Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-beta.
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.
Howard Hughes Medical Institute and Department of Biological Chemistry, University of California, Riverside, 9095-1662, USA.
José G
JG
Abreu
Nan I
NI
Ketpura
Bruno
B
Reversade
E M
EM
De Robertis
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D055513:Connective Tissue Growth Factor; D018076:DNA, Complementary / Q000235:genetics; D006133:Growth Substances / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017874:Immediate-Early Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D010641:Phenotype; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D014981:Xenopus / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029867:Xenopus Proteins
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D018076:DNA, Complementary; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D029867:Xenopus Proteins; C525812:bmp4 protein, Xenopus; D055513:Connective Tissue Growth Factor