 subunits of collagen type-1. Promotes cell CC adhesion and adhesive signaling through integrin alpha-6/beta-1, CC cell migration through integrin alpha-v/beta-5 and cell CC proliferation through integrin alpha-v/beta-3. CC {ECO:0000269|PubMed:11584015}. CC -!- SUBUNIT: Interaction with integrins is heparin- and cell-type- CC dependent and promotes cell adhesion. In skin fibroblasts it binds CC ITGA6/ITGB1, in endothelial cells, binds ITGAV/ITGB3 and in CC platelets, ITGA2B/ITGB3. Binds, in vitro, ITGAV/ITGB5. CC -!- SUBCELLULAR LOCATION: Secreted. CC -!- SIMILARITY: Belongs to the CCN family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/cyr61/"; 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; U62015; AAB58319.1; -; mRNA. DR EMBL; Y11307; CAA72167.1; -; mRNA. DR EMBL; Y12084; CAA72802.1; -; mRNA. DR EMBL; AF003594; AAB61240.1; -; mRNA. DR EMBL; AF031385; AAB84227.1; -; mRNA. DR EMBL; Z98053; CAB10848.1; -; mRNA. DR EMBL; AF307860; AAG59863.1; -; Genomic_DNA. DR EMBL; AY443495; AAR05446.1; -; Genomic_DNA. DR EMBL; BC001271; AAH01271.1; -; mRNA. DR EMBL; BC009199; AAH09199.1; -; mRNA. DR EMBL; BC016952; AAH16952.1; -; mRNA. DR CCDS; CCDS706.1; -. DR RefSeq; NP_001545.2; NM_001554.4. DR UniGene; Hs.8867; -. DR PDB; 4D0Z; X-ray; 2.20 A; X/Y=24-29. DR PDB; 4D11; X-ray; 2.85 A; L/O/P/X/Z=24-29. DR PDBsum; 4D0Z; -. DR PDBsum; 4D11; -. DR ProteinModelPortal; O00622; -. DR SMR; O00622; -. DR BioGrid; 109712; 11. DR CORUM; O00622; -. DR IntAct; O00622; 9. DR STRING; 9606.ENSP00000398736; -. DR iPTMnet; O00622; -. DR PhosphoSitePlus; O00622; -. DR BioMuta; CYR61; -. DR EPD; O00622; -. DR jPOST; O00622; -. DR PaxDb; O00622; -. DR PeptideAtlas; O00622; -. DR PRIDE; O00622; -. DR ProteomicsDB; 47995; -. DR DNASU; 3491; -. DR Ensembl; ENST00000451137; ENSP00000398736; ENSG00000142871. DR GeneID; 3491; -. DR KEGG; hsa:3491; -. DR CTD; 3491; -. DR DisGeNET; 3491; -. DR EuPathDB; HostDB:ENSG00000142871.15; -. DR GeneCards; CYR61; -. DR HGNC; HGNC:2654; CYR61. DR HPA; HPA029853; -. DR MIM; 602369; gene. DR neXtProt; NX_O00622; -. DR OpenTargets; ENSG00000142871; -. DR PharmGKB; PA27126; -. DR eggNOG; ENOG410IIY0; Eukaryota. DR eggNOG; ENOG41119KZ; LUCA. DR GeneTree; ENSGT00940000155151; -. DR HOGENOM; HOG000231462; -. DR HOVERGEN; HBG000635; -. DR InParanoid; O00622; -. DR KO; K06829; -. DR OMA; FTYAGCS; -. DR OrthoDB; 999958at2759; -. DR PhylomeDB; O00622; -. DR TreeFam; TF326070; -. DR Reactome; R-HSA-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs). DR Reactome; R-HSA-8957275; Post-translational protein phosphorylation. DR ChiTaRS; CYR61; human. DR GeneWiki; CYR61; -. DR GenomeRNAi; 3491; -. DR PMAP-CutDB; O00622; -. DR PRO; PR:O00622; -. DR Proteomes; UP000005640; Chromosome 1. DR Bgee; ENSG00000142871; Expressed in 232 organ(s), highest