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|Title:||14-3-3:Shc scaffolds integrate phosphoserine and phosphotyrosine signaling to regulate phosphatidylinositol 3-kinase activation and cell survival|
|Citation:||Journal of Biological Chemistry, 2009; 284(18):12080-12090|
|Publisher:||Amer Soc Biochemistry Molecular Biology Inc|
|Emma F. Barry, Fernando A. Felquer, Jason A. Powell, Lisa Biggs, Frank C. Stomski, Andrea Urbani, Hayley Ramshaw, Peter Hoffmann, Matthew C. Wilce, Michele A. Grimbaldeston, Angel F. Lopez and Mark A. Guthridge|
|Abstract:||Integrated cascades of protein tyrosine and serine/threonine phosphorylation play essential roles in transducing signals in response to growth factors and cytokines. How adaptor or scaffold proteins assemble signaling complexes through both phosphotyrosine and phosphoserine/threonine residues to regulate specific signaling pathways and biological responses is unclear. We show in multiple cell types that endogenous 14-3-3zeta is phosphorylated on Tyr(179) in response to granulocyte macrophage colony-stimulating factor. Importantly, 14-3-3zeta can function as an intermolecular bridge that couples to phosphoserine residues and also directly binds the SH2 domain of Shc via Tyr(179). The assembly of these 14-3-3:Shc scaffolds is specifically required for the recruitment of a phosphatidylinositol 3-kinase signaling complex and the regulation of CTL-EN cell survival in response to cytokine. The biological significance of these findings was further demonstrated using primary bone marrow-derived mast cells from 14-3-3zeta(-/-) mice. We show that cytokine was able to promote Akt phosphorylation and viability of primary mast cells derived from 14-3-3zeta(-/-) mice when reconstituted with wild type 14-3-3zeta, but the Akt phosphorylation and survival response was reduced in cells reconstituted with the Y179F mutant. Together, these results show that 14-3-3:Shc scaffolds can act as multivalent signaling nodes for the integration of both phosphoserine/threonine and phosphotyrosine pathways to regulate specific cellular responses.|
|Keywords:||Cell Line; Mast Cells; Animals; Mice, Knockout; Humans; Mice; Phosphotyrosine; Phosphoserine; 14-3-3 Proteins; Granulocyte-Macrophage Colony-Stimulating Factor; Signal Transduction; Cell Survival; Enzyme Activation; Phosphorylation; Mutation, Missense; Proto-Oncogene Proteins c-akt; Shc Signaling Adaptor Proteins; Phosphatidylinositol 3-Kinases|
|Rights:||© 2009 by The American Society for Biochemistry and Molecular Biology, Inc.|
|Appears in Collections:||Medicine publications|
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