Activation of Ras by receptor tyrosine kinases.
Ras, a small GTP-binding protein, is an important component of the signal transduction pathway used by growth factors to initiate cell growth and differentiation. Cell activation with growth factors such as epidermal growth factor (EGF) induces Ras to move from an inactive GDP-bound state to an active GTP-bound state. Recently, a combination of genetic and biochemical studies has resulted in the elucidation of a signaling pathway that leads from growth factor receptors to Ras. After binding EGF, the EGF receptor tyrosine kinase is activated, leading to receptor autophosphorylation on multiple tyrosine residues. Signaling proteins with Src homology 2 (SH2) domains then bind to these tyrosine-phosphorylated residues, initiating multiple signaling cascades. One of these SH2 domain proteins, Grb2, exists in the cytoplasm in a preformed complex with a second protein, Son of Sevenless (Sos), which can catalyze Ras GTP/GDP exchange. After growth factor stimulation, the tyrosine phosphorylated EGF receptor binds the Grb2/Sos complex, translocating it to the plasma membrane. This translocation is thought to bring Sos into close proximity with Ras, leading to the activation of Ras. In contrast, the insulin receptor does not bind Grb2 directly but rather induces the tyrosine phosphorylation of two proteins, insulin receptor substrate-1 and Shc, that bind the Grb2/Sos complex. Once Ras is activated, it proceeds to stimulate a cascade of protein kinases that are important in a myriad of growth factor responses.
Margolis
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Department of Pharmacology, New York University Medical Center, NY 10016.
Skolnik
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D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics; D004331:Drosophila melanogaster / Q000235:genetics; D004789:Enzyme Activation; D051380:GRB2 Adaptor Protein; D005786:Gene Expression Regulation; D006133:Growth Substances / Q000502:physiology; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007668:Kidney / Q000502:physiology; D010750:Phosphoproteins / Q000502:physiology; D010766:Phosphorylation; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D011972:Receptor, Insulin / Q000502:physiology; D012440:Saccharomyces / Q000235:genetics; D015290:Second Messenger Systems / Q000502:physiology; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D006133:Growth Substances; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D011506:Proteins; D020794:Receptor Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D018631:ras Proteins