INHIBIN INTERFERES WITH ACTIVIN SIGNALING AT THE LEVEL OF THE ACTIVINRECEPTOR COMPLEX IN CHINESE-HAMSTER OVARY CELLS

To gain more insight in the mechanism of action of inhibin, we studied the effect of inhibin on activin signaling in Chinese hamster ovary c ells. Inhibin specifically counteracted activin-induced expression of a plasminogen activator inhibitor 1 promoter element (3TP) and of the junB gent. but was ineffective when the responses were induced by tran sforming growth factor-beta. This indicates that inhibin acts only on the activin-specific part of these signaling cascades. Using a constit utively active activin type IB receptor we determined whether inhibin acted at the level of the activin-receptor complex or downstream of it . The mutant activin receptor stimulated the expression of the 3TP pro moter in the absence of activin. This stimulation was insensitive to i nhibin, indicating that inhibin acts exclusively at or upstream of thi s activin type I receptor. In addition. competition studies using labe led activin showed that inhibin displaced activin from the activin typ e II receptors, especially from the activin type IIB receptor, but not from the type I receptors. In conclusion. these data show that in Chi nese hamster ovary cells inhibin acts directly at the activin receptor complex, most likely through displacement of activin from the activin type II receptor.