Advertisement

Journal of Cell Communication and Signaling

, Volume 4, Issue 3, pp 119–130 | Cite as

CCN5: biology and pathophysiology

  • Joshua W. Russo
  • John J. CastellotJr.Email author
Review

Abstract

CCN5 is one of six proteins in the CCN family. This family of proteins has been shown to play important roles in many processes, including proliferation, migration, adhesion, extracellular matrix regulation, angiogenesis, tumorigenesis, fibrosis, and implantation. In this review, we focus on the biological and putative pathophysiological roles of CCN5. This intriguing protein is structurally unique among the CCN family members, and has a unique biological activity profile as well.

Keywords

CCN proteins Matricellular Nuclear localization Review 

References

  1. Aprelikova O, Wood M, Tackett S, Chandramouli GV, Barrett JC (2006) Role of ETS transcription factors in the hypoxia-inducible factor-2 target gene selection. Cancer Res 66:5641–5647CrossRefPubMedGoogle Scholar
  2. Banerjee S, Saxena N, Sengupta K, Tawfik O, Mayo MS, Banerjee SK (2003) WISP-2 gene in human breast cancer: estrogen and progesterone inducible expression and regulation of tumor cell proliferation. Neoplasia 5:63–73PubMedGoogle Scholar
  3. Banerjee S, Sengupta K, Saxena NK, Dhar K, Banerjee SK (2005) Epidermal growth factor induces WISP-2/CCN5 expression in estrogen receptor-alpha-positive breast tumor cells through multiple molecular cross-talks. Mol Cancer Res 3:151–162CrossRefPubMedGoogle Scholar
  4. Banerjee S, Dhar G, Haque I, Kambhampati S, Mehta S, Sengupta K, Tawfik O, Phillips TA, Banerjee SK (2008) CCN5/WISP-2 expression in breast adenocarcinoma is associated with less frequent progression of the disease and suppresses the invasive phenotypes of tumor cells. Cancer Res 68:7606–7612CrossRefPubMedGoogle Scholar
  5. Bork P (1993) The modular architecture of a new family of growth regulators related to connective tissue growth factor. FEBS Lett 327:125–130CrossRefPubMedGoogle Scholar
  6. Chen CC, Lau LF (2009) Functions and mechanisms of action of CCN matricellular proteins. Int J Biochem Cell Biol 41:771–783CrossRefPubMedGoogle Scholar
  7. Davies SR, Watkins G, Mansel RE, Jiang WG (2007) Differential expression and prognostic implications of the CCN family members WISP-1, WISP-2, and WISP-3 in human breast cancer. Ann Surg Oncol 14:1909–1918CrossRefPubMedGoogle Scholar
  8. Delmolino LM, Stearns NA, Castellot JJ Jr (1997) Heparin induces a member of the CCN family which has characteristics of a growth arrest gene. Mol Biol Cell 8:287aGoogle Scholar
  9. Delmolino LM, Stearns NA, Castellot JJ Jr (2001) COP-1, a member of the CCN family, is a heparin-induced growth arrest specific gene in vascular smooth muscle cells. J Cell Physiol 188:45–55CrossRefPubMedGoogle Scholar
  10. Dhar G, Mehta S, Banerjee S, Gardner A, McCarty BM, Mathur SC, Campbell DR, Kambhampati S, Banerjee SK (2007a) Loss of WISP-2/CCN5 signaling in human pancreatic cancer: a potential mechanism for epithelial-mesenchymal-transition. Cancer Lett 254:63–70CrossRefPubMedGoogle Scholar
  11. Dhar K, Banerjee S, Dhar G, Sengupta K, Banerjee SK (2007b) Insulin-like growth factor-1 (IGF-1) induces WISP-2/CCN5 via multiple molecular cross-talks and is essential for mitogenic switch by IGF-1 axis in estrogen receptor-positive breast tumor cells. Cancer Res 67:1520–1526CrossRefPubMedGoogle Scholar
  12. Dhar G, Banerjee S, Dhar K, Tawfik O, Mayo MS, Vanveldhuizen PJ, Banerjee SK (2008) Gain of oncogenic function of p53 mutants induces invasive phenotypes in human breast cancer cells by silencing CCN5/WISP-2. Cancer Res 68:4580–4587CrossRefPubMedGoogle Scholar
  13. Fritah A, Saucier C, De Wever O, Bracke M, Bieche I, Lidereau R, Gespach C, Drouot S, Redeuilh G, Sabbah M (2008) Role of WISP-2/CCN5 in the maintenance of a differentiated and noninvasive phenotype in human breast cancer cells. Mol Cell Biol 28:1114–1123CrossRefPubMedGoogle Scholar
