title: Mechanisms through which Sos-1 coordinates the activation of Ras and Rac.
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.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti, 435, 20141 Milan, Italy.
authors.forename: Metello
authors.initials: M
authors.lastname: Innocenti
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Tenca
authors.forename: Emanuela
authors.initials: E
authors.lastname: Frittoli
authors.forename: Mario
authors.initials: M
authors.lastname: Faretta
authors.forename: Arianna
authors.initials: A
authors.lastname: Tocchetti
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Di Fiore
authors.forename: Giorgio
authors.initials: G
authors.lastname: Scita
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D003598:Cytoskeletal Proteins; D004789:Enzyme Activation; D051380:GRB2 Adaptor Protein; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D046911:Macromolecular Substances; D008954:Models, Biological; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D020837:SOS1 Protein / Q000378:metabolism*; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C513733:ABI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C489989:EPS8 protein, human; D051380:GRB2 Adaptor Protein; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D011506:Proteins; D020837:SOS1 Protein; D020744:rac GTP-Binding Proteins; D018631:ras Proteins