Abstract 5191: Gab2 phosphorylation by RSK inhibits Shp2 recruitment and cell motility.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC 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 invasive-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. Based on the widespread role of Gab2 in receptor signaling, these findings also suggest that RSK plays a regulatory function in diverse receptor systems. Citation Format: Xiaocui Zhang, Genevieve Lavoie, Loic Fort, Edward L. Huttlin, Joseph Tcherkezian, Jacob A. Galan, Haihua Gu, Steven P. Gygi, Sebastien Carreno, Philippe P. Roux. Gab2 phosphorylation by RSK inhibits Shp2 recruitment and cell motility. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5191. doi:10.1158/1538-7445.AM2013-5191