CTGF

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CTGF, also known as CCN2 or connective tissue growth factor,[1][2] is a matricellular protein of the CCN family of extracellular matrix-associated heparin-binding proteins (see also CCN intercellular signaling protein).[3][4][5] CTGF has important roles in many biological processes, including cell adhesion, migration, proliferation, angiogenesis, skeletal development, and tissue wound repair, and is critically involved in fibrotic disease and several forms of cancers.[1][2][6]

Structure and binding partners

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,[7][8][9] cell surface heparan sulfate proteoglycans (HSPGs),[10] LRPs,[11] and TrkA.[12] In addition, CTGF also binds growth factors and extracellular matrix proteins. The N-terminal half of CTGF interacts with aggrecan,[13] the TSR domain interacts with VEGF,[14] and the CT domain interacts with members of the TGF-β superfamily, fibronectin, perlecan, fibulin-1, slit, and mucins.[1][2]

Role in development

Knockout mice with the Ctgf gene disrupted die at birth due to respiratory stress as a result of severe chondrodysplasia.[15] 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.[16] CTGF is also important for pancreatic beta cell development,[17] and is critical for normal ovarian follicle development and ovulation.[18]

Clinical significance

CTGF is associated with wound healing and virtually all fibrotic pathology.[5][19] It is thought that CTGF can cooperate with TGF-β to induce sustained fibrosis[20] and to exacerbate extracellular matrix production in association other fibrosis-inducing conditions.[19] Overexpression of CTGF in fibroblasts promotes fibrosis in the dermis, kidney, and lung,[21] and deletion of Ctgf in fibroblasts and smooth muscle cells greatly reduces bleomycin-induced skin fibrosis.[22]

In addition to fibrosis, aberrant CTGF expression is also associated with many types of malignancies, diabetic nephropathy[23] 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.[1]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 Jun JI, Lau LF (December 2011). "Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets". Nat Rev Drug Discov. 10 (12): 945–63. doi:10.1038/nrd3599. PMC 3663145. PMID 22129992.
  2. ↑ 2.0 2.1 2.2 Hall-Glenn F, Lyons KM (October 2011). "Roles for CCN2 in normal physiological processes". Cell. Mol. Life Sci. 68 (19): 3209–17. doi:10.1007/s00018-011-0782-7. PMC 3670951. PMID 21858450.
  3. ↑ Chen CC, Lau LF (April 2009). "Functions and mechanisms of action of CCN matricellular proteins". Int. J. Biochem. Cell Biol. 41 (4): 771–83. doi:10.1016/j.biocel.2008.07.025. PMC 2668982. PMID 18775791.
  4. ↑ Holbourn KP, Acharya KR, Perbal B (October 2008). "The CCN family of proteins: structure-function relationships". Trends Biochem. Sci. 33 (10): 461–73. doi:10.1016/j.tibs.2008.07.006. PMC 2683937. PMID 18789696.
  5. ↑ 5.0 5.1 Leask 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. PMID 17130294.
  6. ↑ Kubota S, Takigawa M (August 2011). "The role of CCN2 in cartilage and bone development". J Cell Commun Signal. 5 (3): 209–17. doi:10.1007/s12079-011-0123-5. PMC 3145877. PMID 21484188.
  7. ↑ Babic AM, Chen CC, Lau LF (April 1999). "Fisp12/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin αvβ3, promotes endothelial cell survival, and induces angiogenesis in vivo". Mol. Cell. Biol. 19 (4): 2958–66. PMC 84090. PMID 10082563.
  8. ↑ 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. PMID 10446209.
  9. ↑ 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. PMID 12036876.
  10. ↑ 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. PMID 14684735.
  11. ↑ 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. PMID 11518710.
  12. ↑ 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. PMID 15601748.
  13. ↑ 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. PMID 19298220.
  14. ↑ 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. PMID 12114504.
  15. ↑ Ivkovic S, Yoon BS, Popoff SN, Safadi FF, Libuda DE, Stephenson RC, Daluiski A, Lyons KM (June 2003). "Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development". Development. 130 (12): 2779–91. doi:10.1242/dev.00505. PMC 3360973. PMID 12736220.
  16. ↑ Hall-Glenn F, De Young RA, Huang BL, van Handel B, Hofmann JJ, Chen TT, Choi A, Ong JR, Benya PD, Mikkola H, Iruela-Arispe ML, Lyons KM (2012). "CCN2/connective tissue growth factor is essential for pericyte adhesion and endothelial basement membrane formation during angiogenesis". PLoS ONE. 7 (2): e30562. doi:10.1371/journal.pone.0030562. PMC 3282727. PMID 22363445.
  17. ↑ Crawford LA, Guney MA, Oh YA, Deyoung RA, Valenzuela DM, Murphy AJ, Yancopoulos GD, Lyons KM, Brigstock DR, Economides A, Gannon M (March 2009). "Connective tissue growth factor (CTGF) inactivation leads to defects in islet cell lineage allocation and beta-cell proliferation during embryogenesis". Mol. Endocrinol. 23 (3): 324–36. doi:10.1210/me.2008-0045. PMC 2654514. PMID 19131512.
  18. ↑ Nagashima T, Kim J, Li Q, Lydon JP, DeMayo FJ, Lyons KM, Matzuk MM (October 2011). "Connective tissue growth factor is required for normal follicle development and ovulation". Mol. Endocrinol. 25 (10): 1740–59. doi:10.1210/me.2011-1045. PMC 3182424. PMID 21868453.
  19. ↑ 19.0 19.1 Brigstock DR (March 2010). "Connective tissue growth factor (CCN2, CTGF) and organ fibrosis: lessons from transgenic animals". J Cell Commun Signal. 4 (1): 1–4. doi:10.1007/s12079-009-0071-5. PMC 2821473. PMID 19798591.
  20. ↑ Mori T, Kawara S, Shinozaki M, Hayashi N, Kakinuma T, Igarashi A, Takigawa M, Nakanishi T, Takehara K (October 1999). "Role and interaction of connective tissue growth factor with transforming growth factor-beta in persistent fibrosis: A mouse fibrosis model". J. Cell. Physiol. 181 (1): 153–9. doi:10.1002/(SICI)1097-4652(199910)181:1<153::AID-JCP16>3.0.CO;2-K. PMID 10457363.
  21. ↑ Sonnylal S, Shi-Wen X, Leoni P, Naff K, Van Pelt CS, Nakamura H, Leask A, Abraham D, Bou-Gharios G, de Crombrugghe B (May 2010). "Selective expression of connective tissue growth factor in fibroblasts in vivo promotes systemic tissue fibrosis". Arthritis Rheum. 62 (5): 1523–32. doi:10.1002/art.27382. PMC 3866029. PMID 20213804.
  22. ↑ Liu S, Shi-wen X, Abraham DJ, Leask A (January 2011). "CCN2 is required for bleomycin-induced skin fibrosis in mice". Arthritis Rheum. 63 (1): 239–46. doi:10.1002/art.30074. PMID 20936632.
  23. ↑ Ellina O, Chatzigeorgiou A, Kouyanou S, et al. (January 2012). "Extracellular matrix-associated (GAGs, CTGF), angiogenic (VEGF) and inflammatory factors (MCP-1, CD40, IFN-γ) in type 1 diabetes mellitus nephropathy". Clin. Chem. Lab. Med. 50 (1): 167–74. doi:10.1515/cclm.2011.881. PMID 22505539.

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