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Extracellular Signal-Regulated Kinases 1 and 2 Phosphorylate Gab2 To Promote a Negative-Feedback Loop That Attenuates Phosphoinositide 3-Kinase/Akt Signaling.

Authors :
Xiaocui Zhang
Lavoie, Geneviève
Méant, Antoine
Aubert, Léo
Cargnello, Marie
Haman, André
Trang Hoang
Roux, Philippe P.
Source :
Molecular & Cellular Biology. Apr2017, Vol. 37 Issue 7, p1-16. 16p.
Publication Year :
2017

Abstract

The scaffolding adapter protein Gab2 (Grb2-associated binder) promotes cell proliferation, survival, and motility by engaging several signaling pathways downstream of growth factor and cytokine receptors. In particular, Gab2 plays essential roles in mast cells, as it is required for phosphoinositide 3-kinase (PI3K) activation in response to Kit and the high-affinity IgE receptor. While the positive role of Gab2 in PI3K signaling is well documented, very little is known about the mechanisms that attenuate its function. Here we show that Gab2 becomes phosphorylated on multiple proline-directed sites upon stimulation of the Ras/extracellular signal-regulated kinase (ERK) signaling pathway. We demonstrate that ERK1 and ERK2 interact with Gab2 via a novel docking motif, which is required for subsequent Gab2 phosphorylation in response to ERK1/2 activation. We identified four ERK1/2-dependent phosphorylation sites in Gab2 that prevent the recruitment of the p85 regulatory subunit of PI3K. Using bone marrow-derived mast cells to study Gab2-dependent signaling, we found that the inhibition of ERK1/2 activity promotes Akt signaling in response to Kit and the high-affinity IgE receptor. Together, our results indicate that ERK1/2 participates in a negative-feedback loop that attenuates PI3K/Akt signaling in response to various agonists. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
02707306
Volume :
37
Issue :
7
Database :
Academic Search Index
Journal :
Molecular & Cellular Biology
Publication Type :
Academic Journal
Accession number :
122019817
Full Text :
https://doi.org/10.1128/MCB.00357-16