EGF-receptor specificity for phosphotyrosine-primed substrates provides signal integration with Src Academic Article uri icon


MeSH Major

  • Peptides
  • Phosphotyrosine
  • Receptor, Epidermal Growth Factor
  • Shc Signaling Adaptor Proteins


  • Aberrant activation of the EGF receptor (EGFR) contributes to many human cancers by activating the Ras-MAPK pathway and other pathways. EGFR signaling is augmented by Src-family kinases, but the mechanism is poorly understood. Here, we show that human EGFR preferentially phosphorylates peptide substrates that are primed by a prior phosphorylation. Using peptides based on the sequence of the adaptor protein Shc1, we show that Src mediates the priming phosphorylation, thus promoting subsequent phosphorylation by EGFR. Importantly, the doubly phosphorylated Shc1 peptide binds more tightly than singly phosphorylated peptide to the Ras activator Grb2; this binding is a key step in activating the Ras-MAPK pathway. Finally, a crystal structure of EGFR in complex with a primed Shc1 peptide reveals the structural basis for EGFR substrate specificity. These results provide a molecular explanation for the integration of Src and EGFR signaling with downstream effectors such as Ras.

publication date

  • January 2015



  • Academic Article



  • eng

PubMed Central ID

  • PMC4824005

Digital Object Identifier (DOI)

  • 10.1038/nsmb.3117

PubMed ID

  • 26551075

Additional Document Info

start page

  • 983

end page

  • 90


  • 22


  • 12