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Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-β

Abstract

Connective-tissue growth factor (CTGF) is a secreted protein implicated in multiple cellular events including angiogenesis, skeletogenesis and wound healing1. 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 proteins2, which in some cases have been reported to function as bone morphogenetic protein (BMP) and TGF-β binding domains3,4,5,6. Here we show that CTGF directly binds BMP4 and TGF-β1 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-β1. These results show that CTGF inhibits BMP and activates TGF-β signals by direct binding in the extracellular space.

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Figure 1: CTGF encodes a CR-containing protein.
Figure 2: CTGF mRNA injections induce anti-BMP phenotypes in Xenopus embryos.
Figure 3: CTGF binds BMP4 and TGF-β1 through the CR domain.
Figure 4: CTGF antagonizes BMP4 signalling by inhibiting receptor binding.
Figure 5: CTGF potentiates TGF-β1 receptor binding and signalling.

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Acknowledgements

We thank K. M. Lyons and S. Ivkovic for unpublished information, K. Masuhara and C.H. Heldin for antibodies, J. Massague for reporter plasmid, Naoto Ueno for the protocol to immobilize BMP4 to Biacore chips, M. L. King and Z. Ying for entering the CTGF full-length sequence in GenBank, S.-Y. Li and A. Cuellar for technical assistance, and C. Coffinier, E. Delot, J. I. Kim, J. Larraín, K. M. Lyons, M. Oelgeschläger, E. Pera, O. Wessely for discussions and comments on the manuscript. J.G.A. was a Latin American PEW fellow. This work was supported by the National Institutes of Health (R37 HD21502-16). E.M.D.R. is an Investigator of the Howard Hughes Medical Institute.

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Correspondence to E. M. De Robertis.

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Supplementary figures

Figure S1. Expression pattern of CTGF in Xenopus embryogenesis detected by in situ hybridization. dorsal aspect of the somite (f-i). (PDF 485 kb)

Figure S2. CTGF constructs and expression of CTGF proteins in human 293T cells, Xenopus embryos and Drosophila S2 cells.

Figure S3. Synergy between TGF-β1 and CTGF: Induction of striking morphological changes in Mv1Lu cells.

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Abreu, J., Ketpura, N., Reversade, B. et al. Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-β. Nat Cell Biol 4, 599–604 (2002). https://doi.org/10.1038/ncb826

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