COMPLEMENTATION BETWEEN KINASE-DEFECTIVE AND ACTIVATION-DEFECTIVE TGF-BETA RECEPTORS REVEALS A NOVEL FORM OF RECEPTOR COOPERATIVITY ESSENTIAL FOR SIGNALING

Transforming growth factor-beta (TGF-beta) signals through two transme mbrane serine/threonine kinases, T beta R-I and T beta R-II, TGF-beta binds to T beta R-II, allowing this receptor to associate with and pho sphorylate T beta R-I which then propagates the signal, T beta R-I is phosphorylated within its GS domain, a region immediately preceding th e kinase domain, To further understand the function of T beta R-I in t his complex, we analyzed T beta R-I-inactivating mutations identified in cell lines that are defective in TGF-beta signaling yet retain liga nd binding ability, The three mutations identified here all fall in th e kinase domain of T beta R-I, One mutation disrupts the kinase activi ty of T beta R-I, whereas the other two mutations prevent ligand-induc ed T beta R-T phosphorylation, and thus activation, by T beta R-II, Un expectedly, a kinase-defective T beta R-I mutant can functionally comp lement an activation-defective T beta R-I mutant, by rescuing its T be ta R-II-dependent phosphorylation, Together with evidence that the lig and-induced receptor complex contains two or more T beta R-I molecules , these results support a model in which the kinase domain of one T be ta R-I molecule interacts with the GS domain of another, enabling its phosphorylation and activation by T beta R-II. This cooperative intera ction between T beta R-I molecules appears essential for TGF-beta sign al transduction.