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J. Cell Biol. 156 (1): 125-136

Copyright © 2002 by the Rockefeller University Press.

Article

Mechanisms through which Sos-1 coordinates the activation of Ras and Rac

Metello Innocenti1, Pierluigi Tenca1, Emanuela Frittoli1, Mario Faretta1, Arianna Tocchetti1, Pier Paolo Di Fiore1,2,3, and Giorgio Scita1

1 Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti, 435, 20141 Milan, Italy
2 IFOM, The FIRC Institute for Molecular Oncology, 20134 Milan, Italy
3 Dipartimento di Medicina Chirurgia ed Odontoiatria, Universita' degli Studi di Milano, 20122 Milan, Italy

Address correspondence to Giorgio Scita, Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti, 435, 20141 Milano, Italy. Tel.: 39-0257489825. Fax: 39-0257489851. E-mail: gscita{at}ieo.it

Abstract: Signaling from receptor tyrosine kinases (RTKs)* requires the sequential activation of the small GTPases Ras and Rac. Son of sevenless (Sos-1), a bifunctional guanine nucleotide exchange factor (GEF), activates Ras in vivo and displays Rac-GEF activity in vitro, when engaged in a tricomplex with Eps8 and E3b1–Abi-1, a RTK substrate and an adaptor protein, respectively. A mechanistic understanding of how Sos-1 coordinates Ras and Rac activity is, however, still missing. Here, we demonstrate that (a) Sos-1, E3b1, and Eps8 assemble into a tricomplex in vivo under physiological conditions; (b) Grb2 and E3b1 bind through their SH3 domains to the same binding site on Sos-1, thus determining the formation of either a Sos-1–Grb2 (S/G) or a Sos-1–E3b1–Eps8 (S/E/E8) complex, endowed with Ras- and Rac-specific GEF activities, respectively; (c) the Sos-1–Grb2 complex is disrupted upon RTKs activation, whereas the S/E/E8 complex is not; and (d) in keeping with the previous result, the activation of Ras by growth factors is short-lived, whereas the activation of Rac is sustained. Thus, the involvement of Sos-1 at two distinct and differentially regulated steps of the signaling cascade allows for coordinated activation of Ras and Rac and different duration of their signaling within the cell.

Key Words: Sos-1; Eps8; E3b1; Ras; Rac

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