The TGF beta receptor activation process: an inhibitor- to substrate-binding switch

Mol Cell. 2001 Sep;8(3):671-82. doi: 10.1016/s1097-2765(01)00332-x.


The type I TGF beta receptor (T beta R-I) is activated by phosphorylation of the GS region, a conserved juxtamembrane segment located just N-terminal to the kinase domain. We have studied the molecular mechanism of receptor activation using a homogeneously tetraphosphorylated form of T beta R-I, prepared using protein semisynthesis. Phosphorylation of the GS region dramatically enhances the specificity of T beta R-I for the critical C-terminal serines of Smad2. In addition, tetraphosphorylated T beta R-I is bound specifically by Smad2 in a phosphorylation-dependent manner and is no longer recognized by the inhibitory protein FKBP12. Thus, phosphorylation activates T beta R-I by switching the GS region from a binding site for an inhibitor into a binding surface for substrate. Our observations suggest that phosphoserine/phosphothreonine-dependent localization is a key feature of the T beta R-I/Smad activation process.

Publication types

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

MeSH terms

  • Activin Receptors, Type I*
  • Amino Acid Sequence
  • Cell Cycle Proteins*
  • Checkpoint Kinase 2
  • Crystallography, X-Ray
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Immunoblotting
  • Models, Biological
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Phosphorylation
  • Protein Binding
  • Protein Serine-Threonine Kinases / chemical synthesis
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Saccharomyces cerevisiae Proteins*
  • Smad2 Protein
  • Tacrolimus Binding Protein 1A / metabolism
  • Trans-Activators / chemistry
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / metabolism


  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Receptors, Transforming Growth Factor beta
  • Recombinant Fusion Proteins
  • Saccharomyces cerevisiae Proteins
  • Smad2 Protein
  • Trans-Activators
  • Transforming Growth Factor beta
  • Checkpoint Kinase 2
  • Protein Serine-Threonine Kinases
  • Activin Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type I
  • RAD53 protein, S cerevisiae
  • Tacrolimus Binding Protein 1A

Associated data

  • PDB/1IAS