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.
Mechanisms through which Sos-1 coordinates the activation of Ras and Rac / M. Innocenti, P. Tenca, E. Frittoli, M. Faretta, A. Tocchetti, P. P. Di Fiore, G. Scita. - In: THE JOURNAL OF CELL BIOLOGY. - ISSN 0021-9525. - 156:1(2002 Jan 07), pp. 125-36-136.
|Titolo:||Mechanisms through which Sos-1 coordinates the activation of Ras and Rac|
DI FIORE, PIER PAOLO (Penultimo)
SCITA, GIORGIO (Ultimo)
|Parole Chiave:||E3b1; Eps8; Rac; Ras; Sos-1|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||7-gen-2002|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1083/jcb.200108035|
|Appare nelle tipologie:||01 - Articolo su periodico|