title: Extracellular Signal-Regulated Kinases 1 and 2 Phosphorylate Gab2 To Promote a Negative-Feedback Loop That Attenuates Phosphoinositide 3-Kinase/Akt Signaling.
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.
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Xiaocui
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Lavoie
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Antoine
authors.initials: A
authors.lastname: Méant
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Léo
authors.initials: L
authors.lastname: Aubert
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Cargnello
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: André
authors.initials: A
authors.lastname: Haman
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.|Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Trang
authors.initials: T
authors.lastname: Hoang
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada philippe.roux@umontreal.ca.|Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Philippe P
authors.initials: PP
authors.lastname: Roux
mesh_terms: D000595:Amino Acid Sequence; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D025461:Feedback, Physiological; D051380:GRB2 Adaptor Protein / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008407:Mast Cells / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D000072417:Protein Domains; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
chemical_list: D051380:GRB2 Adaptor Protein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins
keywords: AKT signaling; ERK1/2; Gab2; PI3K; mast cells; mitogen-activated protein kinases; protein phosphorylation