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Endocrinology Vol. 141, No. 6 2254-2256
Copyright © 2000 by The Endocrine Society

ARTICLES

CCN Proteins Are Distinct from and Should Not Be Considered Members of the Insulin-Like Growth Factor-Binding Protein Superfamily

Gary R. Grotendorst, Lester F. Lau and Bernard Perbal

Department of Cell Biology and Anatomy, University of Miami School of Medicine (G.R.G.), Miami, Florida 33136; Department of Molecular Genetics, University of Illinois College of Medicine (L.F.L.), Chicago, Illinois 60607; Laboratoire d’Oncologie Virale et Moléculaire, UFR de Biochimie, Université Paris 7 (B.P.), 75005 Paris, France; and INSERM U-515, Hôpital Saint Antoine (B.P.), Paris 75012, France

Address all correspondence and requests for reprints to: Dr. Lester F. Lau, Department of Molecular Genetics, 900 South Ashland Avenue, Chicago, Illinois 60607-7170. E-mail: lflau{at}uic.edu


   Introduction
Top
 Introduction
References
 
In a recent note, Baxter et al. (1) proposed renaming a family of extensively studied proteins, known in the literature as the CCN family (reviewed in Refs. 2, 3, 4, 5), insulin-like growth factor-binding protein-related proteins (IGFBP-rPs). This proposed name change lacks functional or biological basis, has been suggested unilaterally without consensus or consultation with those working on these proteins, and serves to confuse rather than clarify the literature.

The prototypic members of the CCN family (CTGF, CYR61, and NOV) were discovered in our laboratories in the early 1990s (6, 7, 8). Additional members of the family have been identified, including Elm-1/WISP-1, Cop-1/WISP-2, and WISP-3 (9, 10, 11) (Fig. 1Go). These highly conserved cysteine-rich proteins share four conserved modular domains with sequence similarities to IGFBP, von Willebrand factor, thrombospondin, and a cysteine knot characteristic of some growth factors, including platelet-derived growth factor, nerve growth factor, and transforming growth factor-ß (TGFß) (2). Cop-1/WISP-2 is unique, as it lacks the carboxyl-terminal cysteine knot domain. Each of the modular structural domains is encoded by a separate exon, suggesting that genes of the CCN family arose through exon shuffling of preexisting genes. Sequence similarity with IGFBPs exists only in the N-terminal domain encoded by one exon. From the sequence perspective, CCN proteins are no more related to IGFBPs than to von Willebrand factor, thrombospondin, or growth factor cysteine knots (2, 3, 4, 5) (Fig. 1Go).



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  		Figure 1. Schematic representation of CCN proteins compared with Mac25 and IGFBP-1. After the secretory signal (open oval), CCN proteins exhibit four discrete conserved domains: IGFBP, von Willebrand factor type C repeat (VWC), thrombospondin type 1 repeat (TSP1), and carboxyl-terminal cysteine knot (CT). A central variable region separates the proteins into two halves. The overall percent amino acid sequence identities and homologies, including conservative substitutions (%ID/HO) of the human sequences of each protein, compared with CTGF are listed. Within the N-terminal domain, CTGF shows 48–60% amino acid sequence identity compared with CCN family members, but only 31–33% compared with Mac25 and IGFBP-1. Outside of the N-terminal domain, CCN proteins, Mac25, and IGFBP-1 share no sequence similarity.

 
Functionally, a number of biologically significant activities have been clearly demonstrated for CCN proteins, none of which has any apparent relationship to IGF binding (12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27). Purified CCN proteins have been demonstrated to mediate and promote cell adhesion, migration, proliferation, and survival (3, 4, 5, 12). As matrix-associated, heparin-binding proteins (13), CYR61 and CTGF are novel ligands of the integrins {alpha}Vß3 and {alpha}IIbß3 (14, 15, 16), and NOV interacts with fibulin 1C (17), suggesting their involvement in cell adhesion signaling. Both CYR61 and CTGF induce angiogenesis in vivo (15, 18) and chondrogenesis in vitro (19, 20). CTGF is expressed in fibroblasts during wound healing (21, 22) and can induce fibrosis in vivo (22). Furthermore, CTGF has been demonstrated to mediate both the mitogenic and matrigenic activities of TGFß (23, 24, 25). Other studies have revealed that CYR61 promotes tumor growth (18), whereas Cop-1/WISP-2 or Elm-1/WISP-1 can inhibit tumor growth (9, 10). It has also been established that the expression of NOV is abnormal in tumor cells (26, 27) and that expression of an amino-truncated form of NOV is transforming, but full-length NOV inhibits fibroblast growth (8), suggesting an involvement of this protooncogene in malignancy. If a unified nomenclature were to be proposed for these multifunctional proteins, such nomenclature should reflect their demonstrated biologically activities. The term IGFBP-related proteins does not fulfill this need.

