DIFFERENTIAL MODULATION OF MITOGEN-ACTIVATED PROTEIN (MAP) KINASE EXTRACELLULAR SIGNAL-RELATED KINASE KINASE AND MAP KINASE-ACTIVITIES BY AMUTANT EPIDERMAL GROWTH-FACTOR RECEPTOR

A paradigm has been established whereby mutant tyrosine kinase recepto rs such as the v-erbB and v-fms gene products function as oncoproteins in the absence of ligand. A spontaneously occurring deletional mutant of the human epidermal growth factor receptor (EGFR-vIII) has been is olated from astrocytic neoplasms and transforms NIH3T3 cells in the ab sence of ligand. The EGFRvIII is constitutively completed with the maj ority of cellular GRB2, suggesting a link to the Ras-Mitogen-activated protein (MAP) kinase pathway (D. Moscatello, R. B. Montgomery, P. Sun dareshan, H. McDanel, M. Y. Wong, and A. J. Wong, submitted for public ation). In this report, we document that expression of EGFRvIII in fib roblasts is associated with downstream activation of mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (MEK) and modest activation of p42 and p44 MAP kinases. The presence of EGFRvIII suppresses activation of p42 and p44 MAP kinases by phorbol 12-myrist ate 13-acetate (PMA) and serum; however, MEK activation by PMA is not suppressed by EGFRvIII. Basal and PMA-stimulated MAP kinase activity i n EGFRvIII-transfected cells is augmented by the tyrosine phosphatase inhibitor sodium vanadate. EGFRvIII is capable of transducing downstre am signals through MAP kinase as evidenced by activation of cytoplasmi c phospholipase A(2) at levels similar to that induced by intact EGFR. Our results suggest that EGFRvIII constitutively activates downstream signal transduction through MAP kinase, and this chronic stimulation of the MAP kinase pathway may represent one means by which mutant EGFR transduces an oncogenic signal.