CCN1_HUMAN
ID CCN1_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 03-AUG-2022, entry version 192.
DE RecName: Full=CCN family member 1 {ECO:0000305};
DE AltName: Full=Cellular communication network factor 1 {ECO:0000312|HGNC:HGNC:2654};
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 CYR61;
DE AltName: Full=Protein GIG1;
DE Flags: Precursor;
GN Name=CCN1 {ECO:0000312|HGNC:HGNC:2654};
GN Synonyms=CYR61 {ECO:0000303|PubMed:9135077}, GIG1, IGFBP10;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC 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 to
RT 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 cells
RT 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 immediate
RT 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 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 project:
RT 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 healing
RT 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-early
RT 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 Fisp12/mouse
RT connective tissue growth factor is mediated through integrin
RT 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 integrin
RT alpha 6beta 1 and cell surface heparan sulfate 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 alpha
RT 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 phosphoproteome.";
RL Cell 161:1619-1632(2015).
CC -!- FUNCTION: Promotes cell proliferation, chemotaxis, angiogenesis and
CC cell adhesion. Appears to play a role in wound healing by up-
CC regulating, in skin fibroblasts, the expression of a number of genes
CC involved in angiogenesis, inflammation and matrix remodeling including
CC VEGA-A, VEGA-C, MMP1, MMP3, TIMP1, uPA, PAI-1 and integrins alpha-3 and
CC alpha-5. CCN1-mediated gene regulation is dependent on heparin-binding.
CC Down-regulates the expression of alpha-1 and alpha-2 subunits of
CC collagen type-1. Promotes cell adhesion and adhesive signaling through
CC integrin alpha-6/beta-1, cell migration through integrin alpha-v/beta-5
CC and cell proliferation through integrin alpha-v/beta-3.
CC {ECO:0000269|PubMed:11584015}.
CC -!- SUBUNIT: Interaction with integrins is heparin- and cell-type-dependent
CC and promotes cell adhesion. In skin fibroblasts it binds ITGA6/ITGB1,
CC in endothelial cells, binds ITGAV/ITGB3 and in platelets, ITGA2B/ITGB3.
CC Binds, in vitro, ITGAV/ITGB5. {ECO:0000269|PubMed:10446209,
CC ECO:0000269|PubMed:10821835, ECO:0000269|PubMed:11287419,
CC ECO:0000269|PubMed:9446626}.
CC -!- INTERACTION:
CC O00622; O60906: SMPD2; NbExp=3; IntAct=EBI-1237454, EBI-12828299;
CC O00622; Q9UHD9: UBQLN2; NbExp=3; IntAct=EBI-1237454, EBI-947187;
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/";
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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 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 AlphaFoldDB; O00622; -.
DR SMR; O00622; -.
DR BioGRID; 109712; 29.
DR CORUM; O00622; -.
DR IntAct; O00622; 14.
DR MINT; O00622; -.
DR STRING; 9606.ENSP00000398736; -.
DR iPTMnet; O00622; -.
DR PhosphoSitePlus; O00622; -.
DR BioMuta; CYR61; -.
DR EPD; O00622; -.
DR jPOST; O00622; -.
DR MassIVE; O00622; -.
DR PaxDb; O00622; -.
DR PeptideAtlas; O00622; -.
DR PRIDE; O00622; -.
DR ProteomicsDB; 47995; -.
DR ABCD; O00622; 1 sequenced antibody.
DR Antibodypedia; 19796; 600 antibodies from 38 providers.
DR DNASU; 3491; -.
DR Ensembl; ENST00000451137.7; ENSP00000398736.2; ENSG00000142871.18.
DR GeneID; 3491; -.
DR KEGG; hsa:3491; -.
DR MANE-Select; ENST00000451137.7; ENSP00000398736.2; NM_001554.5; NP_001545.2.
DR CTD; 3491; -.
DR DisGeNET; 3491; -.
DR GeneCards; CCN1; -.
DR HGNC; HGNC:2654; CCN1.
DR HPA; ENSG00000142871; Low tissue specificity.
DR MIM; 602369; gene.
DR neXtProt; NX_O00622; -.
DR OpenTargets; ENSG00000142871; -.
DR PharmGKB; PA27126; -.
DR VEuPathDB; HostDB:ENSG00000142871; -.
DR eggNOG; ENOG502QQQQ; Eukaryota.
DR GeneTree; ENSGT00940000155151; -.
DR HOGENOM; CLU_063247_1_0_1; -.
DR InParanoid; O00622; -.
DR OMA; CPLEVPK; -.
DR OrthoDB; 999958at2759; -.
DR PhylomeDB; O00622; -.
DR TreeFam; TF326070; -.
DR PathwayCommons; O00622; -.
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 SignaLink; O00622; -.
DR BioGRID-ORCS; 3491; 11 hits in 1083 CRISPR screens.
DR ChiTaRS; CYR61; human.
DR GeneWiki; CYR61; -.
DR GenomeRNAi; 3491; -.
DR Pharos; O00622; Tbio.
DR PRO; PR:O00622; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; O00622; protein.
DR Bgee; ENSG00000142871; Expressed in left uterine tube and 205 other tissues.
DR ExpressionAtlas; O00622; baseline and differential.
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:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0050840; F:extracellular matrix binding; IEA:Ensembl.
DR GO; GO:0019838; F:growth factor binding; IEA:UniProtKB-KW.
DR GO; GO:0008201; F:heparin binding; IBA:GO_Central.
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: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:0043065; P:positive regulation of apoptotic process; 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: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:0007165; P:signal transduction; IBA:GO_Central.
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; IPR043973; TSP1_CCN.
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; PF19035; TSP1_CCN; 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; Disulfide bond;
KW Growth factor binding; Heparin-binding; Phosphoprotein; Reference proteome;
KW Secreted; Signal.
FT SIGNAL 1..24
FT /evidence="ECO:0000255"
FT CHAIN 25..381
FT /note="CCN family member 1"
FT /id="PRO_0000014398"
FT DOMAIN 25..94
FT /note="IGFBP N-terminal"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00653"
FT DOMAIN 98..164
FT /note="VWFC"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00220"
FT DOMAIN 228..273
FT /note="TSP type-1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DOMAIN 286..360
FT /note="CTCK"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00039"
FT REGION 279..315
FT /note="Heparin-binding"
FT /evidence="ECO:0000250|UniProtKB:P18406"
FT MOD_RES 188
FT /note="Phosphoserine; by FAM20C"
FT /evidence="ECO:0000269|PubMed:26091039"
FT DISULFID 286..323
FT /evidence="ECO:0000250"
FT DISULFID 303..337
FT /evidence="ECO:0000250"
FT DISULFID 314..353
FT /evidence="ECO:0000250"
FT DISULFID 317..355
FT /evidence="ECO:0000250"
FT DISULFID 322..359
FT /evidence="ECO:0000250"
FT VARIANT 334
FT /note="R -> W (in dbSNP:rs9658587)"
FT /evidence="ECO:0000269|Ref.8"
FT /id="VAR_018934"
FT CONFLICT 165
FT /note="E -> Q (in Ref. 2; CAA72167)"
FT /evidence="ECO:0000305"
FT CONFLICT 210
FT /note="L -> I (in Ref. 5; AAB84227)"
FT /evidence="ECO:0000305"
FT CONFLICT 220
FT /note="L -> R (in Ref. 5; AAB84227)"
FT /evidence="ECO:0000305"
FT CONFLICT 369
FT /note="F -> L (in Ref. 7; AAG59863)"
FT /evidence="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
