Connective-tissue Growth Factor (CTGF) Modulates Cell Signalling by BMP and TGF-beta

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2002 Jul 23

PMID 12134160

Citations 361

Authors

Jose G Abreu

Nan I Ketpura

Bruno Reversade

E M De Robertis

Affiliations

Soon will be listed here.

Abstract

Connective-tissue growth factor (CTGF) is a secreted protein implicated in multiple cellular events including angiogenesis, skeletogenesis and wound healing. It is a member of the CCN family of secreted proteins, named after CTGF, cysteine-rich 61 (CYR61), and nephroblastoma overexpressed (NOV) proteins. The molecular mechanism by which CTGF or other CCN proteins regulate cell signalling is not known. CTGF contains a cysteine-rich domain (CR) similar to those found in chordin and other secreted proteins, which in some cases have been reported to function as bone morphogenetic protein (BMP) and TGF-beta binding domains. Here we show that CTGF directly binds BMP4 and TGF-beta 1 through its CR domain. CTGF can antagonize BMP4 activity by preventing its binding to BMP receptors and has the opposite effect, enhancement of receptor binding, on TGF-beta 1. These results show that CTGF inhibits BMP and activates TGF-beta signals by direct binding in the extracellular space.

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References

Larrain J, Bachiller D, Lu B, Agius E, Piccolo S, De Robertis E . BMP-binding modules in chordin: a model for signalling regulation in the extracellular space. Development. 2000; 127(4):821-30. PMC: 2280033. DOI: 10.1242/dev.127.4.821. View

Smith W, Harland R . Expression cloning of noggin, a new dorsalizing factor localized to the Spemann organizer in Xenopus embryos. Cell. 1992; 70(5):829-40. DOI: 10.1016/0092-8674(92)90316-5. View

Moussad E, Brigstock D . Connective tissue growth factor: what's in a name?. Mol Genet Metab. 2000; 71(1-2):276-92. DOI: 10.1006/mgme.2000.3059. View

Holmes A, Abraham D, Sa S, Shiwen X, Black C, Leask A . CTGF and SMADs, maintenance of scleroderma phenotype is independent of SMAD signaling. J Biol Chem. 2001; 276(14):10594-601. DOI: 10.1074/jbc.M010149200. View

Robson P, Stein P, Zhou B, Schultz R, Baldwin H . Inner cell mass-specific expression of a cell adhesion molecule (PECAM-1/CD31) in the mouse blastocyst. Dev Biol. 2001; 234(2):317-29. DOI: 10.1006/dbio.2001.0274. View

Nakayama N, Han C, Scully S, Nishinakamura R, He C, Zeni L . A novel chordin-like protein inhibitor for bone morphogenetic proteins expressed preferentially in mesenchymal cell lineages. Dev Biol. 2001; 232(2):372-87. DOI: 10.1006/dbio.2001.0200. View

Sakuta H, Suzuki R, Takahashi H, Kato A, Shintani T, Iemura Si . Ventroptin: a BMP-4 antagonist expressed in a double-gradient pattern in the retina. Science. 2001; 293(5527):111-5. DOI: 10.1126/science.1058379. View

Segarini P, Nesbitt J, Li D, Hays L, Yates 3rd J, Carmichael D . The low density lipoprotein receptor-related protein/alpha2-macroglobulin receptor is a receptor for connective tissue growth factor. J Biol Chem. 2001; 276(44):40659-67. DOI: 10.1074/jbc.M105180200. View

Larrain J, Oelgeschlager M, Ketpura N, Reversade B, Zakin L, De Robertis E . Proteolytic cleavage of Chordin as a switch for the dual activities of Twisted gastrulation in BMP signaling. Development. 2001; 128(22):4439-47. PMC: 2277371. DOI: 10.1242/dev.128.22.4439. View

10.

Inoki I, Shiomi T, Hashimoto G, Enomoto H, Nakamura H, Ikeda E . Connective tissue growth factor binds vascular endothelial growth factor (VEGF) and inhibits VEGF-induced angiogenesis. FASEB J. 2001; 16(2):219-21. DOI: 10.1096/fj.01-0332fje. View

11.

Abreu J, Coffinier C, Larrain J, Oelgeschlager M, De Robertis E . Chordin-like CR domains and the regulation of evolutionarily conserved extracellular signaling systems. Gene. 2002; 287(1-2):39-47. DOI: 10.1016/s0378-1119(01)00827-7. View

12.

Roberts A, Sporn M, Assoian R, Smith J, Roche N, Wakefield L . Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A. 1986; 83(12):4167-71. PMC: 323692. DOI: 10.1073/pnas.83.12.4167. View

13.

Hunt L, Barker W . von Willebrand factor shares a distinctive cysteine-rich domain with thrombospondin and procollagen. Biochem Biophys Res Commun. 1987; 144(2):876-82. DOI: 10.1016/s0006-291x(87)80046-3. View

14.

Massague J . Identification of receptors for type-beta transforming growth factor. Methods Enzymol. 1987; 146:174-95. DOI: 10.1016/s0076-6879(87)46020-5. View

15.

Katagiri T, Yamaguchi A, Ikeda T, Yoshiki S, Wozney J, Rosen V . The non-osteogenic mouse pluripotent cell line, C3H10T1/2, is induced to differentiate into osteoblastic cells by recombinant human bone morphogenetic protein-2. Biochem Biophys Res Commun. 1990; 172(1):295-9. DOI: 10.1016/s0006-291x(05)80208-6. View

16.

Wrana J, Attisano L, Carcamo J, Zentella A, Doody J, Laiho M . TGF beta signals through a heteromeric protein kinase receptor complex. Cell. 1992; 71(6):1003-14. DOI: 10.1016/0092-8674(92)90395-s. View

17.

Bork P . The modular architecture of a new family of growth regulators related to connective tissue growth factor. FEBS Lett. 1993; 327(2):125-30. DOI: 10.1016/0014-5793(93)80155-n. View

18.

Sasai Y, Lu B, Steinbeisser H, Geissert D, Gont L, De Robertis E . Xenopus chordin: a novel dorsalizing factor activated by organizer-specific homeobox genes. Cell. 1994; 79(5):779-90. PMC: 3082463. DOI: 10.1016/0092-8674(94)90068-x. View

19.

Masuhara K, Nakase T, Suzuki S, Takaoka K, Matsui M, Anderson H . Use of monoclonal antibody to detect bone morphogenetic protein-4 (BMP-4). Bone. 1995; 16(1):91-6. DOI: 10.1016/s8756-3282(94)00014-x. View

20.

Grotendorst G, Okochi H, Hayashi N . A novel transforming growth factor beta response element controls the expression of the connective tissue growth factor gene. Cell Growth Differ. 1996; 7(4):469-80. View