Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Satoshi KubotaEmail author
  • Masaharu TakigawaEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_559


Historical Background

In the early 1990s, three gene products with novel structural similarity were identified. The first member was discovered as a factor induced upon growth factor stimulation and was designated as cysteine-rich 61 (Cyr61), based on its structural characteristics. The second member was purified as a platelet growth factor-related molecule with a mitogenic effect on fibroblasts and thus, it was initially named connective tissue growth factor (CTGF). Subsequently, a gene with structural similarity to the above two genes was found to be overexpressed in nephroblastomas, which provided the name nephroblastoma-overexpressed (NOV) gene to this third member. Based on these findings, the acronym of the names of these three genes,...

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  1. Brigstock DR, Goldschmeding R, Katsube KI, Lam SC, Lau LF, Lyons K, Naus C, Perbal B, Riser B, Takigawa M, Yeger H. Proposal for a unified CCN nomenclature. Mol Pathol. 2003;56:127–8.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Chen CC, Kim KH, Lau LF. The matricellular protein CCN1 suppresses hepatocarcinogenesis by inhibiting compensatory proliferation. Oncogene. 2016;35:1314–23.PubMedCrossRefGoogle Scholar
  3. Chen CC, Lau LF. Functions and mechanisms of action of CCN matricellular proteins. Int J Biochem Cell Biol. 2009;41:771–83.PubMedCrossRefGoogle Scholar
  4. Chijiiwa M, Mochizuki S, Kimura T, Abe H, Tanaka Y, Fujii Y, Shimizu H, Enomoto H, Toyama Y, Okada Y. CCN1 (Cyr61) is overexpressed in human osteoarthritic cartilage and inhibits ADAMTS-4 (aggrecanase 1) activity. Arthritis Rheum. 2015;67:1557–67.CrossRefGoogle Scholar
  5. Chintala H, Krupska I, Yan L, Lau L, Grant M, Chaqour B. The matricellular protein CCN1 controls retinal angiogenesis by targeting VEGF, Src homology 2 domain phosphatase-1 and Notch signaling. Development. 2015;142:2364–74.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Dotterweich J, Ebert R, Kraus S, Tower RJ, Jakob F, Schütze N. Mesenchymal stem cell contact promotes CCN1 splicing and transcription in myeloma cells. Cell Commun Signal. 2014;12:36.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Du J, Klein JD, Hassounah F, Zhang J, Zhang C, Wang XH. Aging increases CCN1 expression leading to muscle senescence. Am J Phys Cell Physiol. 2014;306:C28–36.CrossRefGoogle Scholar
  8. Fang F, Zhao WY, Li RK, Yang XM, Li J, Ao JP, Jiang SH, Kong FZ, Tu L, Zhuang C, Qin WX, He P, Zhang WM, Cao H, Zhang ZG. Silencing of WISP3 suppresses gastric cancer cell proliferation and metastasis and inhibits Wnt/β-catenin signaling. Int J Clin Exp Pathol. 2014;7:6447–61.PubMedPubMedCentralGoogle Scholar
  9. Habel N, Vilalta M, Bawa O, Opolon P, Blanco J, Fromigué O. Cyr61 silencing reduces vascularization and dissemination of osteosarcoma tumors. Oncogene. 2015;34:3207–13.PubMedCrossRefGoogle Scholar
  10. Haque I, De A, Majumder M, Mehta S, McGregor D, Banerjee SK, Van Veldhuizen P, Banerjee S. The matricellular protein CCN1/Cyr61 is a critical regulator of Sonic Hedgehog in pancreatic carcinogenesis. J Biol Chem. 2012;287:38569–79.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Hara C, Kubota S, Nishida T, Hiasa M, Hattori T, Aoyama E, Moriyama Y, Kamioka H, Takigawa M. Involvement of multiple CCN family members in platelets that support regeneration of joint tissues. Mod Rheumatol. 2016;21:1–10. in pressGoogle Scholar
