Internalized Epidermal Growth Factor Receptors Participate

Regulated activation of the highly conserved Ras GTPase is a central event in the stimulation of cell pro-liferation, motility, and differentiation elicited by recep-tor tyrosine kinases, such as the epidermal growth fac-tor receptor (EGFR). In fibroblasts, this involves formation and membrane localization of ShczGrb2zSos complexes, which increases the rate of Ras guanine nu-cleotide exchange. In order to control Ras-mediated cell responses, this activity is regulated by receptor down-regulation and a feedback loop involving the dual spec-ificity kinase mitogen-activated protein kinase/extracel-lular signal-regulated kinase kinase (MEK). We investigated the role of EGFR endocytosis in the regu-lation of Ras activation. Of fundamental interest is whether activated receptors in endosomes can partici