Modulation of cellular responses to activins and BMPs

Activins and BMPs (bone morphogenetic proteins) are TGFbeta superfamily members that mediate wide-ranging effects in many cell types. Numerous mechanisms exist in target cells to limit and control the actions of these factors. Among these are feedback mechanisms that can impede activin or BMP responses. In certain target cells activins induce a 'cytostatic' response, leading to a long-term decrease in cellular proliferation or complete cell cycle arrest. Studies presented in this dissertation describe the effects of prolonged exposure to activins on Smad signaling, promoter induction, and cellular proliferation in order to determine if these activin responses are subject to feedback suppression during extended exposure to activin. Interestingly, activin-induced Smad phosphorylation and downstream promoter induction are subject to feedback suppression, while the inhibition of cellular proliferation continues unabated as long as activin is present. These results suggest that some as yet unidentified signaling events or pathways maintain cellular growth arrest while Smad2 signaling and some activin responses are suppressed.;In addition to feedback suppression, activin signaling is inhibited by inhibin, another TGFbeta superfamily ligand that acts in conjunction with the cellular receptor betaglycan to bind type II activin receptors, thereby blocking activin access to its receptors. Because BMPs can also utilize type II activin receptors, a prediction of this model of inhibin action is that BMP actions might also be sensitive to inhibin blockade. Indeed, inhibin can block cellular responses to diverse BMP family members, including BMP-induced Smad signaling and transcription responses. Inhibin can compete with BMPs for type II activin receptors and this competition is facilitated by betaglycan. Betaglycan also enables inhibin to bind to and compete with BMPs for binding to the BMP specific type It receptor BMPRII, which does not bind inhibin in the absence of betaglycan. Finally, betaglycan can confer inhibin responsiveness on cells that are otherwise insensitive to inhibin. These findings demonstrate that inhibin, acting through betaglycan, can function as an antagonist of BMP responses.