In brain, Axl recruits Grb2 and the p85 regulatory subunit of PI3 kinase; in vitro mutagenesis defines the requisite binding sites for downstream Akt activation |
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Authors: | Weinger Jason G Gohari Pouyan Yan Ying Backer Jonathan M Varnum Brian Shafit-Zagardo Bridget |
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Affiliation: | Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA; AMGEN, Thousand Oaks, California, USA |
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Abstract: | Axl is a receptor tyrosine kinase implicated in cell survival following growth factor withdrawal and other stressors. The binding of Axl's ligand, growth arrest-specific protein 6 (Gas6), results in Axl autophosphorylation, recruitment of signaling molecules, and activation of downstream survival pathways. Pull-down assays and immunoprecipitations using wildtype and mutant Axl transfected cells determined that Axl directly binds growth factor receptor-bound protein 2 (Grb2) at pYVN and the p85 subunit of phosphatidylinositol-3 kinase (PI3 kinase) at two pYXXM sites (pY779 and pY821). Also, p85 can indirectly bind to Axl via an interaction between p85's second proline-rich region and the N-terminal SH3 domain of Grb2. Further, Grb2 and p85 can compete for binding at the pY821VNM site. Gas6-stimulation of Axl-transfected COS7 cells recruited activated PI3 kinase and phosphorylated Akt. An interaction between Axl, p85 and Grb2 was confirmed in brain homogenates, enriched populations of O4+ oligodendrocytes, and O4− flow-through prepared from day 10 mouse brain, indicating that cells with active Gas6/Axl signal through Grb2 and the PI3 kinase/Akt pathways. |
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Keywords: | Akt signaling Axl receptor tyrosine kinase growth arrest-specific protein 6 growth factor receptor-bound protein 2 oligodendrocytes p85 subunit of phosphatidylinositol-3 kinase |
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