  12. Henshaw FR, Boughton P, Lo L, McLennan SV, Twigg SM. Topically applied connective tissue growth factor/CCN2 improves diabetic preclinical cutaneous wound healing: potential role for CTGF in human diabetic foot ulcer healing. J Diabetes Res. 2015;2015:236238.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Holbourn KP, Acharya KR, Perbal B. The CCN family of proteins: structure-function relationships. Trends Biochem Sci. 2008;33:461–73.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Ishida J, Kurozumi K, Ichikawa T, Otani Y, Onishi M, Fujii K, Shimazu Y, Oka T, Shimizu T, Date I. Evaluation of extracellular matrix protein CCN1 as a prognostic factor for glioblastoma. Brain Tumor Pathol. 2015;32:245–52.PubMedCrossRefGoogle Scholar
  15. Jeong D, Lee MA, Li Y, Yang DK, Kho C, Oh JG, Hong G, Lee A, Song MH, LaRocca TJ, Chen J, Liang L, Mitsuyama S, D’Escamard V, Kovacic JC, Kwak TH, Hajjar RJ, Park WJ. Matricellular protein CCN5 reverses established cardiac fibrosis. J Am Coll Cardiol. 2016;67:1556–68.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Jiang N, Wang Y, Yu Z, Hu L, Liu C, Gao X, Zheng S. WISP3 (CCN6) regulates milk protein synthesis and cell growth through mTOR signaling in dairy cow mammary epithelial cells. DNA Cell Biol. 2015;34:524–33.PubMedCrossRefGoogle Scholar
  17. Johnson SK, Stewart JP, Bam R, Qu P, Barlogie B, van Rhee F, Shaughnessy Jr JD, Epstein J, Yaccoby S. CYR61/CCN1 overexpression in the myeloma microenvironment is associated with superior survival and reduced bone disease. Blood. 2014;124:2051–60.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Jun JI, Kim KH, Lau LF. The matricellular protein CCN1 mediates neutrophil efferocytosis in cutaneous wound healing. Nat Commun. 2015;6:7386.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Jun JI, Lau LF. Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets. Nat Rev Drug Discov. 2011;10:945–63.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Katsube K, Sakamoto K, Tamamura Y, Yamaguchi A. Role of CCN, a vertebrate specific gene family, in development. Develop Growth Differ. 2009;51:55–67.CrossRefGoogle Scholar
  21. Kipkeew F, Kirsch M, Klein D, Wuelling M, Winterhager E, Gellhaus A. CCN1 (CYR61) and CCN3 (NOV) signaling drives human trophoblast cells into senescence and stimulates migration properties. Cell Adhes Migr. 2016;10:163–78.CrossRefGoogle Scholar
  22. Koga K, Yokoi H, Mori K, Kasahara M, Kuwabara T, Imamaki H, Ishii A, Mori KP, Kato Y, Ohno S, Toda N, Saleem MA, Sugawara A, Nakao K, Yanagita M, Mukoyama M. MicroRNA-26a inhibits TGF-β-induced extracellular matrix protein expression in podocytes by targeting CTGF and is downregulated in diabetic nephropathy. Diabetologia. 2015;58:2169–80.PubMedCrossRefGoogle Scholar
  23. Kubota S, Takigawa M. Role of CCN2/CTGF/Hcs24 in Bone Growth. Int Rev Cytol. 2007;257:1–41.PubMedCrossRefGoogle Scholar
  24. Kubota S, Takigawa M. The CCN family acting throughout the body: recent research developments. Biomol Concept. 2013;4:477–94.CrossRefGoogle Scholar
  25. Kubota S, Takigawa M. Cellular and molecular actions of CCN2/CTGF and its role under physiological and pathological conditions. Clin Sci (Lond). 2015;128:181–96.CrossRefGoogle Scholar
  26. Kurundkar AR, Kurundkar D, Rangarajan S, Locy ML, Zhou Y, Liu RM, Zmijewski J, Thannickal VJ. The matricellular protein CCN1 enhances TGF-β1/SMAD3-dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury. FASEB J. 2016;30:2135–50.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Leask A, Abraham DJ. All in the CCN family: essential matricellular signaling modulators emerge from the bunker. J Cell Sci. 2006;119:4803–10.PubMedCrossRefGoogle Scholar
  28. Lemaire R, Farina G, Bayle J, Dimarzio M, Pendergrass SA, Milano A, Whitfield ML, Lafyatis R. Antagonistic effect of the matricellular signaling protein CCN3 on TGF-beta- and Wnt-mediated fibrillinogenesis in systemic sclerosis and Marfan syndrome. J Invest Dermatol. 2010;130:1514–23.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Li H, Sun X, Zhang J, Sun Y, Huo R, Li H, Zhai T, Shen B, Zhang M, Li N. Paeoniflorin ameliorates symptoms of experimental Sjogren’s syndrome associated with down-regulating Cyr61 expression. Int Immunopharmacol. 2016;30:27–35.PubMedCrossRefGoogle Scholar
