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 transmembrane 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 phosphorylate T beta R‐I which then propagates the signal. T beta R‐I is phosphorylated within its GS domain, a region immediately preceding the kinase domain. To further understand the function of T beta R‐I in this complex, we analyzed T beta R‐I‐inactivating mutations identified in cell lines that are defective in TGF‐beta signaling yet retain ligand binding ability. The three mutations identified here all fall in the kinase domain of T beta R‐I. One mutation disrupts the kinase activity of T beta R‐I, whereas the other two mutations prevent ligand‐induced T beta R‐I phosphorylation, and thus activation, by T beta R‐II. Unexpectedly, a kinase‐defective T beta R‐I mutant can functionally complement an activation‐ defective T beta R‐I mutant, by rescuing its T beta R‐II‐ dependent phosphorylation. Together with evidence that the ligand‐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 beta R‐I molecule interacts with the GS domain of another, enabling its phosphorylation and activation by T beta R‐II. This cooperative interaction between T beta R‐I molecules appears essential for TGF‐beta signal transduction.