Induction of cancer cell migration by epidermal growth factor is initiated by specific phosphorylation of tyrosine 1248 of c-erbB-2 receptor via EGFR.
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.
D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D019281:Dimerization; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism*; D004963:Estrenes / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051966:Phospholipase C gamma; D010766:Phosphorylation / Q000187:drug effects; D011760:Pyrrolidinones / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D002118:Calcium; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D004963:Estrenes; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D051966:Phospholipase C gamma; D011760:Pyrrolidinones; D018719:Erb-b2 Receptor Tyrosine Kinases; D010738:Type C Phospholipases; D014443:Tyrosine; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione