GRB2 INTERACTION WITH MEK-KINASE-1 IS INVOLVED IN REGULATION OF JUN-KINASE ACTIVITIES IN RESPONSE TO EPIDERMAL GROWTH-FACTOR

Epidermal growth factor (EGF) receptor was shown to be involved in the activation pathway of the stress-activated protein kinase/c-Jun NH2-t erminal kinase (SAPK/JNK) cascade not only by EGF, but also by UV radi ation or osmotic stress. This paper describes a specific interaction b etween the COOH-terminal SH3 domain of Grb2 and the NH2-terminal regul atory domain of MEKK1 in ER22 cells overexpressing the EGF receptor. T his interaction results in the formation of a constitutive complex bet ween Grb2 and MEKK1 in both proliferating and resting cells. EGF stimu lation causes this complex to be rapidly and transiently recruited by Shc proteins. The subsequent release of the Grb2-MEKK1 complex from Sh c proteins correlates with JNK activation. Transfection of the NH2-ter minal regulatory domain of MEKK1 specifically inhibits EGF-dependent J NK activation indicating that Grb2 is involved in MEKK1 activation. Th us, adaptor proteins have a new role in the regulation of the SAPK/JNK cascade after EGF stimulation.