PMID:23401857

Citation	Zhang, X, Lavoie, G, Fort, L, Huttlin, EL, Tcherkezian, J, Galan, JA, Gu, H, Gygi, SP, Carreno, S and Roux, PP (2013) Gab2 Phosphorylation by RSK Inhibits Shp2 Recruitment and Cell Motility. Mol. Cell. Biol. 33:1657-70
Abstract	The scaffolding adapter protein Gab2 (Grb2-associated binder) participates in the signaling response evoked by various growth factors and cytokines. Gab2 is overexpressed in several human malignancies, including breast cancer, and was shown to promote mammary epithelial cell migration. The role of Gab2 in the activation of different signaling pathways is well documented, but less is known regarding the feedback mechanisms responsible for its inactivation. We now demonstrate that activation of the Ras/mitogen-activated protein kinase (MAPK) pathway promotes Gab2 phosphorylation on basic consensus motifs. More specifically, we show that RSK (p90 ribosomal S6 kinase) phosphorylates Gab2 on three conserved residues, both in vivo and in vitro. Mutation of these phosphorylation sites does not alter Gab2 binding to Grb2, but instead, we show that Gab2 phosphorylation inhibits the recruitment of the tyrosine phosphatase Shp2 in response to growth factors. Expression of an unphosphorylatable Gab2 mutant in mammary epithelial cells promotes an invasion-like phenotype and increases cell motility. Taken together, these results suggest that RSK is part of a negative-feedback loop that restricts Gab2-dependent epithelial cell motility. On the basis of the widespread role of Gab2 in receptor signaling, these findings also suggest that RSK plays a regulatory function in diverse receptor systems.
Links	PubMed Online version:10.1128/MCB.01353-12
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:GAB2		GO:0008360: regulation of cell shape	ECO:0000315:		P		Figure 7A illustrates a more elongated cellular morphology in Gab2 mutants. Figure 7C provides further evidence by showing Gab2 mutants were 2 to 7 times more likely to have an elongated cell shape.	complete CACAO 7055
MOUSE:GAB2		GO:0010634: positive regulation of epithelial cell migration	ECO:0000315:		P		Figure 8	complete CACAO 7056
MOUSE:GAB2	involved_in	GO:0010634: positive regulation of epithelial cell migration	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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