title: Phospholipase D2-generated phosphatidic acid couples EGFR stimulation to Ras activation by Sos.
abstract: The activation of Ras by the guanine nucleotide-exchange factor Son of sevenless (Sos) constitutes the rate-limiting step in the transduction process that links receptor tyrosine kinases to Ras-triggered intracellular signalling pathways. A prerequisite for the function of Sos in this context is its ligand-dependent membrane recruitment, and the prevailing model implicates both the Sos carboxy-terminal proline-rich motifs and amino-terminal pleckstrin homology (PH) domain in this process. Here, we describe a previously unrecognized pathway for the PH domain-dependent membrane recruitment of Sos that is initiated by the growth factor-induced generation of phosphatidic acid via the signalling enzyme phospholipase D2 (PLD2). Phosphatidic acid interacts with a defined site in the Sos PH domain with high affinity and specificity. This interaction is essential for epidermal growth factor (EGF)-induced Sos membrane recruitment and Ras activation. Our findings establish a crucial role for PLD2 in the coupling of extracellular signals to Sos-mediated Ras activation, and provide new insights into the spatial coordination of this activation event.
authors.affiliation: Graduate Program in Genetics, Stony Brook University, Stony Brook NY 11794, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
authors.forename: Guangwei
authors.initials: G
authors.lastname: Du
authors.forename: Karl
authors.initials: K
authors.lastname: Skowronek
authors.forename: Michael A
authors.initials: MA
authors.lastname: Frohman
authors.forename: Dafna
authors.initials: D
authors.lastname: Bar-Sagi
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D019556:COS Cells; D002450:Cell Communication / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004705:Endocytosis / Q000502:physiology; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010712:Phosphatidic Acids / Q000378:metabolism*; D010739:Phospholipase D / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D020837:SOS1 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D010712:Phosphatidic Acids; D020837:SOS1 Protein; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; C105606:phospholipase D2; D010739:Phospholipase D; D018631:ras Proteins