Modulation of Activin Signal Transduction by Inhibin B and Inhibin-Binding Protein (InhBP)

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Abstract
An antagonistic relationship between inhibin and activin is essential to the control of pituitary FSH release and to normal gonadal function. Two in- hibin ligands, inhibin A and inhibin B, are made by the ovary in females, and each regulate pituitary FSH at different times during the reproductive cy- cle. Inhibin B, but not inhibin A, is produced by the testes and is therefore responsible for all inhibin- dependent FSH regulation in males. Although the activin signal transduction pathway has been well characterized, little is known about the mechanism of inhibin signaling and its relationship to activin antagonism. A recently cloned inhibin-binding pro- tein, InhBP (p120), associates strongly with the type IB activin receptor (Alk4) in a ligand-respon- sive manner and interacts to a lesser extent with other activin and bone morphogenetic protein (BMP) type I and activin type II receptors. Activin stimulates the association of InhBP and Alk4, and inhibin B, but not inhibin A, interferes with InhBP- Alk4 complex formation. InhBP is necessary to me- diate a specific antagonistic effect of inhibin B on activin-stimulated transcription. Appropriate stoi- chiometry between InhBP and the activin type I receptor is crucial to InhBP function. These find- ings suggest that InhBP is an inhibin B-specific receptor that mediates antagonism of activin sig- nal transduction through the modulation of activin heteromeric receptor complex assembly. (Molecu- lar Endocrinology 15: 668-679, 2001)

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