SRC-3Delta4 mediates the interaction of EGFR with FAK to promote cell migration

Mol Cell. 2010 Feb 12;37(3):321-32. doi: 10.1016/j.molcel.2010.01.004.


EGF induces signal transduction between EGFR and FAK, and FAK is required for EGF-induced cell migration. It is unknown, however, what factor mediates the interaction between EGFR and FAK and leads to EGF-induced FAK phosphorylation. Here, we identify SRC-3Delta4, a splicing isoform of the SRC-3 oncogene, as a signaling adaptor that links EGFR and FAK and promotes EGF-induced phosphorylations of FAK and c-Src. We identify three PAK1-mediated phosphorylations in SRC-3Delta4 that promote the localization of SRC-3Delta4 to the plasma membrane and mediate the interactions with EGFR and FAK. Importantly, overexpression of SRC-3Delta4 promotes MDA-MB231-induced breast tumor metastasis. Our findings identify phosphorylated SRC-3Delta4 as a missing adaptor between EGFR and its downstream signaling molecule FAK to coordinately regulate EGF-induced cell migration. Our study also reveals that a nuclear receptor coactivator can act in the periphery of a cell to directly mediate activation of an enzyme.

Publication types

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

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement / physiology*
  • ErbB Receptors / metabolism*
  • Female
  • Focal Adhesion Kinase 1 / analysis
  • Focal Adhesion Kinase 1 / metabolism*
  • Humans
  • Lung Neoplasms / secondary
  • Lymph Nodes / pathology
  • Lymphatic Metastasis
  • Mice
  • Neoplasm Metastasis
  • Nuclear Receptor Coactivator 3 / analysis
  • Nuclear Receptor Coactivator 3 / genetics
  • Nuclear Receptor Coactivator 3 / physiology*
  • Phosphorylation
  • Protein Isoforms / genetics
  • Protein Isoforms / physiology
  • Signal Transduction
  • p21-Activated Kinases / metabolism
  • src-Family Kinases / metabolism
  • src-Family Kinases / physiology


  • Protein Isoforms
  • NCOA3 protein, human
  • Nuclear Receptor Coactivator 3
  • EGFR protein, human
  • ErbB Receptors
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • src-Family Kinases
  • p21-Activated Kinases