TGF-beta activates Erk MAP kinase signalling through direct phosphorylation of ShcA

EMBO J. 2007 Sep 5;26(17):3957-67. doi: 10.1038/sj.emboj.7601818. Epub 2007 Aug 2.

Abstract

Erk1/Erk2 MAP kinases are key regulators of cell behaviour and their activation is generally associated with tyrosine kinase signalling. However, TGF-beta stimulation also activates Erk MAP kinases through an undefined mechanism, albeit to a much lower level than receptor tyrosine kinase stimulation. We report that upon TGF-beta stimulation, the activated TGF-beta type I receptor (TbetaRI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic TbetaRI tyrosine kinase activity that complements its well-defined serine-threonine kinase function. TGF-beta-induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well-characterised pathway linking receptor tyrosine kinases with Erk MAP kinases. We also found that TbetaRI is tyrosine phosphorylated in response to TGF-beta. Thus, TbetaRI, like the TGF-beta type II receptor, is a dual-specificity kinase. Recruitment of tyrosine kinase signalling pathways may account for aspects of TGF-beta biology that are independent of Smad signalling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Line
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / physiology*
  • GRB2 Adaptor Protein / metabolism
  • Humans
  • Mice
  • Phosphorylation
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Shc Signaling Adaptor Proteins
  • Signal Transduction*
  • Son of Sevenless Protein, Drosophila / metabolism
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Transforming Growth Factor beta / physiology*

Substances

  • Adaptor Proteins, Signal Transducing
  • GRB2 Adaptor Protein
  • Receptors, Transforming Growth Factor beta
  • SHC1 protein, human
  • Shc Signaling Adaptor Proteins
  • Shc1 protein, mouse
  • Son of Sevenless Protein, Drosophila
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Transforming Growth Factor beta
  • Extracellular Signal-Regulated MAP Kinases