Epidermal growth factor (EGF) receptor tyrosine kinase activity is inhibited by growth factor-stimulated kinases involved in cellular signaling. Mitogen-activated protein (MAP) kinase is activated in response to a wide variety of growth modulating agents including EGF. To determine whether MAP kinase can inactivate the EGF receptor tyrosine kinase, we investigated the effect of pp42 MAP kinase on the EGF receptor. The results indicate that direct phosphorylation of the EGF receptor by MAP kinase does not alter receptor tyrosine kinase activity. However, MAP kinase can decrease EGF receptor tyrosine phosphorylation through a vanadate-sensitive pathway involving activation of a tyrosine phosphatase.