Epidermal growth factor-induced tumor cell invasion and metastasis initiated by dephosphorylation and downregulation of focal adhesion kinase

Upregulated epidermal growth factor (EGF) receptor (EGFR) expression and EG FR-induced signaling have been correlated with progression to invasion and metastasis in a,vide variety of carcinomas, but the mechanism behind this i s not well understood. We show here that, in various human carcinoma cells that overexpress EGFR, EGF treatment induced rapid tyrosine dephosphorylati on of focal adhesion kinase (FAK) associated with downregulation of its kin ase activity. The downregulation of FAK activity was both required and suff icient for EGF-induced refractile morphological changes, detachment of cell s from the extracellular matrix, and increased tumor cell motility, invasio n, and metastasis. Tumor cells with downregulated FAK activity became less adherent to the extracellular matrix. However, once cells started reattachi ng, FAK activity was restored by activated integrin signaling. Moreover, th is process of readhesion and spreading could not be abrogated by further EG F stimulation. Interruption of transforming growth factor alpha-EGFR autocr ine regulation,vith an EGFR tyrosine kinase inhibitor led to a substantial increase in FAK tyrosine phosphorylation and inhibition of tumor cell invas ion in vitro. Consistent with this, FAK tyrosine phosphorylation was reduce d in cells from tumors growing in transplanted, athymic, nude mice, which h ave an intact autocrine regulation of the EGFR. We suggest that the dynamic regulation of FAK activity, initiated by EGF induced downregulation of FAK leading to cell detachment and increased motility and invasion, followed b y integrin dependent reactivation during readhesion, plays a role in EGF-as sociated tumor invasion and metastasis.