Identification of important regions in the cytoplasmic juxtamembrane domain of type I receptor that separate signaling pathways of transforming growth factor-beta

J Biol Chem. 1996 Feb 2;271(5):2769-75. doi: 10.1074/jbc.271.5.2769.


Proteins in the transforming growth factor-beta (TGF-beta) superfamily exert their effects by forming heteromeric complexes of their type I and type II serine/threonine kinase receptors. The type I and type II receptors form distinct subgroups in the serine/threonine kinase receptor family based on the sequences of the kinase domains and the presence of a highly conserved region called the GS domain (or type I box) located just N-terminal to the kinase domain in the type I receptors. Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signaling. Here we investigated the role of cytoplasmic juxtamembrane region located between the transmembrane domain and the GS domain of T beta R-I by mutational analyses using mutant mink lung epithelial cells, which lack endogenous T beta R-I. Upon transfection, wild-type T beta R-I restored the TGF-beta signals for growth inhibition and production of plasminogen activator inhibitor-1 (PAI-1) and fibronectin. A deletion mutant, T beta R-I/JD1(delta 150-181), which lacks the juxtamembrane region preceding the GS domain, bound TGF-beta in concert with T beta R-II and transduced a signal leading to production of PAI-I but not growth inhibition. Recombinant receptors with mutations that change serine 172 to alanine (S172A) or threonine 176 to valine (T176V) were similar to wild-type T beta R-I in their abilities to bind TGF-beta, formed complexes with T beta R-II, and transduced a signal for PAI-1 and fibronectin. Similar to T beta R-I/JD1 (delta 150-181), however, these missence mutant receptors were impaired to mediate a growth inhibitory signal. These observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cell Division
  • Cells, Cultured
  • Cytoplasm / metabolism*
  • DNA Primers
  • Epithelial Cells
  • Epithelium / metabolism
  • Lung / cytology
  • Lung / metabolism
  • Mink
  • Molecular Sequence Data
  • Mutagenesis
  • Phosphorylation
  • Receptors, Transforming Growth Factor beta / chemistry
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Sequence Deletion
  • Sequence Homology, Amino Acid
  • Serine / metabolism
  • Signal Transduction*
  • Threonine / metabolism
  • Transforming Growth Factor beta / metabolism*


  • DNA Primers
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • Threonine
  • Serine