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Sci. STKE, 19 September 2000
Vol. 2000, Issue 50, p. tw8
[DOI: 10.1126/stke.2000.50.tw8]

EDITORS' CHOICE

Receptor Biology Activating PI3K by Gab2

Gu et al. investigated how phosphatidylinositol-3 kinase (PI3K) is activated in response to cytokine receptors that do not directly bind PI3K. They now report that the 97-kD adaptor protein Gab2 is involved. By utilizing tyrosine to phenylalanine mutagenesis, the authors show that Tyr577 on the cytokine common beta (βc) receptor chain and Tyr338 on the interleukin 2 receptor β chain, residues already known to be important for binding the adaptor protein Shc, are important for mediating tyrosine phosphorylation of Gab2. Gab2 phosphorylation was also dependent on intact SH2 and SH3 domains on the adaptor protein Grb2, which suggests that, upon ligand binding, these receptors phosphorylate appropriate tyrosine residues for subsequent docking by Shc and then Grb2 and Gab2. Gu et al. also demonstrated that Gab2 and PI3K associate, albeit weakly, in a ligand-binding and time-dependent manner. Cells expressing Gab2 mutants unable to bind PI3K did not activate Akt (a substrate of PI3K) after treatment with interleukin 3, a cytokine that utilizes the βc chain. Thus, Shc and Grb2, which are known to associate with Sos, a nucleotide exchange factor for Ras, also associate with Gab2 and can mediate the activation of the PI3K signal pathway.

Gu, H., Maeda, H., Moon, J.J., Lord, J.D., Yoakim, M., Nelson, B.H., and Neel, B.G. (2000) New role for Shc in activation of the phosphatidylinositol 3-kinase/Akt pathway. Mol. Cell. Biol. 20: 7109-7120. [Abstract] [Full Text]

Citation: Activating PI3K by Gab2. Sci. STKE 2000, tw8 (2000).


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