Skip to main content
Log in

CCN proteins: A centralized communication network

  • Review
  • Published:
Journal of Cell Communication and Signaling Aims and scope

Abstract

The CCN family of proteins includes six members presently known as CCN1, CCN2, CCN3, CCN4, CCN5 and CCN6. These proteins were originally designated CYR61, CTGF, NOV, and WISP-1, WISP-2, WISP-3. Although these proteins share a significant amount of structural features and a partial identity with other large families of regulatory proteins, they exhibit different biological functions. A critical examination of the progress made over the past two decades, since the first CCN proteins were discovered brings me to the conclusion that most of our present knowledge regarding the functions of these proteins was predicted very early after their discovery. In an effort to point out some of the gaps that prevent us to reach a comprehensive view of the functional interactions between CCN proteins, it is necessary to reconsider carefully data that was already published and put aside, either because the scientific community was not ready to accept them, or because they were not fitting with the « consensus » when they were published. This review article points to avenues that were not attracting the attention that they deserved. However, it is quite obvious that the six members of this unique family of tetra-modular proteins must act in concert, either simultaneously or sequentially, on the same sites or at different times in the life of living organisms. A better understanding of the spatio-temporal regulation of CCN proteins expression requires considering the family as such, not as a set of single proteins related only by their name. As proposed in this review, there is enough convincing pieces of evidence, at the present time, in favor of these proteins playing a role in the coordination of multiple signaling pathways, and constituting a Centralized Communication Network. Deciphering the hierarchy of regulatory circuits involved in this complex system is an important challenge for the near future. In this article, I would like to briefly review the concept of a CCN family of proteins and critically examine the progress made over the past 10 years in the understanding of their biological functions and involvement in both normal and pathological processes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Notes

  1. For example, who still remembers the pivotal contribution of JC Chermann in the identification of the HIV as AIDS associated virus see « http://nobelchermann.com/ »

References

  • Arnott JA, Lambi AG, Mundy C, Hendesi H, Pixley RA, Owen TA, Safadi FF, Popoff SN (2011) The role of connective tissue growth factor (CTGF/CCN2) in skeletogenesis. Crit Rev Eukaryot Gene Expr 21(1):43–69

    Article  PubMed  CAS  Google Scholar 

  • Ayer-Lelievre C, Brigstock D, Lau L, Pennica D, Perbal B, Yeger H (2001) Report and abstracts on the first international workshop on the CCN family of genes. Mol Pathol 54(2):105–120

    Article  PubMed  CAS  Google Scholar 

  • Ball DK, Surveyor GA, Diehl JR, Steffen CL, Uzumcu M, Mirando MA, Brigstock DR (1998) Characterization of 16- to 20-kilodalton (kDa) connective tissue growth factors (CTGFs) and demonstration of proteolytic activity for 38-kDa CTGF in pig uterine luminal flushings. Biol Reprod 59(4):828–835

    Article  PubMed  CAS  Google Scholar 

  • Benini S, Perbal B, Zambelli D, Colombo MP, Manara MC, Serra M, Parenza M, Martinez V, Picci P, Scotlandi K (2005) In Ewing’s sarcoma CCN3(NOV) inhibits proliferation while promoting migration and invasion of the same cell type. Oncogene 24(27):4349–4361

    Article  PubMed  CAS  Google Scholar 

  • Bleau AM, Planque N, Perbal B (2005) CCN proteins and cancer: two to tango. Front Biosci 10:998–1009

    Article  PubMed  CAS  Google Scholar 

  • Bleau AM, Planque N, Lazar N, Zambelli D, Ori A, Quan T, Fisher G, Scotlandi K, Perbal B (2007) Antiproliferative activity of CCN3: involvement of the C-terminal module and post-translational regulation. J Cell Biochem 101(6):1475–1491

    Article  PubMed  CAS  Google Scholar 

  • Blom IE, Goldschmeding R, Leask A (2002) Gene regulation of connective tissue growth factor: new targets for antifibrotic therapy? Matrix Biol 21(6):473–482

    Article  PubMed  CAS  Google Scholar 

  • Bork P (1993) The modular architecture of a new family of growth regulators related to connective tissue growth factor. FEBS Lett 327:125–130

