title: Inhibin α-subunit N terminus interacts with activin type IB receptor to disrupt activin signaling.
abstract: Inhibin is a heterodimeric peptide hormone produced in the ovary that antagonizes activin signaling and FSH synthesis in the pituitary. The inhibin β-subunit interacts with the activin type II receptor (ActRII) to functionally antagonize activin. The inhibin α-subunit mature domain (N terminus) arose relatively early during the evolution of the hormone, and inhibin function is decreased by an antibody directed against the α-subunit N-terminal extension region or by deletion of the N-terminal region. We hypothesized that the α-subunit N-terminal extension region interacts with the activin type I receptor (ALK4) to antagonize activin signaling in the pituitary. Human or chicken free α-subunit inhibited activin signaling in a pituitary gonadotrope-derived cell line (LβT2) in a dose-dependent manner, whereas an N-terminal extension deletion mutant did not. An α-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 α-subunit in LβT2 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 α-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.
authors.affiliation: Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.forename: S Jack
authors.initials: SJ
authors.lastname: Lin
authors.forename: Chao
authors.initials: C
authors.lastname: Zou
authors.forename: Yogeshwar
authors.initials: Y
authors.lastname: Makanji
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Jardetzky
authors.forename: Teresa K
authors.initials: TK
authors.lastname: Woodruff
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002645:Chickens; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007265:Inhibins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D009154:Mutation; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D010455:Peptides; C094377:inhibin-alpha subunit; D007265:Inhibins; C498932:ACVR1B protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498933:Acvr1b protein, mouse; C425585:activin receptor type II-A