A Novel Positive Feedback Loop Mediated by the Docking Protein Gab1 and Phosphatidylinositol 3-Kinase in Epidermal Growth Factor Receptor Signaling
作者： Gerard A. Rodrigues , Marco Falasca , Zhongtao Zhang , Siew Hwa Ong , Joseph Schlessinger
DOI: 10.1128/MCB.20.4.1448-1459.2000
关键词: Biology 、 Cancer research 、 Cell biology 、 Cyclin-dependent kinase 9 、 Protein kinase A 、 ERBB3 、 Mitogen-activated protein kinase kinase 、 Cyclin-dependent kinase 8 、 ASK1 、 MAP kinase kinase kinase 、 Akt/PKB signaling pathway
摘要: The Gab1 protein is tyrosine phosphorylated in response to various growth factors and serves as a docking that recruits number of downstream signaling proteins, including phosphatidylinositol 3-kinase (PI-3 kinase). To determine the role via epidermal factor (EGF) receptor (EGFR) we tested ability associate with modulate by this receptor. We show associates EGFR vivo vitro pTyr sites 1068 1086 carboxy-terminal tail overexpression potentiates EGF-induced activation mitogen-activated kinase Jun pathways. A mutant unable bind p85 subunit PI-3 defective potentiating signaling, confirming for effector Gab1. Inhibition dominant-interfering or Wortmannin treatment similarly impairs Gab1-induced enhancement EGFR. PH domain was shown specifically 3,4,5-triphosphate [PtdIns(3,4,5)P3], product kinase, required Gab1-mediated signaling. Moreover, mediates translocation plasma membrane EGF efficient phosphorylation upon stimulation. In addition, blocks potentiation Finally, expression gene lipid phosphatase PTEN, which dephosphorylates PtdIns(3,4,5)P3, inhibits membrane. These results reveal novel positive feedback loop, modulated functions both an upstream regulator
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