Induction of cancer cell migration by epidermal growth factor is initiated by specific phosphorylation of tyrosine 1248 of c-erbB-2 receptor via EGFR

FASEB J. 2002 Nov;16(13):1823-5. doi: 10.1096/fj.02-0096fje. Epub 2002 Sep 19.


Induction of tumor cell migration is a key step in invasion and metastasis. Here we report that the epidermal growth factor (EGF)-induced cell migration of breast cancer cells is attributed to a transient, rather than a sustained, activation of phospholipase C (PLC)-gamma1 due to c-erbB-2 signaling. EGF stimulation of EGF receptor (EGFR) overexpressing cells resulted in long-term PLC-gamma1 tyrosine phosphorylation and sustained levels of inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG) producing sinusoidal calcium oscillations. In contrast, c-erbB-2/EGFR expressing cells displayed baseline transient calcium oscillations after EGF treatment due to short-term PLC-gamma1 tyrosine phosphorylation and short-term IP3 and DAG turnover. A third cell line expressing a point-mutated c-erbB-2 receptor that lacks the autophosphorylation Y1248 was generated to investigate whether the different PLC-gamma1 activation was attributed to this structure. Neither PLC-gamma1 tyrosine phosphorylation nor IP3 and DAG turnover and calcium oscillations were observed in this cell line, indicating the modulation of the PLC-g1 activation time course by c-erbB-2 signaling. Induction of cell migration was solely observable in the c-erbB-2-positive cell line as proved by the mode of actin reorganization and a cell migration assay, using a 3D-collagen lattice. In summary, c-erbB-2 up-regulation switches on the cell migration program by modulating the time course of PLC-gamma1 activation.

MeSH terms

  • Calcium / metabolism
  • Cell Movement / drug effects*
  • Dimerization
  • Enzyme Activation / drug effects
  • Epidermal Growth Factor / pharmacology*
  • ErbB Receptors / chemistry
  • ErbB Receptors / metabolism*
  • Estrenes / pharmacology
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Phosphodiesterase Inhibitors / pharmacology
  • Phospholipase C gamma
  • Phosphorylation / drug effects
  • Pyrrolidinones / pharmacology
  • Receptor, ErbB-2 / chemistry
  • Receptor, ErbB-2 / metabolism*
  • Signal Transduction
  • Tumor Cells, Cultured
  • Type C Phospholipases / antagonists & inhibitors
  • Type C Phospholipases / metabolism
  • Tyrosine / metabolism


  • Estrenes
  • Isoenzymes
  • Phosphodiesterase Inhibitors
  • Pyrrolidinones
  • 1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
  • Tyrosine
  • Epidermal Growth Factor
  • ErbB Receptors
  • Receptor, ErbB-2
  • Type C Phospholipases
  • Phospholipase C gamma
  • Calcium