The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5 (original) (raw)

Nature volume 408, pages 374–377 (2000)Cite this article

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.

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Acknowledgements

We thank B. Matoskova for reagents and for helpful discussions, and N. Gholami-Shangolabad for technical assistance. This work was supported by grants from Associazione Italiana Ricerca sul Cancro, from the Armenise-Harvard Foundation and from the CNR (Progetto Biotecnologie).

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  1. Savvas Christoforidis
    Present address: Laboratory of Biological Chemistry, Medical School University of Ioannina, 45110, Ioannina, Greece

Authors and Affiliations

  1. Department of Experimental Oncology European Institute of Oncology, Milan, 20141, Italy
    Letizia Lanzetti, Maria Grazia Malabarba, Giorgio Scita & Pier Paolo Di Fiore
  2. Max Planck Institute for Molecular Cell Biology and Genetics, 01307 Dresden, c/o European Molecular Biology Laboratory (EMBL), Heidelberg, 69117, Germany
    Vladimir Rybin, Savvas Christoforidis & Marino Zerial
  3. IFOM, The FIRC Institute for Molecular Oncology, Milan, 20134, Italy
    Pier Paolo Di Fiore

Authors

  1. Letizia Lanzetti
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  2. Vladimir Rybin
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  3. Maria Grazia Malabarba
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  4. Savvas Christoforidis
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  5. Giorgio Scita
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  6. Marino Zerial
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  7. Pier Paolo Di Fiore
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Correspondence toPier Paolo Di Fiore.

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Lanzetti, L., Rybin, V., Malabarba, M. et al. The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5.Nature 408, 374–377 (2000). https://doi.org/10.1038/35042605

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