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

C Zhao, G Du, K Skowronek, MA Frohman… - Nature cell …, 2007 - nature.com
C Zhao, G Du, K Skowronek, MA Frohman, D Bar-Sagi
Nature cell biology, 2007nature.com
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 …
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.
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