title: Gab2 phosphorylation by RSK inhibits Shp2 recruitment and cell motility.
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.
authors: Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.
authors: Xiaocui
authors: X
authors: Zhang
authors: Genevieve
authors: G
authors: Lavoie
authors: Loic
authors: L
authors: Fort
authors: Edward L
authors: EL
authors: Huttlin
authors: Joseph
authors: J
authors: Tcherkezian
authors: Jacob A
authors: JA
authors: Galan
authors: Haihua
authors: H
authors: Gu
authors: Steven P
authors: SP
authors: Gygi
authors: Sebastien
authors: S
authors: Carreno
authors: Philippe P
authors: PP
authors: Roux
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement; D005260:Female; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D009154:Mutation; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D048868:Adaptor Proteins, Signal Transducing; D001549:Benzamides; C490895:GAB2 protein, human; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D034741:RNA, Small Interfering; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
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