  30. Li X, Chen Y, Ye W, Tao X, Zhu J, Wu S, Lou L. Blockade of CCN4 attenuates CCl4-induced liver fibrosis. Arch Med Sci. 2015;11:647–53.PubMedPubMedCentralCrossRefGoogle Scholar
  31. McCallum L, Irvine AE. CCN3 – A key regulator of the hematopoietic compartment. Blood Rev. 2009;23:79–85.PubMedCrossRefGoogle Scholar
  32. Mendes FA, Coelho Aguiar JM, Kahn SA, Reis AH, Dubois LG, Romão LF, Ferreira LS, Chneiweiss H, Moura Neto V, Abreu JG. Connective-tissue growth factor (CTGF/CCN2) induces astrogenesis and fibronectin expression of embryonic neural cells in vitro. PLoS One. 2015;10:e0133689.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Moon HG, Kim SH, Gao J, Quan T, Qin Z, Osorio JC, Rosas IO, Wu M, Tesfaigzi Y, Jin Y. CCN1 secretion and cleavage regulate the lung epithelial cell functions after cigarette smoke. Am J Phys Lung Cell Mol Phys. 2014;307:L326–37.Google Scholar
  34. Mu S, Kang B, Zeng W, Sun Y, Yang F. MicroRNA-143-3p inhibits hyperplastic scar formation by targeting connective tissue growth factor CTGF/CCN2 via the Akt/mTOR pathway. Mol Cell Biochem. 2016;416:99–108.PubMedCrossRefGoogle Scholar
  35. Myers RB, Wei L, Castellot Jr JJ. The matricellular protein CCN5 regulates podosome function via interaction with integrin αvβ 3. J Cell Commun Signal. 2014;8:135–46.PubMedPubMedCentralCrossRefGoogle Scholar
  36. Niu CC, Zhao C, Yang Z, Zhang XL, Pan J, Zhao C, Si WK. Inhibiting CCN1 blocks AML cell growth by disrupting the MEK/ERK pathway. Cancer Cell Int. 2014;14:74.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Oh CD, Yasuda H, Zhao W, Henry SP, Zhang Z, Xue M, de Crombrugghe B, Chen D. SOX9 directly regulates CTGF/CCN2 transcription in growth plate chondrocytes and in nucleus pulposus cells of intervertebral disc. Sci Rep. 2016;6:29916.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Ono M, Inkson CA, Kilts TM, Young MF. WISP-1/CCN4 regulates osteogenesis by enhancing BMP-2 activity. J Bone Miner Res. 2011;26:193–208.PubMedCrossRefGoogle Scholar
  39. Pakradouni J, Le Goff W, Calmel C, Antoine B, Villard E, Frisdal E, Abifadel M, Tordjman J, Poitou C, Bonnefont-Rousselot D, Bittar R, Bruckert E, Clément K, Fève B, Martinerie C, Guérin M. Plasma NOV/CCN3 levels are closely associated with obesity in patients with metabolic disorders. PLoS One. 2013;8:e66788.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Perbal A, Takigawa M, Perbal B. CCN proteins in health and disease. Dordrecht: Springer; 2010.CrossRefGoogle Scholar
  41. Perbal B, Takigawa M. CCN proteins: a new family of cell growth and differentiation regulators. London: Imperial college Press; 2005.CrossRefGoogle Scholar
  42. Perrot A, Schmitt KR, Roth EM, Stiller B, Posch MG, Browne EN, Timmann C, Horstmann RD, Berger F, Özcelik C. CCN1 mutation is associated with atrial septal defect. Pediatr Cardiol. 2015;36:295–9.PubMedCrossRefGoogle Scholar
  43. Piszczatowski RT, Rafferty BJ, Rozado A, Parziale JV, Lents NH. Myeloid zinc finger 1 (MZF-1) regulates expression of the CCN2/CTGF and CCN3/NOV genes in the hematopoietic compartment. J Cell Physiol. 2015;230:2634–9.PubMedCrossRefGoogle Scholar
  44. Qin Z, Robichaud P, He T, Fisher GJ, Voorhees JJ, Quan T. Oxidant exposure induces cysteine-rich protein 61 (CCN1) via c-Jun/AP-1 to reduce collagen expression in human dermal fibroblasts. PLoS One. 2014;9:e115402.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Riser BL, Najmabadi F, Garchow K, Barnes JL, Peterson DR, Sukowski EJ. Treatment with the matricellular protein CCN3 blocks and/or reverses fibrosis development in obesity with diabetic nephropathy. Am J Pathol. 2014;184:2908–21.PubMedCrossRefGoogle Scholar
