Modulation of the SH2 binding specificity and kinase activity of Src by tyrosine phosphorylation within its SH2 domain

J Biol Chem. 1996 May 24;271(21):12481-7. doi: 10.1074/jbc.271.21.12481.


The Src family of kinases are held in an inactive state by interaction of their SH2 domain with a C-terminal phosphotyrosine. Dephosphorylation of this site can reactivate Src; however, recent evidence suggests that activation can also occur without dephosphorylation. In this study, platelet-derived growth factor receptor phosphorylation of Src on Tyr-213 specifically blocked binding of its SH2 domain to a phosphopeptide corresponding to the C-terminal regulatory sequence, while binding to other sequences, such as the platelet-derived growth factor receptor or a peptide from the epidermal growth factor receptor, was unaffected. Consequently, Src was activated over 50-fold. This is the first demonstration of regulation of a SH2 domain specificity by post-translational modification and is likely to be a general mechanism for regulation of all Src-like kinases.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Enzyme Activation
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Molecular Sequence Data
  • Oncogene Protein pp60(v-src) / chemistry
  • Oncogene Protein pp60(v-src) / metabolism*
  • Peptide Mapping
  • Phosphopeptides / chemistry
  • Phosphorylation
  • Protein-Tyrosine Kinases / chemistry
  • Protein-Tyrosine Kinases / metabolism*
  • Receptors, Platelet-Derived Growth Factor / metabolism
  • Spodoptera
  • Substrate Specificity
  • Tyrosine / metabolism*
  • src Homology Domains*


  • Phosphopeptides
  • Tyrosine
  • Protein-Tyrosine Kinases
  • Receptors, Platelet-Derived Growth Factor
  • Oncogene Protein pp60(v-src)