Biology:CTGF

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A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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]

CTGF (CCN2) has recently been implicated in mood disorders, notably in the postpartum period; these effects may be mediated by its effects on myelination [24]

See also

  • Ctgf/hcs24 CAESAR
  • CYR61 (CCN1)

References

  1. ↑ 1.0 1.1 1.2 1.3 "Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets". Nat Rev Drug Discov 10 (12): 945–63. December 2011. doi:10.1038/nrd3599. PMID 22129992. 
  2. ↑ 2.0 2.1 2.2 "Roles for CCN2 in normal physiological processes". Cell. Mol. Life Sci. 68 (19): 3209–17. October 2011. doi:10.1007/s00018-011-0782-7. PMID 21858450. 
  3. ↑ "Functions and mechanisms of action of CCN matricellular proteins". Int. J. Biochem. Cell Biol. 41 (4): 771–83. April 2009. doi:10.1016/j.biocel.2008.07.025. PMID 18775791. 
  4. ↑ "The CCN family of proteins: structure-function relationships". Trends Biochem. Sci. 33 (10): 461–73. October 2008. doi:10.1016/j.tibs.2008.07.006. PMID 18789696. 
  5. ↑ 5.0 5.1 "All in the CCN family: essential matricellular signaling modulators emerge from the bunker". J. Cell Sci. 119 (Pt 23): 4803–10. December 2006. doi:10.1242/jcs.03270. PMID 17130294. 
  6. ↑ "The role of CCN2 in cartilage and bone development". J Cell Commun Signal 5 (3): 209–17. August 2011. doi:10.1007/s12079-011-0123-5. PMID 21484188. 
  7. ↑ "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. April 1999. doi:10.1128/mcb.19.4.2958. PMID 10082563. 
  8. ↑ "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. August 1999. doi:10.1074/jbc.274.34.24321. PMID 10446209. 
  9. ↑ "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. June 2002. doi:10.1182/blood.V99.12.4457. PMID 12036876. 
  10. ↑ "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. March 2004. doi:10.1074/jbc.M313204200. PMID 14684735. 
  11. ↑ "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. November 2001. doi:10.1074/jbc.M105180200. PMID 11518710. 
  12. ↑ "Connective tissue growth factor CCN2 interacts with and activates the tyrosine kinase receptor TrkA". J. Am. Soc. Nephrol. 16 (2): 340–51. February 2005. doi:10.1681/ASN.2003100905. PMID 15601748. http://jasn.asnjournals.org/content/16/2/340.full.pdf. 
  13. ↑ "N-terminal domains of CCN family 2/connective tissue growth factor bind to aggrecan". Biochem. J. 420 (3): 413–20. June 2009. doi:10.1042/BJ20081991. PMID 19298220. 
  14. ↑ "Matrix metalloproteinases cleave connective tissue growth factor and reactivate angiogenic activity of vascular endothelial growth factor 165". J. Biol. Chem. 277 (39): 36288–95. September 2002. doi:10.1074/jbc.M201674200. PMID 12114504. 
  15. ↑ "Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development". Development 130 (12): 2779–91. June 2003. doi:10.1242/dev.00505. PMID 12736220. 
  16. ↑ "CCN2/connective tissue growth factor is essential for pericyte adhesion and endothelial basement membrane formation during angiogenesis". PLOS ONE 7 (2): e30562. 2012. doi:10.1371/journal.pone.0030562. PMID 22363445. Bibcode: 2012PLoSO...730562H. 
  17. ↑ "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. March 2009. doi:10.1210/me.2008-0045. PMID 19131512. 
  18. ↑ "Connective tissue growth factor is required for normal follicle development and ovulation". Mol. Endocrinol. 25 (10): 1740–59. October 2011. doi:10.1210/me.2011-1045. 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. PMID 19798591. 
  20. ↑ "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. October 1999. doi:10.1002/(SICI)1097-4652(199910)181:1<153::AID-JCP16>3.0.CO;2-K. PMID 10457363. 
  21. ↑ "Selective expression of connective tissue growth factor in fibroblasts in vivo promotes systemic tissue fibrosis". Arthritis Rheum. 62 (5): 1523–32. May 2010. doi:10.1002/art.27382. PMID 20213804. 
  22. ↑ "CCN2 is required for bleomycin-induced skin fibrosis in mice". Arthritis Rheum. 63 (1): 239–46. January 2011. doi:10.1002/art.30074. PMID 20936632. 
  23. ↑ "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. January 2012. doi:10.1515/cclm.2011.881. PMID 22505539. 
  24. ↑ "An analysis of Cellular Communication Network Factor Proteins as candidate mediators of postpartum psychosis risk". Frontiers in Psychiatry 10: 876. Nov 2019. doi:10.3389/fpsyt.2019.00876. PMID 31849729. 

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