expression level in thyroid gland. DR Genevisible; O00622; HS. DR GO; GO:0062023; C:collagen-containing extracellular matrix; HDA:UniProtKB. DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome. DR GO; GO:0031012; C:extracellular matrix; IBA:GO_Central. DR GO; GO:0050840; F:extracellular matrix binding; IEA:Ensembl. DR GO; GO:0005201; F:extracellular matrix structural constituent; HDA:BHF-UCL. DR GO; GO:0008201; F:heparin binding; IBA:GO_Central. DR GO; GO:0005520; F:insulin-like growth factor binding; IEA:InterPro. DR GO; GO:0005178; F:integrin binding; IBA:GO_Central. DR GO; GO:0003278; P:apoptotic process involved in heart morphogenesis; IEA:Ensembl. DR GO; GO:0060413; P:atrial septum morphogenesis; IEA:Ensembl. DR GO; GO:0003181; P:atrioventricular valve morphogenesis; IEA:Ensembl. DR GO; GO:0007155; P:cell adhesion; IBA:GO_Central. DR GO; GO:0044267; P:cellular protein metabolic process; TAS:Reactome. DR GO; GO:0006935; P:chemotaxis; IEA:UniProtKB-KW. DR GO; GO:0060591; P:chondroblast differentiation; IEA:Ensembl. DR GO; GO:0060710; P:chorio-allantoic fusion; IEA:Ensembl. DR GO; GO:0030198; P:extracellular matrix organization; IEA:Ensembl. DR GO; GO:0002041; P:intussusceptive angiogenesis; IEA:Ensembl. DR GO; GO:0060716; P:labyrinthine layer blood vessel development; IEA:Ensembl. DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl. DR GO; GO:0060548; P:negative regulation of cell death; IBA:GO_Central. DR GO; GO:0001649; P:osteoblast differentiation; IEA:Ensembl. DR GO; GO:0030513; P:positive regulation of BMP signaling pathway; IGI:BHF-UCL. DR GO; GO:0030501; P:positive regulation of bone mineralization; IDA:BHF-UCL. DR GO; GO:0061036; P:positive regulation of cartilage development; IEA:Ensembl. DR GO; GO:0030335; P:positive regulation of cell migration; IDA:BHF-UCL. DR GO; GO:0010811; P:positive regulation of cell-substrate adhesion; IEA:Ensembl. DR GO; GO:2000304; P:positive regulation of ceramide biosynthetic process; IEA:Ensembl. DR GO; GO:0043280; P:positive regulation of cysteine-type endopeptidase activity involved in apoptotic process; IEA:Ensembl. DR GO; GO:0045669; P:positive regulation of osteoblast differentiation; IDA:BHF-UCL. DR GO; GO:0033690; P:positive regulation of osteoblast proliferation; IDA:BHF-UCL. DR GO; GO:0010518; P:positive regulation of phospholipase activity; IEA:Ensembl. DR GO; GO:0045860; P:positive regulation of protein kinase activity; IDA:BHF-UCL. DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IDA:BHF-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:BHF-UCL. DR GO; GO:0043687; P:post-translational protein modification; TAS:Reactome. DR GO; GO:0072593; P:reactive oxygen species metabolic process; IEA:Ensembl. DR GO; GO:0070372; P:regulation of ERK1 and ERK2 cascade; IDA:BHF-UCL. DR