Phospholipase D2-generated phosphatidic acid couples EGFR stimulation to Ras activation by Sos
Phospholipase D2-generated phosphatidic acid couples EGFR stimulation to Ras activation by Sos
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DOI：
10.1038/ncb1594
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发表时间：
2007-06-01
影响因子：
21.3
通讯作者：
Bar-Sagi, Dafna
中科院分区：
文献类型：
--
作者：
Zhao, Chen;Du, Guangwei;Bar-Sagi, Dafna
由鸟嘌呤核苷酸交换因子Son of sevenless（Sos）激活Ras构成了将受体酪氨酸激酶与Ras触发的细胞内信号传导途径联系起来的转导过程中的限速步骤。在这种情况下，Sos的功能的先决条件是它的配体依赖性膜招聘，和流行的模型牵连的Sos羧基末端脯氨酸丰富的图案和氨基末端pleckstrin同源（PH）域在这个过程中。在这里，我们描述了一个以前未被识别的途径，为PH结构域依赖性膜招聘的Sos的是由生长因子诱导的磷脂酸的产生通过信号传导酶磷脂酶D2（PLD 2）。磷脂酸以高亲和力和特异性与Sos PH结构域中的限定位点相互作用。这种相互作用对于表皮生长因子（EGF）诱导的Sos膜募集和Ras活化是必不可少的。我们的研究结果确立了PLD 2在细胞外信号与Sos介导的Ras激活偶联中的关键作用，并为该激活事件的空间协调提供了新的见解。
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.