    Article  PubMed  CAS  Google Scholar 

  • Bradham DM, Igarashi A, Potter RL, Grotendorst GR (1991) Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10. J Cell Biol 114:1285–1294

    Article  PubMed  CAS  Google Scholar 

  • Brigstock DR (1999) The connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed (CCN) family. Endocr Rev 20:189–206, Review

    Article  PubMed  CAS  Google Scholar 

  • Brigstock DR (2003) The CCN family: a new stimulus package. J Endocrinol 178(2):169–175

    Article  PubMed  CAS  Google Scholar 

  • Brigstock DR, Goldschmeding R, Katsube KI, Lam SCT, Lau LF, Lyons K, Naus C, Perbal B, Riser B, Takigawa M, Yeger H (2003) Proposal for a unified CCN nomenclature. J Clin Pathol Mol Pathol 56:127–128

    Article  CAS  Google Scholar 

  • Chaqour B, Goppelt-Struebe M (2006) Mechanical regulation of the Cyr61/CCN1 and CTGF/CCN2 proteins. FEBS J 273(16):3639–3649

    Article  PubMed  CAS  Google Scholar 

  • Fukunaga-Kalabis M, Martinez G, Liu ZJ, Kalabis J, Mrass P, Weninger W, Firth SM, Planque N, Perbal B, Herlyn M (2006) CCN3 controls 3D spatial localization of melanocytes in the human skin through DDR1. J Cell Biol 175(4):563–569

    Article  PubMed  CAS  Google Scholar 

  • Fukunaga-Kalabis M, Martinez G, Telson SM, Liu ZJ, Balint K, Juhasz I, Elder DE, Perbal B, Herlyn M (2008) Downregulation of CCN3 expression as a potential mechanism for melanoma progression. Oncogene 27(18):2552–2560

    Article  PubMed  CAS  Google Scholar 

  • Gellhaus A, Dong X, Propson S, Maass K, Klein-Hitpass L, Kibschull M, Traub O, Willecke K, Perbal B, Lye SJ, Winterhager E (2004) Connexin43 interacts with NOV: a possible mechanism for negative regulation of cell growth in choriocarcinoma cells. J Biol Chem 279(35):36931–36942

    Article  PubMed  CAS  Google Scholar 

  • Gupta N, Wang H, McLeod TL, Naus CC, Kyurkchiev S, Advani S, Yu J, Perbal B, Weichselbaum RR (2001) Inhibition of glioma cell growth and tumorigenic potential by CCN3 (NOV). Mol Pathol 54(5):293–299

    Article  PubMed  CAS  Google Scholar 

  • Hall-Glenn F, Lyons KM (2011) Roles for CCN2 in normal physiological processes. Cell Mol Life Sci 68(19):3209–3217

    Article  PubMed  CAS  Google Scholar 

  • Hirschfeld M, van Hausen A, Bettendorf H, Jäger M, Stickeler E (2009) Alternative splicing of Cyr61 is regulated by hypoxia and significantly changed in breast cancer. Cancer Res 69(5):2082–2090

    Article  PubMed  CAS  Google Scholar 

  • Holbourn KP, Acharya KR, Perbal B (2008) The CCN family of proteins: structure-function relationships. Trends Biochem Sci 33(10):461–473

    Article  PubMed  CAS  Google Scholar 

  • Joliot V, Martinerie C, Dambrine G, Plassiart G, Brisac M, Crochet J, Perbal B (1992) Proviral rearrangements and overexpression of a new cellular gene (nov) in myeloblastosis-associated virus type 1-induced nephroblastomas. Mol Cell Biol 12:10–21

    PubMed  CAS  Google Scholar 

  • Jun JI, Lau LF (2011) Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets. Nat Rev Drug Discov 10(12):945–963

    Article  PubMed  CAS  Google Scholar 

  • Kawaki H, Kubota S, Suzuki A, Lazar N, Yamada T, Matsumura T, Ohgawara T, Maeda T, Perbal B, Lyons KM, Takigawa M (2008) Cooperative regulation of chondrocyte differentiation by CCN2 and CCN3 shown by a comprehensive analysis of the CCN family proteins in cartilage. J Bone Miner Res 23(11):1751–1764

