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

Letizia Lanzetti, Vladimir Rybin, Maria Grazia Malabarba, Savvas Christoforidis, Giorgio Scita, Marino Zerial and Pier Paolo Di Fiore ()
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Letizia Lanzetti: Department of Experimental Oncology European Institute of Oncology
Vladimir Rybin: Max Planck Institute for Molecular Cell Biology and Genetics, 01307 Dresden, c/o European Molecular Biology Laboratory (EMBL)
Maria Grazia Malabarba: Department of Experimental Oncology European Institute of Oncology
Savvas Christoforidis: Max Planck Institute for Molecular Cell Biology and Genetics, 01307 Dresden, c/o European Molecular Biology Laboratory (EMBL)
Giorgio Scita: Department of Experimental Oncology European Institute of Oncology
Marino Zerial: Max Planck Institute for Molecular Cell Biology and Genetics, 01307 Dresden, c/o European Molecular Biology Laboratory (EMBL)
Pier Paolo Di Fiore: Department of Experimental Oncology European Institute of Oncology

Nature, 2000, vol. 408, issue 6810, 374-377

Abstract: Abstract How epidermal growth factor receptor (EGFR) signalling is linked to EGFR trafficking is largely unknown. Signalling and trafficking involve small GTPases of the Rho and Rab families, respectively. But it remains unknown whether the signalling relying on these two classes of GTPases is integrated, and, 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 EGFR1, which is held in a complex with Sos1 by the adaptor protein E3b1 (ref. 2), thereby mediating activation of Rac2. Through its src homology-3 domain, Eps8 interacts with RN-tre3. We show that RN-tre is a Rab5 GTPase-activating protein, whose activity is regulated by the EGFR. By entering in a complex with Eps8, RN-tre acts on Rab5 and inhibits internalization of the EGFR. Furthermore, RN-tre diverts Eps8 from its Rac-activating function, resulting in the attenuation of Rac signalling. Thus, depending on its state of association with E3b1 or RN-tre, Eps8 participates in both EGFR signalling through Rac, and trafficking through Rab5.

Date: 2000
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DOI: 10.1038/35042605

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