INACTIVATION OF ACTIVIN-DEPENDENT TRANSCRIPTION BY KINASE-DEFICIENT ACTIVIN RECEPTORS

Activin, a member of the transforming growth factor-beta superfamily, binds to two classes of cell surface receptors. These receptors, desig nated type I and type II, are structurally related members of transmem brane serine kinase superfamily. Antibodies specific for either type I or type II activin receptor can coprecipitate complexes containing bo th affinity-labeled receptors from activin-responsive cells. Two type I receptors show cell-specific expression and associate with the ligan d-binding, type II receptors. To investigate the roles of the cytoplas mic receptor domains in signaling through a heteromeric ligand recepto r complex, we have made kinase-deficient activin receptors and correla ted their losses in kinase activity with inhibitory effects on an acti vin-dependent transcriptional response in activin-responsive cell line s. Wild-type activin type II receptors phosphorylate activin type I re ceptors in transfected COS cells. In contrast, kinase-deficient activi n type II receptors fail to phosphorylate type I receptors in transfec ted COS cells and act as dominant negative mutants to block activin-in duced transcriptional activity in both Chinese hamster ovary and K562 (human erythroleukemia) cells. Kinase-deficient activin type IB recept ors also block activin-induced transcriptional activity in both Chines e hamster ovary and K562 cells, whereas kinase-deficient activin type I receptors have no effect in either cell line. These results indicate that kinase activities of both type II and type I receptors are requi red for activin signaling, and that the two type I receptors, which ar e expressed in a tissue-specific manner, are functionally distinct.