    Article  PubMed  CAS  Google Scholar 

  • Kleer CG, Zhang Y, Merajver SD (2007) CCN6 (WISP3) as a new regulator of the epithelial phenotype in breast cancer. Cells Tissues Organs 185(1–3):95–99

    Article  PubMed  CAS  Google Scholar 

  • Kubota S, Takigawa M (2007) Role of CCN2/CTGF/Hcs24 in bone growth. Int Rev Cytol 257:1–41

    Article  PubMed  CAS  Google Scholar 

  • Kyurkchiev S, Yeger H, Bleau AM, Perbal B (2004) Potential cellular conformations of the CCN3(NOV) protein. Cell Commun Signal 2(1):9

    Article  PubMed  Google Scholar 

  • Lau LF (2011) CCN1/CYR61: the very model of a modern matricellular protein. Cell Mol Life Sci 68(19):3149–3163

    Article  PubMed  CAS  Google Scholar 

  • Lau LF, Lam SC (1999) The CCN family of angiogenic regulators: the integrin connection. Exp Cell Res 248(1):44–57

    Article  PubMed  CAS  Google Scholar 

  • Leask A, Abraham DJ (2006) All in the CCN family: essential matricellular signaling modulators emerge from the bunker. J Cell Sci 119(Pt 23):4803–4810

    Article  PubMed  CAS  Google Scholar 

  • Lin Z, Natesan V, Shi H, Hamik A, Kawanami D, Hao C, Mahabaleshwar GH, Wang W, Jin ZG, Atkins GB, Firth SM, Rittié L, Perbal B, Jain MK (2010) A novel role of CCN3 in regulating endothelial inflammation. J Cell Commun Signal 4(3):141–153

    Article  PubMed  Google Scholar 

  • Manara MC, Perbal B, Benini S, Strammiello R, Cerisano V, Perdichizzi S, Serra M, Astolfi A, Bertoni F, Alami J, Yeger H, Picci P, Scotlandi K (2002) The expression of ccn3(nov) gene in musculoskeletal tumors. Am J Pathol 160(3):849–859

    Article  PubMed  CAS  Google Scholar 

  • Mason RM (2013) Fell-Muir lecture: connective tissue growth factor (CCN2)—a pernicious and pleiotropic player in the development of kidney fibrosis. Int J Exp Pathol 94(1):1–16

    Article  PubMed  CAS  Google Scholar 

  • McCallum L, Price S, Planque N, Perbal B, Pierce A, Whetton AD, Irvine AE (2006) A novel mechanism for BCR-ABL action: stimulated secretion of CCN3 is involved in growth and differentiation regulation. Blood 108(5):1716–1723

    Article  PubMed  CAS  Google Scholar 

  • O’Brien TP, Yang GP, Sanders L, Lau LF (1990) Expression of cyr61, a growth factor-inducible immediate-early gene. Mol Cell Biol 10:3569–3577

    PubMed  Google Scholar 

  • Ouellet V, Siegel PM (2012) CCN3 modulates bone turnover and is a novel regulator of skeletal metastasis. J Cell Commun Signal 6(2):73–85

    Article  PubMed  Google Scholar 

  • Pennica D, Swanson TA, Welsh JW, Roy M, Lawrence D, Lee J, Brush J, Taneyhill L, Deuel B, Lew M, Watanabe C, Cohen R, Melhem M, Finley G, Quirke P, Goddard A, Hillan K, Gurney A, Botstein D, Levine A (1998) WISP genes are members of the connective tissue growth factor family that are up-regulated in Wnt-1-transformed cells and aberrantly expressed in human colon tumors. Proc Natl Acad Sci USA 95:14717–14722

    Article  PubMed  CAS  Google Scholar 

  • Perbal B (1994) Caractérisation et expression du proto-oncogène nov humain dans les tumeurs de Wilms. Bull Cancer (Paris) 81:957–961

    Google Scholar 

  • Perbal B (1995) Contribution of MAV-1-induced nephroblastoma to the study of genes involved in human Wilms’ tumor development. Crit Rev Oncog 5:589–613

    Google Scholar 

  • Perbal B (1999) Nuclear localization of NOV protein: a potential role for nov in the regulation of gene expression. Mol Pathol 52:84–91

    Article  PubMed  CAS  Google Scholar 

  • Perbal B (2001) NOV (nephroblastoma overexpressed) and the CCN family of genes: structural and functional issues. Mol Pathol 54:57–79

