Complementation between kinase-defective and activation-defective TGF-beta receptors reveals a novel form of receptor cooperativity essential for signaling

EMBO J. 1996 Jan 15;15(2):276-89.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cell Line
  • Conserved Sequence
  • Genetic Complementation Test
  • Humans
  • Macromolecular Substances
  • Models, Structural
  • Molecular Sequence Data
  • Mutation*
  • Point Mutation
  • Polymerase Chain Reaction
  • Protein Structure, Secondary*
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / chemistry
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Sequence Deletion
  • Sequence Homology, Amino Acid
  • Signal Transduction*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transfection

Substances

  • Macromolecular Substances
  • Receptors, Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • Tetradecanoylphorbol Acetate