GO; GO:0003281; P:ventricular septum development; IEA:Ensembl. DR GO; GO:0044319; P:wound healing, spreading of cells; IDA:BHF-UCL. DR Gene3D; 2.20.100.10; -; 1. DR InterPro; IPR006207; Cys_knot_C. DR InterPro; IPR006208; Glyco_hormone_CN. DR InterPro; IPR009030; Growth_fac_rcpt_cys_sf. DR InterPro; IPR000867; IGFBP-like. DR InterPro; IPR012395; IGFBP_CNN. DR InterPro; IPR017891; Insulin_GF-bd_Cys-rich_CS. DR InterPro; IPR000884; TSP1_rpt. DR InterPro; IPR036383; TSP1_rpt_sf. DR InterPro; IPR001007; VWF_dom. DR Pfam; PF00007; Cys_knot; 1. DR Pfam; PF00219; IGFBP; 1. DR Pfam; PF00093; VWC; 1. DR PIRSF; PIRSF036495; IGFBP_rP_CNN; 1. DR SMART; SM00041; CT; 1. DR SMART; SM00121; IB; 1. DR SMART; SM00209; TSP1; 1. DR SMART; SM00214; VWC; 1. DR SUPFAM; SSF57184; SSF57184; 1. DR SUPFAM; SSF82895; SSF82895; 1. DR PROSITE; PS01185; CTCK_1; 1. DR PROSITE; PS01225; CTCK_2; 1. DR PROSITE; PS00222; IGFBP_N_1; 1. DR PROSITE; PS51323; IGFBP_N_2; 1. DR PROSITE; PS50092; TSP1; 1. DR PROSITE; PS01208; VWFC_1; 1. DR PROSITE; PS50184; VWFC_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Cell adhesion; Chemotaxis; Complete proteome; KW Disulfide bond; Growth factor binding; Heparin-binding; KW Phosphoprotein; Polymorphism; Reference proteome; Secreted; Signal. FT SIGNAL 1 24 {ECO:0000255}. FT CHAIN 25 381 Protein CYR61. FT /FTId=PRO_0000014398. FT DOMAIN 25 94 IGFBP N-terminal. {ECO:0000255|PROSITE- FT ProRule:PRU00653}. FT DOMAIN 98 164 VWFC. {ECO:0000255|PROSITE- FT ProRule:PRU00220}. FT DOMAIN 228 273 TSP type-1. {ECO:0000255|PROSITE- FT ProRule:PRU00210}. FT DOMAIN 286 360 CTCK. {ECO:0000255|PROSITE- FT ProRule:PRU00039}. FT REGION 279 315 Heparin-binding. {ECO:0000250}. FT MOD_RES 188 188 Phosphoserine; by FAM20C. FT {ECO:0000269|PubMed:26091039}. FT DISULFID 286 323 {ECO:0000250}. FT DISULFID 303 337 {ECO:0000250}. FT DISULFID 314 353 {ECO:0000250}. FT DISULFID 317 355 {ECO:0000250}. FT DISULFID 322 359 {ECO:0000250}. FT VARIANT 334 334 R -> W (in dbSNP:rs9658587). FT {ECO:0000269|Ref.8}. FT /FTId=VAR_018934. FT CONFLICT 165 165 E -> Q (in Ref. 2; CAA72167). FT {ECO:0000305}. FT CONFLICT 210 210 L -> I (in Ref. 5; AAB84227). FT {ECO:0000305}. FT CONFLICT 220 220 L -> R (in Ref. 5; AAB84227). FT {ECO:0000305}. FT CONFLICT 369 369 F -> L (in Ref. 7; AAG59863). FT {ECO:0000305}. SQ SEQUENCE 381 AA; 42027 MW; FC0BD39C078CA0B1 CRC64; MSSRIARALA LVVTLLHLTR LALSTCPAAC HCPLEAPKCA PGVGLVRDGC GCCKVCAKQL NEDCSKTQPC DHTKGLECNF GASSTALKGI CRAQSEGRPC EYNSRIYQNG ESFQPNCKHQ CTCIDGAVGC IPLCPQELSL PNLGCPNPRL VKVTGQCCEE WVCDEDSIKD PMEDQDGLLG KELGFDASEV ELTRNNELIA VGKGSSLKRL PVFGMEPRIL YNPLQGQKCI VQTTSWSQCS KTCGTGISTR VTNDNPECRL VKETRICEVR PCGQPVYSSL KKGKKCSKTK KSPEPVRFTY AGCLSVKKYR PKYCGSCVDG RCCTPQLTRT VKMRFRCEDG ETFSKNVMMI QSCKCNYNCP HANEAAFPFY RLFNDIHKFR D //