Members of the CCN protein family, including CTGF, are structurally characterized by having four conserved, cysteine-rich domains. These domains are, from N- to C-termini, the insulin-like growth factor binding protein (IGFBP) domain, the von Willebrand type C repeats (vWC) domain, the thrombospondin type 1 repeat (TSR) domain, and a C-terminal domain (CT) with a cysteine knot motif. CTGF exerts its functions by binding to various cell surface receptors in a context-dependent manner, including integrin receptors, cell surface heparan sulfate proteoglycans (HSPGs),LRPs, and TrkA. In addition, CTGF also binds growth factors and extracellular matrix proteins. The N-terminal half of CTGF interacts with aggrecan, the TSR domain interacts with VEGF, and the CT domain interacts with members of the TGF-β superfamily, fibronectin, perlecan, fibulin-1, slit, and mucins.
Knockout mice with the Ctgf gene disrupted die at birth due to respiratory stress as a result of severe chondrodysplasia. Ctgf-null mice also show defects in angiogenesis, with impaired interaction between endothelial cells and pericytes and collagen IV deficiency in the endothelial basement membrane. CTGF is also important for pancreatic beta cell development, and is critical for normal ovarian follicle development and ovulation.
CTGF is associated with wound healing and virtually all fibrotic pathology. It is thought that CTGF can cooperate with TGF-β to induce sustained fibrosis and to exacerbate extracellular matrix production in association other fibrosis-inducing conditions. Overexpression of CTGF in fibroblasts promotes fibrosis in the dermis, kidney, and lung, and deletion of Ctgf in fibroblasts and smooth muscle cells greatly reduces bleomycin-induced skin fibrosis.
In addition to fibrosis, aberrant CTGF expression is also associated with many types of malignancies, diabetic nephropathy and retinopathy, arthritis, and cardiovascular diseases. Several clinical trials are now ongoing that investigate the therapeutic value of targeting CTGF in fibrosis, diabetic nephropathy, and pancreatic cancer.
^ abLeask A, Abraham DJ (December 2006). "All in the CCN family: essential matricellular signaling modulators emerge from the bunker". J. Cell. Sci. 119 (Pt 23): 4803–10. doi:10.1242/jcs.03270. PMID17130294.
^Jedsadayanmata A, Chen CC, Kireeva ML, Lau LF, Lam SC (August 1999). "Activation-dependent adhesion of human platelets to Cyr61 and Fisp12/mouse connective tissue growth factor is mediated through integrin αIIbβ3". J. Biol. Chem. 274 (34): 24321–7. doi:10.1074/jbc.274.34.24321. PMID10446209.
^Schober JM, Chen N, Grzeszkiewicz TM, Jovanovic I, Emeson EE, Ugarova TP, Ye RD, Lau LF, Lam SC (June 2002). "Identification of integrin alpha(M)beta(2) as an adhesion receptor on peripheral blood monocytes for Cyr61 (CCN1) and connective tissue growth factor (CCN2): immediate-early gene products expressed in atherosclerotic lesions". Blood. 99 (12): 4457–65. doi:10.1182/blood.V99.12.4457. PMID12036876.
^Gao R, Brigstock DR (March 2004). "Connective tissue growth factor (CCN2) induces adhesion of rat activated hepatic stellate cells by binding of its C-terminal domain to integrin α(v)β(3) and heparan sulfate proteoglycan". J. Biol. Chem. 279 (10): 8848–55. doi:10.1074/jbc.M313204200. PMID14684735.
^Segarini PR, Nesbitt JE, Li D, Hays LG, Yates JR, Carmichael DF (November 2001). "The low density lipoprotein receptor-related protein/alpha2-macroglobulin receptor is a receptor for connective tissue growth factor". J. Biol. Chem. 276 (44): 40659–67. doi:10.1074/jbc.M105180200. PMID11518710.
^Wahab NA, Weston BS, Mason RM (February 2005). "Connective tissue growth factor CCN2 interacts with and activates the tyrosine kinase receptor TrkA". J. Am. Soc. Nephrol. 16 (2): 340–51. doi:10.1681/ASN.2003100905. PMID15601748.
^Aoyama E, Hattori T, Hoshijima M, Araki D, Nishida T, Kubota S, Takigawa M (June 2009). "N-terminal domains of CCN family 2/connective tissue growth factor bind to aggrecan". Biochem. J. 420 (3): 413–20. doi:10.1042/BJ20081991. PMID19298220.
^Hashimoto G, Inoki I, Fujii Y, Aoki T, Ikeda E, Okada Y (September 2002). "Matrix metalloproteinases cleave connective tissue growth factor and reactivate angiogenic activity of vascular endothelial growth factor 165". J. Biol. Chem. 277 (39): 36288–95. doi:10.1074/jbc.M201674200. PMID12114504.