Is there any functional or biological basis for addressing the CCN proteins as members of the IGFBP superfamily? The only data in existence is that CTGF (28) and NOV (29) bind IGF in vitro with a 100- to 1000-fold lower affinity than authentic IGFBPs. Inasmuch as no IGF binding to NOV was observed under standard ligand blotting assay conditions (27), the low affinity binding for IGF remains controversial. No published data speak to any potential binding of CYR61 to IGF. Clearly, these proteins cannot compete with the high affinity IGFBPs that are so abundant in serum. More importantly, to date there is no demonstrated physiological significance of IGF binding by any member of the CCN family. Thus, proposing to abandon the established names of the CCN proteins and to rename and reclassify them on a speculative basis does not make sense and serves only to divert attention from the carefully documented and published work that has identified specific biological activities of these molecules.

The proposal of Baxter et al. (1) to reclassify substantively different molecules under the same rubric is misleading, exemplified in this case by the placement of CCN proteins in the same category as Mac25, a protein homologous to the activin-binding protein follistatin (30). Even a cursory inspection of Fig. 1Go reveals that the CCN proteins form a distinct family, separate and distinct from Mac25 and IGFBPs. The proposed renaming misleadingly suggests an intimate relationship among CCN proteins, Mac25, and IGFBPs that does not exist and implies that the biological activities of CCN proteins function through an IGF-binding activity, which has not been demonstrated in any context.

Changes in nomenclature often make good sense in a field where clarity and focus can be served based on accumulated new information. However, this should be done with the consensus of those who work in the field, rather than unilaterally. In this instance, as the very low affinity binding of IGF by CCN proteins has no demonstrated biological significance, this proposed name change serves no scientific or intellectual purpose. The proposed renaming of the CCN family as IGFBP-rPs simply ignores the multitude of well documented and established biological activities of these proteins (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27). The use of superfluous names such as IGFBP-rP serves only to add confusion, rather than insight, to the functions and activities of this complex and important emerging family of proteins.

Received December 3, 1999.


