title: Activation of Ras requires the ERM-dependent link of actin to the plasma membrane.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  Taking 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.
authors: Morrison Laboratory, Leibniz Institute for Age Research-Fritz Lipmann Institute, Jena, Germany.
authors: Tobias
authors: T
authors: Sperka
authors: Katja J
authors: KJ
authors: Geissler
authors: Ulrike
authors: U
authors: Merkel
authors: Ingmar
authors: I
authors: Scholl
authors: Ignacio
authors: I
authors: Rubio
authors: Peter
authors: P
authors: Herrlich
authors: Helen L
authors: HL
authors: Morrison
mesh_terms: D000199:Actins / Q000378:metabolism; D000495:Allosteric Site; D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020664:Son of Sevenless Proteins / Q000737:chemistry / Q000378:metabolism; D053778:Thiazolidines / Q000494:pharmacology; D020663:ras Guanine Nucleotide Exchange Factors / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*; D000099149:Ezrin
chemical_list: D000199:Actins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D050505:Mutant Proteins; D017479:Receptors, Platelet-Derived Growth Factor; D020664:Son of Sevenless Proteins; D053778:Thiazolidines; D020663:ras Guanine Nucleotide Exchange Factors; D018631:ras Proteins; D000099149:Ezrin; C071058:moesin; C071776:radixin; C037068:latrunculin B