Inhibin is an antagonist of bone morphogenetic protein signaling.
Inhibins are endogenous antagonists of activin signaling, long recognized as important regulators of gonadal function and pituitary FSH release. Inhibin, in concert with its co-receptor, betaglycan, can compete with activin for binding to type II activin receptors and, thus, prevent activin signaling. Because bone morphogenetic proteins (BMPs) also utilize type II activin receptors, we hypothesized that BMP signaling might also be sensitive to inhibin blockade. Here we show that inhibin blocks cellular responses to diverse BMP family members in a variety of BMP-responsive cell types. Inhibin abrogates BMP-induced Smad signaling and transcription responses. Inhibin competes with BMPs for type II activin receptors, and this competition is facilitated by betaglycan. Betaglycan also enables inhibin to bind to and compete with BMPs for binding to the BMP-specific type II receptor BMPRII, which does not bind inhibin in the absence of betaglycan. Betaglycan can confer inhibin responsiveness on cells that are otherwise insensitive to inhibin. These findings demonstrate that inhibin, acting through betaglycan, can function as an antagonist of BMP responses, suggesting a broader role for inhibin and betaglycan in restricting and refining a wide spectrum of transforming growth factor beta superfamily signals.
Wiater
Ezra
E
Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Vale
Wylie
W
D030201:Activin Receptors, Type I / Q000378:metabolism; D030301:Activin Receptors, Type II / Q000378:metabolism / Q000502:physiology; D001667:Binding, Competitive; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007265:Inhibins / Q000378:metabolism / Q000502:physiology*; D011506:Proteins; D011509:Proteoglycans / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D019485:Bone Morphogenetic Proteins; D011506:Proteins; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; C071736:betaglycan; D007265:Inhibins; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B