CYR61

4D0Z, 4D11349116007ENSG00000142871ENSMUSG00000028195O00622P18406NM_001554NM_010516NP_001545NP_034646Cysteine-rich angiogenic inducer 61 (CYR61) or CCN family member 1 (CCN1), is a matricellular protein that in humans is encoded by the CYR61 gene. Cysteine-rich angiogenic inducer 61 (CYR61) or CCN family member 1 (CCN1), is a matricellular protein that in humans is encoded by the CYR61 gene. CYR61 is a secreted, extracellular matrix (ECM)-associated signaling protein of the CCN family (CCN intercellular signaling protein). CYR61 is capable of regulating a broad range of cellular activities, including cell adhesion, migration, proliferation, differentiation, apoptosis, and senescence through interaction with cell surface integrin receptors and heparan sulfate proteoglycans. During embryonic development, CYR61 is critical for cardiac septal morphogenesis, blood vessel formation in placenta, and vascular integrity. In adulthood CYR61 plays important roles in inflammation and tissue repair, and is associated with diseases related to chronic inflammation, including rheumatoid arthritis, atherosclerosis, diabetes-related nephropathy and retinopathy, and many different forms of cancers. CYR61 was first identified as a protein encoded by a serum-inducible gene in mouse fibroblasts. Other highly conserved homologs were later identified to comprise the CCN protein family (CCN intercellular signaling protein). The CCN acronym is derived from the first three members of the family identified, namely CYR61 (CCN1), CTGF (connective tissue growth factor, or CCN2), and NOV (nephroblastoma overexpressed, or CCN3). These proteins, together with WISP1 (CCN4), WISP2 (CCN5), and WISP3 (CCN6) comprise the six members of the family in vertebrates and have been renamed CCN1-6 in order of their discovery by international consensus. CCN proteins function as matricellular proteins, which are extracellular matrix proteins that play regulatory roles, particularly in the context of wound repair. CYR61 is located at human chromosome 1p22.3, whereas the mouse Cyr61 gene is located at chromosome 3, 72.9cM. The mouse CYR61 coding region spans ~3.2 Kb, containing 5 exons interspaced with 4 introns. The first exon encodes 5’-UTR sequence and the first several amino acids in the secretory signal peptide. The remaining four exons each encode a distinct CCN1 domain. The 5th exon also contains the 3’-UTR sequences, which has 5 copies of AU-rich elements that confers a short mRNA half life, and a mir-155 target site.The CYR61 promoter is a TATA box containing promoter, with binding sites for many transcription factors including AP1, ATF, E2F, HNF3b, NF1, NFκB, SP1, and SRF, and 2 poly(CA) stretches that may form Z-DNA structure. Transcriptional activation of CYR61 is exquisitely sensitive to a wide range of environmental perturbations, including stimulation by platelet-derived growth factor and basic fibroblast growth factor, transforming growth factor β1 (TGF-β1), growth hormone, the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), cAMP, vitamin D3, estrogen and tamoxifen, angiotensin II, hypoxia, UV light, and mechanical stretch. Full-length CYR61 protein contains 381 amino acids with an N-terminal secretory signal peptide followed by four structurally distinct domains. The four CYR61 domains are, from N- to C-termini, the insulin-like growth factor binding protein (IGFBP) domain, von Willebrand type C repeats (vWC) domain, thrombospondin type 1 repeat domain (TSR), and the C-terminal (CT) domain that contains a cysteine-knot motif. CCN1 has unusually high cysteine residue content (10% or 38 in total). The number and spacing of cysteine residues are completely conserved among CYR61 (CCN1), CTGF (CCN2), NOV (CCN3), and WISP-1 (CCN4), and are largely conserved with WISP-2 (CCN5), which lacks precisely the CT domain, and WISP3 (CCN6), which lacks 4 cysteines in the vWC domain. CYR61 is glycosylated, although the regulation and function of gylcosylation are unknown. CYR61 binds directly to various integrin receptors in a cell type-dependent manner, including integrin αvβ3 in endothelial cells, α6β1 and heparan sulfate proteoglycans (HSPGs) in fibroblasts and smooth muscle cells αIIbβ3 in activated platelets, αMβ2 in monocytes and macrophages, and αDβ2 in macrophage foam cells. Where examined, syndecan-4 has been identified as the HSPG critical for CCN1 functions. The CYR61 binding sites for some of these integrins have been mapped (Figure 1). Due to the cell type specificity of integrin expression, CYR61 acts through distinct integrins to mediate specific functions in different types of cells. For example, CYR61 induces angiogenic functions in endothelial cells through αvβ3, and in fibroblasts promotes cellular senescence and enables TNFα to induce apoptosis through binding to α6β1-HSPGs. However, CYR61 supports cell adhesion through all of the integrins identified above. As a cell adhesive substrate, CYR61 induces the activation of focal adhesion kinase, paxillin, RAC, and sustained activation of MAPK/ERK1-2. In macrophages, CYR61 also activates the transcription factor NFκB and stimulates M1 polarization. CYR61 activates Akt signaling in thymic epithelial cells, promoting their proliferation and thus thymic size growth. CYR61 has potent angiogenic activity upon endothelial cells and induces neovascularization, first demonstrated in a corneal micropocket implant assay and subsequently confirmed in a rabbit ischemic hindlimb model. CYR61 also accelerates and promotes the chondrogenic differentiation of mouse limb bud mesenchymal cells, and stimulates osteoblast differentiation but inhibits osteoclastogenesis. Cyr61 is a strong inducer of reactive oxygen species accumulation in fibroblastic cells, and this activity underlies many CYR61-induced apoptosis and senescence. CYR61 is able to support cell adhesion, stimulate cell migration, promote growth factor-induced cell proliferation and differentiation in some cell types, promote apoptosis in synergy with TNF family cytokines, and induce cellular senescence in fibroblasts. During embryo development in mice, Cyr61 is highly expressed in the cardiovascular, skeletal, and neuronal systems. Cyr61 knockout mice are embryonic lethal due to defects in cardiac septal morphogenesis, deficient blood vessel formation in placenta, and compromised vascular integrity. In Xenopus laevis, Cyr61 is required for normal gastrulation and modulation of Wnt signaling. CYR61 is highly expressed at sites of inflammation and wound repair, and is associated with diseases involving chronic inflammation and tissue injury.