Abstract
BackgroundReceptor tyrosine kinases (RTKs) participate in a multitude of signaling pathways, some of them via the small G-protein Ras. An important component in the activation of Ras is Son of sevenless (SOS), which catalyzes the nucleotide exchange on Ras.Principal FindingsWe can now demonstrate that the activation of Ras requires, in addition, the essential participation of ezrin, radixin and/or moesin (ERM), a family of actin-binding proteins, and of actin. Disrupting either the interaction of the ERM proteins with co-receptors, down-regulation of ERM proteins by siRNA, expression of dominant-negative mutants of the ERM proteins or disruption of F-actin, abolishes growth factor-induced Ras activation. Ezrin/actin catalyzes the formation of a multiprotein complex consisting of RTK, co-receptor, Grb2, SOS and Ras. We also identify binding sites for both Ras and SOS on ezrin; mutations of these binding sites destroy the interactions and inhibit Ras activation. Finally, we show that the formation of the ezrin-dependent complex is necessary to enhance the catalytic activity of SOS and thereby Ras activation.ConclusionsTaking these findings together, we propose that the ERM proteins are novel scaffolds at the level of SOS activity control, which is relevant for both normal Ras function and dysfunction known to occur in several human cancers.
Highlights
The small G-protein Ras functions as a molecular switch relaying extracellular stimuli to diverse intracellular effector pathways, which are responsible for controlling proliferation, motility and differentiation
Taking these findings together, we propose that the ERM proteins are novel scaffolds at the level of Son of sevenless (SOS) activity control, which is relevant for both normal Ras function and dysfunction known to occur in several human cancers
Kinetic resolution of platelet-derived growth factor (PDGF) signaling revealed attenuated Erk activation characterized by a shifted phosphorylation maximum and lower fold-induction
Summary
The small G-protein Ras functions as a molecular switch relaying extracellular stimuli to diverse intracellular effector pathways, which are responsible for controlling proliferation, motility and differentiation. Because of this central role Ras activity and its downstream signaling pathways must be tightly regulated. Specificity of GEF activity e.g. Son of sevenless (SOS) is linked to active RTKs through the adaptor protein, Growth factor receptor-bound protein 2 (Grb2), but is influenced in its activity through interaction with membrane lipids [1,2,3]. Receptor tyrosine kinases (RTKs) participate in a multitude of signaling pathways, some of them via the small G-protein Ras. An important component in the activation of Ras is Son of sevenless (SOS), which catalyzes the nucleotide exchange on Ras
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