Modulation of activin signal transduction by inhibin B and inhibin-bindingprotein (InhBP)

An antagonistic relationship between inhibin and activin is essential to th e control of pituitary FSH release and to normal gonadal function. Two inhi bin ligands, inhibin A and inhibin B, are made by the ovary in females, and each regulate pituitary FSH at different times during the reproductive cyc le. Inhibin B, but not inhibin A, is produced by the testes and is therefor e responsible for all inhibin-dependent FSH regulation in males. Although t he activin signal transduction pathway has been well characterized, little is known about the mechanism of inhibin signaling and its relationship to a ctivin antagonism. A recently cloned inhibin-binding protein, InhBP (p120), associates strongly with the type IB activin receptor (Alk4) in a ligand-r esponsive manner and interacts to a lesser extent with other activin and bo ne morphogenetic protein (BMP) type I and activin type II receptors. Activi n stimulates the association of InhBP and Alk4, and inhibin B, but not inhi bin A, interferes with InhBP-Alk4 complex formation. InhBP is necessary to mediate a specific antagonistic effect of inhibin B on activin-stimulated t ranscription. Appropriate stoichiometry between InhBP and the activin type I receptor is crucial to InhBP function. These findings suggest that InhBP is an inhibin B-specific receptor that mediates antagonism of activin signa l transduction through the modulation of activin heteromeric receptor compl ex assembly.