  14. Fukutomi T, Zhou Y, Kawai S, Eguchi H, Wands JR, Li J (2005) Hepatitis C virus core protein stimulates hepatocyte growth: correlation with upregulation of wnt-1 expression. Hepatology 41:1096–1105CrossRefPubMedGoogle Scholar
  15. Gray MR, Malmquist JA, Sullivan M, Blea M, Castellot JJ Jr (2007) CCN5 Expression in mammals. II. Adult rodent tissues. J Cell Commun Signal 1:145–158CrossRefPubMedGoogle Scholar
  16. Hashimoto G, Inoki I, Fujii Y, Aoki T, Ikeda E, Okada Y (2002) Matrix metalloproteinases cleave connective tissue growth factor and reactivate angiogenic activity of vascular endothelial growth factor 165. J Biol Chem 277:36288–36295CrossRefPubMedGoogle Scholar
  17. Holbourn KP, Perbal B, Ravi Acharya K (2009) Proteins on the catwalk: modelling the structural domains of the CCN family of proteins. J Cell Commun Signal 3:25–41CrossRefPubMedGoogle Scholar
  18. Iliopoulos D, Bimpaki EI, Nesterova M, Stratakis CA (2009) MicroRNA signature of primary pigmented nodular adrenocortical disease: clinical correlations and regulation of Wnt signaling. Cancer Res 69(8):3278–3782Google Scholar
  19. Inadera H (2003) Estrogen-induced genes, WISP-2 and pS2, respond divergently to protein kinase pathway. Biochem Biophys Res Commun 309:272–278CrossRefPubMedGoogle Scholar
  20. Inadera H, Hashimoto S, Dong HY, Suzuki T, Nagai S, Yamashita T, Toyoda N, Matsushima K (2000) WISP-2 as a novel estrogen-responsive gene in human breast cancer cells. Biochem Biophys Res Commun 275:108–114CrossRefPubMedGoogle Scholar
  21. Inadera H, Dong HY, Matsushima K (2002) WISP-2 is a secreted protein and can be a marker of estrogen exposure in MCF-7 cells. Biochem Biophys Res Commun 294:602–608CrossRefPubMedGoogle Scholar
  22. Inadera H, Shimomura A, Tachibana S (2009) Effect of Wnt-1 inducible signaling pathway protein-2 (WISP-2/CCN5), a downstream protein of Wnt signaling, on adipocyte differentiation. Biochem Biophys Res Commun 379:969–974CrossRefPubMedGoogle Scholar
  23. Johnsen SA, Gungor C, Prenzel T, Riethdorf S, Riethdorf L, Taniguchi-Ishigaki N, Rau T, Tursun B, Furlow JD, Sauter G, Scheffner M, Pantel K, Gannon F, Bach I (2009) Regulation of estrogen-dependent transcription by the LIM cofactors CLIM and RLIM in breast cancer. Cancer Res 69:128–136CrossRefPubMedGoogle Scholar
  24. Jones JA, Gray MR, Oliveira BE, Koch M, Castellot JJ Jr (2007) CCN5 expression in mammals: I. Embryonic and fetal tissues of mouse and human. J Cell Commun Signal 1:127–143CrossRefPubMedGoogle Scholar
  25. Karagiannis ED, Popel AS (2007) Peptides derived from type I thrombospondin repeat-containing proteins of the CCN family inhibit proliferation and migration of endothelial cells. Int J Biochem Cell Biol 39:2314–2323CrossRefPubMedGoogle Scholar
  26. Kubota S, Takigawa M (2007) CCN family proteins and angiogenesis: from embryo to adulthood. Angiogenesis 10:1–11CrossRefPubMedGoogle Scholar
  27. Kumar S, Hand AT, Connor JR, Dodds RA, Ryan PJ, Trill JJ, Fisher SM, Nuttall ME, Lipshutz DB, Zou C, Hwang SM, Votta BJ, James IE, Rieman DJ, Gowen M, Lee JC (1999) Identification and cloning of a connective tissue growth factor-like cDNA from human osteoblasts encoding a novel regulator of osteoblast functions. J Biol Chem 274:17123–17131CrossRefPubMedGoogle Scholar
  28. Lake AC, Castellot JJ Jr (2003) CCN5 modulates the antiproliferative effect of heparin and regulates cell motility in vascular smooth muscle cells. Cell Commun Signal 1:5CrossRefPubMedGoogle Scholar
  29. Lake AC, Bialik A, Walsh K, Castellot JJ Jr (2003) CCN5 is a growth arrest-specific gene that regulates smooth muscle cell proliferation and motility. Am J Pathol 162:219–231PubMedGoogle Scholar
  30. Mason HR, Grove-Strawser D, Rubin BS, Nowak RA, Castellot JJ Jr (2004a) Estrogen induces CCN5 expression in the rat uterus in vivo. Endocrinology 145:976–982CrossRefPubMedGoogle Scholar
  31. Mason HR, Lake AC, Wubben JE, Nowak RA, Castellot JJ Jr (2004b) The growth arrest-specific gene CCN5 is deficient in human leiomyomas and inhibits the proliferation and motility of cultured human uterine smooth muscle cells. Mol Hum Reprod 10:181–187CrossRefPubMedGoogle Scholar
