The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5

How epidermal growth factor receptor (EGFR) signalling is linked to EGFR tr afficking is largely unknown. Signalling and trafficking involve small GTPa ses of the Rho and Rab families, respectively. But it remains unknown wheth er the signalling relying on these two classes of GTPases is integrated, an d, if it is, what molecular machinery is involved. Here we report that the protein Eps8 connects these signalling pathways. Eps8 is a substrate of the EGFR(1), which is held in a complex with Sos1 by the adaptor protein E3b1 (ref. 2), thereby mediating activation of Rac(2). Through its src homology- 3 domain, Eps8 interacts with RN-tre(3). We show that RN-tre is a Rab5 GTPa se-activating protein, whose activity is regulated by the EGFR. By entering in a complex with Eps8, RN-tre acts on Rab5 and inhibits internalization o f the EGFR. Furthermore, RN-tre diverts Eps8 from its Rac-activating functi on, resulting in the attenuation of Rac signalling. Thus, depending on its state of association with E3b1 or RN-tre, Eps8 participates in both EGFR si gnalling through Rac, and trafficking through Rab5.