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, designated type I and type II, are structurally related members of transmembrane serine kinase superfamily. Antibodies specific for either type I or type II activin receptor can coprecipitate complexes containing both affinity-labeled receptors from activin-responsive cells. Two type I receptors show cell-specific expression and associate with the ligand-binding, type II receptors. To investigate the roles of the cytoplasmic receptor domains in signaling through a heteromeric ligand receptor complex, we have made kinase-deficient activin receptors and correlated their losses in kinase activity with inhibitory effects on an activin-dependent transcriptional response in activin-responsive cell lines. Wild-type activin type II receptors phosphorylate activin type I receptors in transfected COS cells. In contrast, kinase-deficient activin type II receptors fail to phosphorylate type I receptors in transfected COS cells and act as dominant negative mutants to block activin-induced transcriptional activity in both Chinese hamster ovary and K562 (human erythroleukemia) cells. Kinase-deficient activin type IB receptors also block activin-induced transcriptional activity in both Chinese 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 required for activin signaling, and that the two type I receptors, which are expressed in a tissue-specific manner, are functionally distinct.
Tsuchida
K
K
Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Vaughan
J M
JM
Wiater
E
E
Gaddy-Kurten
D
D
Vale
W W
WW
D029404:Activin Receptors; D028341:Activins; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D006224:Cricetinae; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D007265:Inhibins / Q000494:pharmacology*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011494:Protein Kinases / Q000172:deficiency*; D011817:Rabbits; D017978:Receptors, Growth Factor / Q000502:physiology*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection
D006133:Growth Substances; D017978:Receptors, Growth Factor; D018125:Receptors, Transforming Growth Factor beta; D028341:Activins; D007265:Inhibins; D011494:Protein Kinases; D029404:Activin Receptors