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CCN2
Identifiers
Aliases	CCN2, HCS24, IGFBP8, NOV2, connective tissue growth factor, cellular communication network factor 2, CTGF
External IDs	OMIM: 121009; MGI: 95537; HomoloGene: 1431; GeneCards: CCN2; OMA:CCN2 - orthologs
Gene location (Human) Chr. Chromosome 6 (human) Band 6q23.2 Start 131,948,176 bp End 131,951,372 bp
Gene location (Mouse) Chr. Chromosome 10 (mouse) Band 10 A4|10 11.84 cM Start 24,471,340 bp End 24,474,581 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in tibia thoracic aorta ascending aorta smooth muscle tissue gastric mucosa right coronary artery gallbladder Descending thoracic aorta left coronary artery tendon of biceps brachii Top expressed in tunica media of zone of aorta stroma of bone marrow ascending aorta semi-lunar valve ankle joint aortic valve skin of external ear ankle ciliary body epithelium of lens More reference expression data BioGPS More reference expression data
Gene ontology Molecular function fibronectin binding insulin-like growth factor binding protein C-terminus binding protein binding growth factor activity integrin binding heparin binding Cellular component cytosol cis-Golgi network plasma membrane extracellular region cell cortex perinuclear region of cytoplasm extracellular space extracellular matrix collagen-containing extracellular matrix Biological process positive regulation of collagen biosynthetic process positive regulation of cell activation cell differentiation regulation of chondrocyte differentiation response to amino acid response to estradiol response to anoxia intracellular signal transduction response to mineralocorticoid response to fatty acid DNA biosynthetic process positive regulation of cell death ossification response to organic cyclic compound extracellular matrix constituent secretion lung development response to peptide hormone positive regulation of G0 to G1 transition positive regulation of JNK cascade response to glucose negative regulation of gene expression reactive oxygen species metabolic process fibroblast growth factor receptor signaling pathway positive regulation of cysteine-type endopeptidase activity involved in apoptotic process positive regulation of gene expression connective tissue development response to wounding regulation of cell growth angiogenesis tissue homeostasis positive regulation of cell population proliferation chondrocyte proliferation positive regulation of cell differentiation epidermis development positive regulation of cardiac muscle contraction positive regulation of ERK1 and ERK2 cascade positive regulation of protein phosphorylation integrin-mediated signaling pathway transcription initiation from RNA polymerase II promoter cell-matrix adhesion cell migration cartilage condensation positive regulation of stress fiber assembly ageing cell adhesion cell-cell signaling negative regulation of cell death regulation of signaling receptor activity Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1490 14219 Ensembl ENSG00000118523 ENSMUSG00000019997 UniProt P29279 P29268 RefSeq (mRNA) NM_001901 NM_010217 RefSeq (protein) NP_001892 NP_034347 Location (UCSC) Chr 6: 131.95 – 131.95 Mb Chr 10: 24.47 – 24.47 Mb PubMed search
Wikidata
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CTGF, also known as CCN2 or connective tissue growth factor, is a matricellular protein of the CCN family of extracellular matrix-associated heparin-binding proteins (see also CCN intercellular signaling protein). 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.

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, 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.

Role in development

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.

Clinical significance

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.

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

See also

• Ctgf/hcs24 CAESAR
• CYR61 (CCN1)

References

1. ^ GRCh38: Ensembl release 89: ENSG00000118523 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000019997 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. ^ 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.
6. ^ 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.
7. 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.
8. 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.
9. ^ 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.
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11. Babic AM, Chen CC, Lau LF (April 1999). "Fisp12/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin α_vβ₃, promotes endothelial cell survival, and induces angiogenesis in vivo". Mol. Cell. Biol. 19 (4): 2958–66. doi:10.1128/mcb.19.4.2958. PMC 84090. PMID 10082563.
12. 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 α_IIbβ₃". J. Biol. Chem. 274 (34): 24321–7. doi:10.1074/jbc.274.34.24321. PMID 10446209.
13. 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.
14. 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.
15. 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.
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17. 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.
18. 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.
19. 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.
20. 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. Bibcode:2012PLoSO...730562H. doi:10.1371/journal.pone.0030562. PMC 3282727. PMID 22363445.
21. 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.
22. 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.
23. ^ 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.
24. 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. S2CID 21284888.
25. 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.
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27. 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. S2CID 26045011.
28. Davies W (Nov 2019). "An analysis of Cellular Communication Network Factor Proteins as candidate mediators of postpartum psychosis risk". Frontiers in Psychiatry. 10: 876. doi:10.3389/fpsyt.2019.00876. PMC 6901936. PMID 31849729.

External links

• Human CTGF genome location and CTGF gene details page in the UCSC Genome Browser.

• Genes on human chromosome 6
• Growth factors
• CCN proteins