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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.
Highlights
A major mechanism of signal transduction by receptor tyrosine kinases (RTKs)* involves the activation of small GTPases, among which Ras and Rac are pivotal (Scita et al, 2000)
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, 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 guanine nucleotide exchange factor (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 shortlived, whereas the activation of Rac is sustained
We showed that Sos-1, E3b1, and Eps8 could form a trimeric complex in vivo upon concomitant overexpression of the three proteins
Summary
A major mechanism of signal transduction by receptor tyrosine kinases (RTKs)* involves the activation of small GTPases, among which Ras and Rac are pivotal (Scita et al, 2000). There is evidence for hierarchical organization of small GTPases in signal transduction pathways (Van Aelst and D’Souza-Schorey, 1997; Hall, 1998; Scita et al, 2000). Regulators of small GTPase activity, such as the guanine nucleotide exchange factor (GEF) son of sevenless (Sos-1), appear to control different events in the signaling cascade (for review see Bar-Sagi and Hall, 2000; Schlessinger, 2000; Scita et al, 2000). Sos-1 contains a Dbl homology domain in tandem with a Pleckstrin homology domain, a module responsible for GEF activity on Rho GTPases
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