Zhu J, Lin SJ, Zou C, Makanji Y, Jardetzky TS, Woodruff TK

Inhibin is a heterodimeric peptide hormone produced in the ovary that antagonizes activin signaling and FSH synthesis in the pituitary. The inhibin ?-subunit interacts with the activin type II receptor (ActRII) to functionally antagonize activin. The inhibin ?-subunit mature domain (N terminus) arose relatively early during the evolution of the ...

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hormone, and inhibin function is decreased by an antibody directed against the ?-subunit N-terminal extension region or by deletion of the N-terminal region. We hypothesized that the ?-subunit N-terminal extension region interacts with the activin type I receptor (ALK4) to antagonize activin signaling in the pituitary. Human or chicken free ?-subunit inhibited activin signaling in a pituitary gonadotrope-derived cell line (L?T2) in a dose-dependent manner, whereas an N-terminal extension deletion mutant did not. An ?-subunit N-terminal peptide, but not a control peptide, was able to inhibit activin A signaling and decrease activin-stimulated FSH synthesis. Biotinylated inhibin A, but not activin A, bound ALK4. Soluble ALK4-ECD bioneutralized human free ?-subunit in L?T2 cells, but did not affect activin A function. Competitive binding ELISAs with N-terminal mutants and an N-terminal region peptide confirmed that this region is critical for direct interaction of the ?-subunit with ALK4. These data expand our understanding of how endocrine inhibin achieves potent antagonism of local, constitutive activin action in the pituitary, through a combined mechanism of competitive binding of both ActRII and ALK4 by each subunit of the inhibin heterodimer, in conjunction with the co-receptor betaglycan, to block activin receptor-ligand binding, complex assembly, and downstream signaling.

Date: Mar. 09, 2012

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