  32. McManus EJ, Sakamoto K, Armit LJ, Ronaldson L, Shpiro N, Marquez R, Alessi DR (2005) Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis. EMBO J 24:1571–1583CrossRefPubMedGoogle Scholar
  33. Mo FE, Muntean AG, Chen CC, Stolz DB, Watkins SC, Lau LF (2002) CYR61 (CCN1) is essential for placental development and vascular integrity. Mol Cell Biol 22:8709–8720CrossRefPubMedGoogle Scholar
  34. Parisi MS, Gazzerro E, Rydziel S, Canalis E (2006) Expression and regulation of CCN genes in murine osteoblasts. Bone 38:671–677CrossRefPubMedGoogle Scholar
  35. Pecha J, Ankrapp D, Jiang C, Tang W, Hoshino I, Bruck K, Wagner KU, Xiao H (2007) Deletion of Tip30 leads to rapid immortalization of murine mammary epithelial cells and ductal hyperplasia in the mammary gland. Oncogene 26:7423–7431CrossRefPubMedGoogle Scholar
  36. Pennica D, Swanson TA, Welsh JW, Roy MA, Lawrence DA, Lee J, Brush J, Taneyhill LA, Deuel B, Lew M, Watanabe C, Cohen RL, Melhem MF, Finley GG, Quirke P, Goddard AD, Hillan KJ, Gurney AL, Botstein D, Levine AJ (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 95:14717–14722CrossRefPubMedGoogle Scholar
  37. Quan T, Shin S, Qin Z, Fisher GJ (2009) Expression of CCN family of genes in human skin in vivo and alterations by solar-simulated ultraviolet irradiation. J Cell Commun Signal 3:19–23CrossRefPubMedGoogle Scholar
  38. Robinson JA, Chatterjee-Kishore M, Yaworsky PJ, Cullen DM, Zhao W, Li C, Kharode Y, Sauter L, Babij P, Brown EL, Hill AA, Akhter MP, Johnson ML, Recker RR, Komm BS, Bex FJ (2006) Wnt/beta-catenin signaling is a normal physiological response to mechanical loading in bone. J Biol Chem 281:31720–31728CrossRefPubMedGoogle Scholar
  39. Saxena N, Banerjee S, Sengupta K, Zoubine MN, Banerjee SK (2001) Differential expression of WISP-1 and WISP-2 genes in normal and transformed human breast cell lines. Mol Cell Biochem 228:99–104CrossRefPubMedGoogle Scholar
  40. Schutze N, Noth U, Schneidereit J, Hendrich C, Jakob F (2005) Differential expression of CCN-family members in primary human bone marrow-derived mesenchymal stem cells during osteogenic, chondrogenic and adipogenic differentiation. Cell Commun Signal 3:5CrossRefPubMedGoogle Scholar
  41. Sengupta K, Banerjee S, Dhar K, Saxena NK, Mehta S, Campbell DR, Banerjee SK (2006) WISP-2/CCN5 is involved as a novel signaling intermediate in phorbol ester-protein kinase Calpha-mediated breast tumor cell proliferation. Biochemistry 45:10698–10709CrossRefPubMedGoogle Scholar
  42. Suzuki A, Ozono K, Kubota T, Kondou H, Tachikawa K, Michigami T (2008) PTH/cAMP/PKA signaling facilitates canonical Wnt signaling via inactivation of glycogen synthase kinase-3beta in osteoblastic Saos-2 cells. J Cell Biochem 104:304–317CrossRefPubMedGoogle Scholar
  43. Tanaka I, Morikawa M, Okuse T, Shirakawa M, Imai K (2005) Expression and regulation of WISP2 in rheumatoid arthritic synovium. Biochem Biophys Res Commun 334(4):973–997Google Scholar
  44. Visser S, Yang X (2010) Identification of LATS transcriptional targets in HeLa cells using whole human genome oligonucleotide microarray. Gene 449:22–29CrossRefPubMedGoogle Scholar
  45. 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 18:6131–6141PubMedGoogle Scholar
  46. Zhong N, Gersch RP, Hadjiargyrou M (2006) Wnt signaling activation during bone regeneration and the role of dishevelled in chondrocyte proliferation and differentiation. Bone 39:5–16CrossRefPubMedGoogle Scholar
  47. Zoubine MN, Banerjee S, Saxena NK, Campbell DR, Banerjee SK (2001) WISP-2: a serum-inducible gene differentially expressed in human normal breast epithelial cells and in MCF-7 breast tumor cells. Biochem Biophys Res Commun 282:421–425CrossRefPubMedGoogle Scholar

Copyright information

© The International CCN Society 2010

Authors and Affiliations

  1. 1.Program in Cell, Molecular and Developmental BiologyTufts University Sackler School of Graduate Biomedical SciencesBostonUSA
  2. 2.Department of Anatomy and Cell BiologyTufts University School of MedicineBostonUSA

Personalised recommendations