  46. Sar JI, Yang CJ, Tsai YS, Deng YT, Chen HM, Chang HH, Liu CM. Sphingosine-1-phosphate stimulated connective tissue growth factor expression in human buccal fibroblasts: Inhibition by epigallocatechin-3-gallate. J Formos Med Assoc. 2015;114:860–4.PubMedCrossRefGoogle Scholar
  47. Song WW, McLennan SV, Tam C, Williams PF, Baxter RC, Twigg SM. CCN2 requires TGF-β signalling to regulate CCAAT/enhancer binding proteins and inhibit fat cell differentiation. J Cell Commun Signal. 2015;9:27–36.PubMedCrossRefGoogle Scholar
  48. Sumiyoshi K, Kubota S, Ohgawara T, Kawata K, Abd El Kader TA, Nishida T, Ikeda N, Shimo T, Yamashiro T, Takigawa M. Novel role of miR-181a in cartilage metabolism. J Cell Biochem. 2013;114:2094–100.PubMedCrossRefGoogle Scholar
  49. Sun Y, Zhang J, Zhou Z, Wu P, Huo R, Wang B, Shen Z, Li H, Zhai T, Shen B, Chen X, Li N. CCN1, a pro-Inflammatory factor, aggravates psoriasis skin lesions by promoting keratinocyte activation. J Invest Dermatol. 2015;135:2666–75.PubMedCrossRefGoogle Scholar
  50. Takigawa M. CCN2: a master regulator of the genesis of bone and cartilage. J Cell Commun Signal. 2013;7:191–201.PubMedPubMedCentralCrossRefGoogle Scholar
  51. Wells JE, Howlett M, Halse HM, Heng J, Ford J, Cheung LC, Samuels AL, Crook M, Charles AK, Cole CH, Kees UR. High expression of connective tissue growth factor accelerates dissemination of leukaemia. Oncogene. 2016;35:4591–600.PubMedCrossRefGoogle Scholar
  52. Williams H, Mill CA, Monk BA, Hulin-Curtis S, Johnson JL, George SJ. Wnt2 and WISP-1/CCN4 induce intimal thickening via promotion of smooth muscle cell migration. Arterioscler Thromb Vasc Biol. 2016;36:1417–24.PubMedCrossRefGoogle Scholar
  53. Xu X, Dai H, Geng J, Wan X, Huang X, Li F, Jiang D, Wang C. Rapamycin increases CCN2 expression of lung fibroblasts via phosphoinositide 3-kinase. Lab Investig. 2015;95:846–59.PubMedCrossRefGoogle Scholar
  54. Yan L, Lee S, Lazzaro DR, Aranda J, Grant MB, Chaqour B. Single and compound knock-outs of microRNA (miRNA)-155 and its angiogenic gene target CCN1 in mice alter vascular and neovascular growth in the retina via resident microglia. J Biol Chem. 2015;290:23264–81.PubMedPubMedCentralCrossRefGoogle Scholar
  55. Yoshioka Y, Ono M, Maeda A, Kilts TM, Hara ES, Khattab H, Ueda J, Aoyama E, Oohashi T, Takigawa M, Young MF, Kuboki T. CCN4/WISP-1 positively regulates chondrogenesis by controlling TGF-β3 function. Bone. 2016;83:162–70.PubMedCrossRefGoogle Scholar
  56. Yu ZL, Li DQ, Huang XY, Xing X, Yu RQ, Li Z, Li ZB. Lysophosphatidic acid upregulates connective tissue growth factor expression in osteoblasts through the GPCR/PKC and PKA pathways. Int J Mol Med. 2016;37:468–74.PubMedCrossRefGoogle Scholar
  57. Yuda A, Maeda H, Fujii S, Monnouchi S, Yamamoto N, Wada N, Koori K, Tomokiyo A, Hamano S, Hasegawa D, Akamine A. Effect of CTGF/CCN2 on osteo/cementoblastic and fibroblastic differentiation of a human periodontal ligament stem/progenitor cell line. J Cell Physiol. 2015;230:150–9.PubMedCrossRefGoogle Scholar
  58. Zhang P, Cui W, Hankey KG, Gibbs AM, Smith CP, Taylor-Howell C, Kearney SR, MacVittie TJ. Increased expression of connective tissue growth factor (CTGF) in multiple organs after exposure of non-human primates (NHP) to lethal doses of radiation. Health Phys. 2015;109:374–90.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Zhang T, Zhao C, Luo L, Xiang J, Sun Q, Cheng J, Chen D. The clinical and prognostic significance of CCN3 expression in patients with cervical cancer. Adv Clin Exp Med. 2013;22:839–45.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular DentistryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
  2. 2.Advanced Research Center for Oral and Craniofacial SciencesOkayama University Dental School/Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan