Desensitization of Ras Activation by a Feedback Disassociation of the SOS-Grb2 Complex

作者：Steven B. Waters, Kathleen H. Holt, Susan E. Ross, Li-Jyun Syu, Kun‐Liang Guan, Alan R. Saltiel, Gary A. Koretzky, Jeffrey E. Pessin · 发表于：Journal of Biological Chemistry · 年份：1995 · DOI：10.1074/jbc.270.36.20883 · 被引用次数：158 · 研究领域：Protein Kinase Regulation and GTPase Signaling、Endoplasmic Reticulum Stress and Disease、Cellular transport and secretion

Activation of Ras by the exchange of bound GDP for GTP is predominantly catalyzed by the guanylnucleotide exchange factor SOS. Receptor tyrosine kinases increase Ras-GTP loading by targeting SOS to the plasma membrane location of Ras through the small adaptor protein Grb2. However, despite the continuous stimulation of receptor tyrosine kinase activity, Ras activation is transient and, in the case of insulin, begins returning to the GDP-bound state within 5 min. We report here that the cascade of serine kinases activated directly by Ras results in a mitogen-activated protein kinase kinase (MEK)-dependent phosphorylation of SOS and subsequent disassociation of the Grb2-SOS complex, thereby interrupting the ability of SOS to catalyze nucleotide exchange on Ras. These data demonstrate a molecular feedback mechanism accounting for the desensitization of Ras-GTP loading following insulin stimulation.