The pleckstrin homology domain of Gab-2 is required for optimal interleukin-3 signalsome-mediated responses

Reference:

Edmead, C. E., Fox, B. C., Stace, C., Ktistakis, N. and Welham, M. J., 2006. The pleckstrin homology domain of Gab-2 is required for optimal interleukin-3 signalsome-mediated responses. Cellular Signalling, 18 (8), pp. 1147-1155.

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Official URL:

http://dx.doi.org/10.1016/j.cellsig.2005.09.002

Abstract

The adaptor protein Gab-2 coordinates the assembly of the IL-3 signalsome comprising Gab-2, Grb2, Shc, SHP-2 and PI3K. To investigate the role of the pleckstrin homology domain of Gab-2 in this process, epitope-tagged wild type Gab-2 (WTGab-2), Gab-2 lacking its PH domain (ΔPHGab-2) and the Gab-2 PH domain alone (PHGab-2) were inducibly expressed in IL-3-dependent BaF/3 cells. Expression of ΔPHGab-2 reduced IL-3-dependent proliferation and long-term activation of ERK1 and 2 and PKB by IL-3. While we demonstrate that the Gab-2 PH domain can bind PI(3,4,5)P3, it is dispensable for Gab-2 membrane localisation, tyrosine phosphorylation and signalsome formation. Rather, the proline-rich motifs of Gab-2 appear to contribute to the constitutive membrane localisation we observe, independently of tyrosine phosphorylation or the PH domain. Taken together, these findings suggest that once Gab-2 is tyrosine phosphorylated its PH domain is required for the optimal stabilisation of the signalsome, enabling full activation of downstream signals.

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