    Article  PubMed  CAS  Google Scholar 

  • Perbal B (2003) The CCN3 (NOV) cell growth regulator: a new tool for molecular medicine. Expert Rev Mol Diagn 3(5):597–604

    Article  PubMed  CAS  Google Scholar 

  • Perbal B (2004) CCN proteins: multifunctional signalling regulators. Lancet 363(9402):62–64

    Article  PubMed  CAS  Google Scholar 

  • Perbal B (2006a) The CCN3 protein and cancer. Adv Exp Med Biol 587:23–40

    Article  PubMed  CAS  Google Scholar 

  • Perbal B (2006b) New insight into CCN3 interactions–nuclear CCN3: fact or fantasy? Cell Commun Signal 4:6

    Article  PubMed  Google Scholar 

  • Perbal B (2007) CCN3-mutant mice are distinct from CCN3-null mice. J Cell Commun Signal 1(3–4):229–230

    Article  PubMed  CAS  Google Scholar 

  • Perbal B (2008) CCN3: Doctor Jekyll and Mister Hyde. J Cell Commun Signal 2(1–2):3–7

    Article  PubMed  Google Scholar 

  • Perbal B (2009) Alternative splicing of CCN mRNAs .... it has been upon us. J Cell Commun Signal 3(2):153–157

    Article  PubMed  Google Scholar 

  • Perbal A, Perbal B (2007) CCN proteins, microenvironment, communication and signaling: why did we need a new journal? J Cell Commun Signal 1(1):1–3

    Article  PubMed  Google Scholar 

  • Perbal B, Martinerie C, Sainson R, Werner M, He B, Roizman B (1999) The C-terminal domain of the regulatory proteinNOVH is sufficient to promote interaction with fibulin 1C: a clue for a role of NOVH in cell-adhesion signaling. Proc Natl Acad Sci U S A 96:869–874

    Article  PubMed  CAS  Google Scholar 

  • Perbal B, Brigstock DR, Lau L (2003) Report of the second international workshop on the CCN family of genes. J Clin Pathol Mol Pathol 56:80–85

    Article  CAS  Google Scholar 

  • Perbal B, Zuntini M, Zambelli D, Serra M, Sciandra M, Cantiani L, Lucarelli E, Picci P, Scotlandi K (2008) Prognostic value of CCN3 in osteosarcoma. Clin Cancer Res 14(3):701–709

    Article  PubMed  CAS  Google Scholar 

  • Planque N, Perbal B (2003) A structural approach to the role of CCN (CYR61/CTGF/NOV) proteins in tumourigenesis. Cancer Cell Int 3(1):15

    Article  PubMed  Google Scholar 

  • Planque N, Long Li C, Saule S, Bleau AM, Perbal B (2006) Nuclear addressing provides a clue for the transforming activity of amino-truncated CCN3 proteins. J Cell Biochem 99(1):105–116

    Article  PubMed  CAS  Google Scholar 

  • Riser BL, Najmabadi F, Perbal B, Peterson DR, Rambow JA, Riser ML, Sukowski E, Yeger H, Riser SC (2009) CCN3 (NOV) is a negative regulator of CCN2 (CTGF) and a novel endogenous inhibitor of the fibrotic pathway in an in vitro model of renal disease. Am J Pathol 174(5):1725–1734

    Article  PubMed  CAS  Google Scholar 

  • Rittié L, Perbal B, Castellot JJ Jr, Orringer JS, Voorhees JJ, Fisher GJ (2011) Spatial-temporal modulation of CCN proteins during wound healing in human skin in vivo. J Cell Commun Signal 5(1):69–80

    Article  PubMed  Google Scholar 

  • Sakamoto K, Yamaguchi S, Ando R, Miyawaki A, Kabasawa Y, Takagi M, Li CL, Perbal B, Katsube K (2002) The nephroblastoma overexpressed gene (NOV/ccn3) protein associates with Notch1 extracellular domain and inhibits myoblast differentiation via Notch signaling pathway. J Biol Chem 277:29399–29405

    Article  PubMed  CAS  Google Scholar 

  • Scholz G, Martinerie C, Perbal B, Hanafusa H (1996) Transcriptional down regulation of the nov proto-oncogene in fibroblasts transformed by p60v-src. Mol Cell Biol 16(2):481–486

