Phospholipase D2-generated phosphatidic acid couples EGFR stimulation to Ras activation by Sos

Nat Cell Biol. 2007 Jun;9(6):706-12. doi: 10.1038/ncb1594. Epub 2007 May 7.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs / physiology
  • Animals
  • Binding Sites / physiology
  • COS Cells
  • Cell Communication / physiology
  • Cell Membrane / metabolism*
  • Chlorocebus aethiops
  • Endocytosis / physiology
  • Epidermal Growth Factor / metabolism
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • HeLa Cells
  • Humans
  • Mice
  • NIH 3T3 Cells
  • Phosphatidic Acids / metabolism*
  • Phospholipase D / metabolism*
  • Protein Structure, Tertiary / physiology
  • Protein Transport / physiology
  • SOS1 Protein / chemistry
  • SOS1 Protein / genetics
  • SOS1 Protein / metabolism*
  • Signal Transduction / physiology
  • ras Proteins / metabolism*


  • Phosphatidic Acids
  • SOS1 Protein
  • Epidermal Growth Factor
  • EGFR protein, human
  • ErbB Receptors
  • phospholipase D2
  • Phospholipase D
  • ras Proteins