   References
Top
 Introduction
 References
 

  1. Baxter RC, Binoux MA, Clemmons DR, Conover CA, Drop SLS, Holly JMP, Mohan S, Oh Y, Rosenfeld RG 1998 Recommendations for nomenclature of the insulin-like growth factor binding protein superfamily. Endocrinology 139:4036[Free Full Text]
  2. Bork P 1993 The modular architecture of a new family of growth regulators related to connective tissue growth factor. FEBS Lett 327:125–130[CrossRef][Medline]
  3. Grotendorst GR 1997 Connective tissue growth factor: a mediator of TGF-ß action on fibroblasts. Cytokine Growth Factor Rev 8:171–179[CrossRef][Medline]
  4. Lau LF, Lam SC-T 1999 The CCN family of angiogenic regulators: the integrin connection. Exp Cell Res 248:44–57[CrossRef][Medline]
  5. Brigstock DR 1999 The connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed (CCN) family. Endocr Rev 20:189–206[Abstract/Free Full Text]
  6. 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[Abstract/Free Full Text]
  7. Bradham DM, Igarshi 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[Abstract/Free Full Text]
  8. Joliot V, Marinerie 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[Abstract/Free Full Text]
  9. Hashimoto Y, Shindo-Okada N, Tani M, Nagamachi Y, Takeuchi K, Shiroishi T, Toma H, Yokota J 1998 Expression of the Elm1 gene, a novel gene of the CCN (connective tissue growth factor, Cyr61/cef10, and nephroblastoma overexpressed gene) family, suppresses in vivo tumor growth and metastasis of K-1735 murine melanoma cells. J Exp Med 187:289–296[Abstract/Free Full Text]
  10. 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[Abstract/Free Full Text]
  11. Pennica D, Swanson TA, Welsh JW, Roy MA, Lawrence DA, Lee J, Brush J, Taneyhill LA, Deuel B, Lew M, 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 95:14717–14722[Abstract/Free Full Text]
  12. Kireeva ML, Mo F-E, Yang GP, Lau LF 1996 Cyr61, product of a growth factor-inducible immediate-early gene, promotes cell proliferation, migration, and adhesion. Mol Cell Biol 16:1326–1334[Abstract]
  13. 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 2:351–357[Abstract]
  14. Kireeva ML, Lam SC-T, Lau LF 1998 Adhesion of human umbilical vein endothelial cells to the immediate-early gene product Cyr61 is mediated through integrin {alpha}Vß3. J Biol Chem 273:3090–3096[Abstract/Free Full Text]
  15. Babic AM, Chen C-C, Lau LF 1999 Fisp12/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin {alpha}Vß3, promotes endothelial cell survival, and induces angiogenesis in vivo. Mol Cell Biol 19:2958–2966[Abstract/Free Full Text]
  16. Jedsadayanmata A., Chen C-C, Kireeva ML, Lau LF, Lam SC-T 1999 Activation-dependent adhesion of human platelets to Cyr61 and Fisp12/mouse connective tissue growth factor is mediated through integrin {alpha}IIbß3. J Biol Chem 274:24321–24327[Abstract/Free Full Text]
  17. Perbal B, Martinerie C, Sainson R, Werner M, He B, Roizman B 1999 The C-terminal domain of the regulatory protein NOVH is sufficient to promote interaction with fibulin 1C: a clue for a role of NOVH in cell-adhesion signaling. Proc Natl Acad Sci USA 96:869–874[Abstract/Free Full Text]
  18. Babic AM, Kireeva ML, Kolesnikova TV, Lau LF 1998 CYR61, a product of a growth factor-inducible immediate early genes, promotes angiogenesis and tumor growth. Proc Natl Acad Sci USA 95:6355–6360[Abstract/Free Full Text]
  19. Wong M, Kireeva ML, Kolesnikova TV, Lau LF 1997 Cyr61, product of a growth factor-inducible immediate early gene, regulates chondrogenesis in mouse limb bud mesenchymal cells. Dev. Biol. 192:492–508
  20. Grotendorst GR November 17, 1998. Induction of tissue, bone or cartilage formation using connective tissue growth factor. U.S. Patent 5:837,258
  21. Igarashi A, Okochi H, Bradham DM, Grotendorst GR 1993 Regulation of connective tissue growth factor gene expression in human skin fibroblasts and during wound repair. Mol Biol Cell 4:637–645[Abstract]
  22. Frazier K, Williams S, Kothapalli D, Klapper H, Grotendorst GR 1996 Stimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor. J Invest Dermatol 107:404–411[CrossRef][Medline]
  23. Kothapalli D, Frazier K, Grotendorst GR 1997 TGF-ß induces anchorage-independent growth of NRK fibroblasts via the synergistic action of CTGF-dependent and CTGF-independent signaling pathways. Cell Growth Differ 8:61–68[Abstract]
  24. Kopthapalli D, Hayashi N, Grotendorst GR 1998 Inhibition of TGF-ß stimulated CTGF gene expression and anchorage independent growth by elevation of intracellular cAMP. FASEB J 12:1151–1161[Abstract/Free Full Text]
  25. Duncan MR, Frazier KS, Abramson S, Williams S, Klapper H, Huang X, Grotendorst GR 1999 Connective tissue growth factor mediates transforming growth factor-collagen synthesis: downregulation by cAMP. FASEB J 13:1774–1786[Abstract/Free Full Text]
  26. Li WX, Martinerie C, Zumkeller W, Westphal M, Perbal B 1996 Differential expression of novH and CTGF in human glioma cell lines. J Clin Mol Pathol 49:M91–M97
  27. Chevalier G, Yeger H, Martinerie C, Laurent M, Alami J, Schofield PN, Perbal B 1998 novH: differential expression in developing kidney and a marker of heterotypic differentiation in Wilms’ tumor. Am J Pathol 52:1563–1575
  28. Kim HS, Nagalla SR, Oh,Y, Wilson E, Roberts CTJ, Rosenfeld RG 1997 Identification of a family of low-affinity insulin-like growth factor binding proteins (IGFBPs): characterization of connective tissue growth factor as a member of the IGFBP superfamily. Proc Natl Acad Sci USA 94:12981–12986[Abstract/Free Full Text]
  29. Burren CP, Wilson EM, Hwa V, OhY, Rosenfeld RG 1999 Binding properties and distribution of insulin-like growth factor binding protein-related protein 3 (IGFBP-rP3/NovH), and additional member of the IGFBP superfamily. J Clin Endocrinol Metab 84:1096–1103[Abstract/Free Full Text]
  30. Kato MV, Sato H, Tsukada T, Ikawa Y, Aizawa S, Nagayoshi M 1996 A follistatin-like gene, mac25, may act as a growth suppressor of osteosarcoma cells. Oncogene 12:1361–1364[Medline]



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