Letter abstract
Nature Cell Biology 9, 707 - 712 (2007)
Published online: 7 May 2007 | doi:10.1038/ncb1594
Phospholipase D2-generated phosphatidic acid couples EGFR stimulation to Ras activation by Sos
Chen Zhao1,2,3, Guangwei Du4, Karl Skowronek5, Michael A. Frohman1,4 & Dafna Bar-Sagi1,2,5
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.
- Graduate Program in Genetics, Stony Brook University, Stony Brook NY 11794, USA.
- Department of Molecular Genetics and Microbiology Stony Brook University, Stony Brook NY 11794, USA.
- Department of Biochemistry, NYU School of Medicine New York, NY 10016, USA.
- Department of Pharmacology and Center for Developmental Genetics, Stony Brook University, Stony Brook NY 11794, USA.
- Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794, USA.
Correspondence to: Dafna Bar-Sagi1,2,5 e-mail: Dafna.Bar-Sagi@med.nyu.edu
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