    PubMed  CAS  Google Scholar 

  • Sha W, Leask A (2011) CCN2 expression and localization in melanoma cells. J Cell Commun Signal 5(3):219–226

    Article  PubMed  Google Scholar 

  • Shimoyama T, Hiraoka S, Takemoto M, Koshizaka M, Tokuyama H, Tokuyama T, Watanabe A, Fujimoto M, Kawamura H, Sato S, Tsurutani Y, Saito Y, Perbal B, Koseki H, Yokote K (2010) CCN3 inhibits neointimal hyperplasia through modulation of smooth muscle cell growth and migration. Arterioscler Thromb Vasc Biol 30(4):675–682

    Article  PubMed  CAS  Google Scholar 

  • Shi-Wen X, Leask A, Abraham D (2008) Regulation and function of connective tissue growth factor/CCN2 in tissue repair, scarring and fibrosis. Cytokine Growth Factor Rev 19(2):133–144

    Article  PubMed  Google Scholar 

  • Thomopoulos GN, Kyurkchiev S, Perbal B (2001) Immunocytochemical localization of NOVH protein and ultrastructural characteristics of NCI-H295R cells. J Submicrosc Cytol Pathol 33:251–260

    PubMed  CAS  Google Scholar 

  • Vallacchi V, Daniotti M, Ratti F, Di Stasi D, Deho P, De Filippo A, Tragni G, Balsari A, Carbone A, Rivoltini L, Parmiani G, Lazar N, Perbal B, Rodolfo M (2008) CCN3/nephroblastoma overexpressed matricellular protein regulates integrin expression, adhesion, and dissemination in melanoma. Cancer Res 68(3):715–723

    Article  PubMed  CAS  Google Scholar 

  • van Roeyen CR, Eitner F, Scholl T, Boor P, Kunter U, Planque N, Gröne HJ, Bleau AM, Perbal B, Ostendorf T, Floege J (2008) CCN3 is a novel endogenous PDGF-regulated inhibitor of glomerular cell proliferation. Kidney Int 73(1):86–94, Epub 2007 Oct 10

    Article  PubMed  Google Scholar 

  • Wahab NA, Brinkman H, Mason RM (2001) Uptake and intracellular transport of the connective tissue growth factor: a potential mode of action. Biochem J 359(Pt 1):89–97

    Article  PubMed  CAS  Google Scholar 

  • Wiesman KC, Wei L, Baughman C, Russo J, Gray MR, Castellot JJ (2010) CCN5, a secreted protein, localizes to the nucleus. J Cell Commun Signal 4(2):91–98

    Article  PubMed  Google Scholar 

  • Yang GP, Lau LF (1991) Cyr61, product of a growth factor-inducible immediate early gene, is associated with the extracellular matrix and the cell surface. Cell Growth Differ 2(7):351–357

    PubMed  CAS  Google Scholar 

  • Yeger H, Perbal B (2007) The CCN family of genes: a perspective on CCN biology and therapeutic potential. J Cell Commun Signal 1(3–4):159–164

    Article  PubMed  Google Scholar 

  • Zhang R, Averboukh L, Zhu W, Zhang H, Jo H, Dempsey PJ, Coffey RJ, Pardee AB, Liang P (1998) Identification of rCop-1, a new member of the CCN protein family, as a negative regulator for cell transformation. Mol Cell Biol 18:6131–6141

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

I am grateful to all the colleagues with whom I could engage very fruitful collaborative projects. The International Workshops on the CCN family of Genes have been the source the inspirational discussions. Again this review provides me the opportunity to deeply thank my wife Annick for her tremendous help in organizing the workshops and my friend and colleague Herman Yeger for his early involvement and support in this venture. The work that was performed in my laboratory was funded by grants from the European Union : PROTHETS (Prognosis and Therapeutic Targets of Ewing Family of Tumors, FP6 Contract 503036), grants from the Ligue Nationale Contre le Cancer, and the French Ministry of Education.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bernard Perbal.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Perbal, B. CCN proteins: A centralized communication network. J. Cell Commun. Signal. 7, 169–177 (2013). https://doi.org/10.1007/s12079-013-0193-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12079-013-0193-7

Keywords

Navigation