title: Properties of inhibin binding to betaglycan, InhBP/p120 and the activin type II receptors.
abstract: Activin-stimulated FSH synthesis and release by the pituitary gonadotrope is antagonized by gonadally derived inhibins. The two isoforms of inhibin, inhibin A and B, bind to the activin type II receptors, though at a lower affinity than the activins, but do not stimulate intracellular signaling. Theoretically, therefore, inhibins can prevent activin signaling through competitive binding if present at higher concentrations than the activins. In reality, the inhibins have been shown to antagonize activin signaling when the two ligand types are present at equimolar concentrations. These observations led to the hypothesis that inhibin binding proteins or co-receptors exist that either increase the affinity of the inhibins for the activin receptors or propagate inhibin-specific intracellular signals. Two candidate inhibin co-receptors, betaglycan and InhBP/p120, interact with activin receptors and augment inhibin antagonism of activin action. Here, we report the effect of betaglycan and InhBP/p120 on both inhibin A and inhibin B binding to the activin receptors ActRIIA and ActRIIB2. InhBP/p120 did not bind inhibin A or B when expressed alone or in combination with activin receptors, requiring a re-examination of the role of this protein in inhibin biology. Both inhibins bound the activin type II receptor, ActRIIB2. Inhibin B had a higher affinity for this receptor than inhibin A but an approximately 10-fold lower affinity than that of activin A. Inhibin A and B bound betaglycan with high affinity; however, only inhibin A binding to ActRIIB2 was significantly enhanced in the presence of betaglycan. Both inhibin isoforms showed slight but significant binding to ActRIIA, yet this binding was potentiated in the presence of betaglycan. Additionally, the complex formed between the inhibins, ActRIIA, and betaglycan was resistant to disruption by activin A, whereas activin A potently competed for inhibin binding to ActRIIB2 and betaglycan. Collectively, these data show that the inhibin isoforms have different affinities for the activin type II receptors but bind betaglycan with high affinity. A recently developed model of inhibin action proposes that inhibins form a high affinity, activin-resistant ternary complex with activin type II receptors and betaglycan, thereby providing a mechanism for inhibin antagonism of activin signaling. Importantly, the results presented here clearly show that this model does not apply equally to both forms of inhibin nor to the different activin type II receptor isoforms. Thus, it appears that the mechanisms of inhibin action may vary depending on the ligand and receptor types involved.
authors.affiliation: Department of Neurobiology and Physiology, Northwestern University, OT Hogan 4-150, 2153 N Campus Dr, Evanston, IL, USA.
authors.forename: Stacey C
authors.initials: SC
authors.lastname: Chapman
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Bernard
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Jelen
authors.forename: Teresa K
authors.initials: TK
authors.lastname: Woodruff
mesh_terms: D029404:Activin Receptors; D030201:Activin Receptors, Type I / Q000378:metabolism; D030301:Activin Receptors, Type II / Q000378:metabolism*; D028341:Activins / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D005260:Female; D006801:Humans; D028322:Inhibin-beta Subunits / Q000378:metabolism; D007265:Inhibins / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins; D011509:Proteoglycans / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D018000:Receptors, Peptide / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D011506:Proteins; D011509:Proteoglycans; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; C422405:activin A; C422362:inhibin A; C422364:inhibin B; D028341:Activins; C071736:betaglycan; D007265:Inhibins; D028322:Inhibin-beta Subunits; C425423:ACVR1 protein, human; D029404:Activin Receptors; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C425585:activin receptor type II-A; C425584:activin receptor type II-B