title: Regulation of Son of sevenless by the membrane-actin linker protein ezrin.
abstract: Receptor tyrosine kinases participate in several signaling pathways through small G proteins such as Ras (rat sarcoma). An important component in the activation of these G proteins is Son of sevenless (SOS), which catalyzes the nucleotide exchange on Ras. For optimal activity, a second Ras molecule acts as an allosteric activator by binding to a second Ras-binding site within SOS. This allosteric Ras-binding site is blocked by autoinhibitory domains of SOS. We have reported recently that Ras activation also requires the actin-binding proteins ezrin, radixin, and moesin. Here we report the mechanism by which ezrin modulates SOS activity and thereby Ras activation. Active ezrin enhances Ras/MAPK signaling and interacts with both SOS and Ras in vivo and in vitro. Moreover, in vitro kinetic assays with recombinant proteins show that ezrin also is important for the activity of SOS itself. Ezrin interacts with GDP-Ras and with the Dbl homology (DH)/pleckstrin homology (PH) domains of SOS, bringing GDP-Ras to the proximity of the allosteric site of SOS. These actions of ezrin are antagonized by the neurofibromatosis type 2 tumor-suppressor protein merlin. We propose an additional essential step in SOS/Ras control that is relevant for human cancer as well as all physiological processes involving Ras.
authors.affiliation: H.M. Laboratory, P.H. Laboratory, and M.E.T. Laboratory, Leibniz Institute for Age Research - Fritz Lipmann Institute, 07745 Jena, Germany.
authors.forename: Katja J
authors.initials: KJ
authors.lastname: Geissler
authors.forename: M Juliane
authors.initials: MJ
authors.lastname: Jung
authors.forename: Lars Björn
authors.initials: LB
authors.lastname: Riecken
authors.forename: Tobias
authors.initials: T
authors.lastname: Sperka
authors.forename: Yan
authors.initials: Y
authors.lastname: Cui
authors.forename: Stephan
authors.initials: S
authors.lastname: Schacke
authors.forename: Ulrike
authors.initials: U
authors.lastname: Merkel
authors.forename: Robby
authors.initials: R
authors.lastname: Markwart
authors.forename: Ignacio
authors.initials: I
authors.lastname: Rubio
authors.forename: Manuel E
authors.initials: ME
authors.lastname: Than
authors.forename: Constanze
authors.initials: C
authors.lastname: Breithaupt
authors.forename: Sebastian
authors.initials: S
authors.lastname: Peuker
authors.forename: Reinhard
authors.initials: R
authors.lastname: Seifert
authors.forename: Ulrich Benjamin
authors.initials: UB
authors.lastname: Kaupp
authors.forename: Peter
authors.initials: P
authors.lastname: Herrlich
authors.forename: Helen
authors.initials: H
authors.lastname: Morrison
mesh_terms: D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D006153:Guanosine Diphosphate / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D025581:Neurofibromin 2 / Q000235:genetics / Q000378:metabolism*; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D020664:Son of Sevenless Proteins / Q000235:genetics / Q000378:metabolism*; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D006153:Guanosine Diphosphate; D025581:Neurofibromin 2; D015689:Oncogene Protein p21(ras); D020664:Son of Sevenless Proteins; D000099149:Ezrin
keywords: ERM proteins; GEF regulation; autoinhibition