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Sci. STKE, 21 November 2000
Vol. 2000, Issue 59, p. tw7
[DOI: 10.1126/stke.2000.59.tw7]

EDITORS' CHOICE

Small GTPases Balancing Signaling versus Endocytosis

The small guanosine triphosphatases (GTPases) Rab5 and Rac are involved, respectively, in endocytosis and signal transduction to the c-Jun-NH2-terminal kinase (JNK). Epidermal growth factor receptors (EGFRs), when activated, stimulate multiple signal transduction cascades, including the Rac pathway to JNK, and are also endocytosed in a ligand-dependent manner. Lanzetti et al. have uncovered a link between these two processes in the form of the protein Eps8, which is recruited to the activated EGFR and, in a complex with E3b1and Sos-1, can act as a Rac guanine exchange factor (GEF). Eps8 also influences Rab5, in this case through RN-tre, a GTPase-activating protein (GAP) for Rab5 that can inhibit constitutive endocytosis (represented by transferrin uptake) and ligand-dependent endocytosis (of the ligand-bound EGFR) when overexpressed in cells. In order for RN-tre to inhibit EGFR endocytosis, it must interact with Eps8 through the same domain on Eps8 that interacts with E3bl. Thus, a complex regulatory process exists to balance the signal transmitted from the EGFR through the Eps8 GEF complex to Rac and through the Eps8 interaction with RN-tre to stimulate endocytosis of the activated receptor.

Lanzetti, L., Rybin, V., Malabarba, M.G., Christoforidis, S., Scita, G., Zerial, M., and Di Fiore, P.P. (2000) The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5. Nature 408: 374-377. [Online Journal]

Citation: Balancing Signaling versus Endocytosis. Sci. STKE 2000, tw7 (2000).


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