The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5.
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 EGFR, which is held in a complex with Sos1 by the adaptor protein E3bl (ref. 2), thereby mediating activation of Rac. Through its src homology-3 domain, Eps8 interacts with RN-tre. 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.
Lanzetti
L
L
Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
Rybin
V
V
Malabarba
M G
MG
Christoforidis
S
S
Scita
G
G
Zerial
M
M
Di Fiore
P P
PP
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism; D002384:Catalysis; D003001:Cloning, Molecular; D003598:Cytoskeletal Proteins; D004705:Endocytosis; D066246:ErbB Receptors / Q000378:metabolism*; D020690:GTPase-Activating Proteins; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D020837:SOS1 Protein / Q000378:metabolism; D015398:Signal Transduction; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
C513733:ABI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C489989:EPS8 protein, human; D020690:GTPase-Activating Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015514:Oncogene Proteins, Fusion; D011506:Proteins; D011993:Recombinant Fusion Proteins; D020837:SOS1 Protein; C100665:USP6NL protein, human; D066246:ErbB Receptors; D020696:rab5 GTP-Binding Proteins; D020744:rac GTP-Binding Proteins