title: 14-3-3:Shc scaffolds integrate phosphoserine and phosphotyrosine signaling to regulate phosphatidylinositol 3-kinase activation and cell survival.
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.
authors.affiliation: Cell Growth and Differentiation Laboratory, Division of Human Immunology, Hanson Institute, Institute of Medical and Veterinary Science, Frome Road, Adelaide, South Australia 5000, Australia.
authors.forename: Emma F
authors.initials: EF
authors.lastname: Barry
authors.forename: Fernando A
authors.initials: FA
authors.lastname: Felquer
authors.forename: Jason A
authors.initials: JA
authors.lastname: Powell
authors.forename: Lisa
authors.initials: L
authors.lastname: Biggs
authors.forename: Frank C
authors.initials: FC
authors.lastname: Stomski
authors.forename: Andrea
authors.initials: A
authors.lastname: Urbani
authors.forename: Hayley
authors.initials: H
authors.lastname: Ramshaw
authors.forename: Peter
authors.initials: P
authors.lastname: Hoffmann
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Wilce
authors.forename: Michele A
authors.initials: MA
authors.lastname: Grimbaldeston
authors.forename: Angel F
authors.initials: AF
authors.lastname: Lopez
authors.forename: Mark A
authors.initials: MA
authors.lastname: Guthridge
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D010768:Phosphoserine / Q000378:metabolism*; D019000:Phosphotyrosine / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D048948:14-3-3 Proteins; D055765:Shc Signaling Adaptor Proteins; D010768:Phosphoserine; D019000:Phosphotyrosine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt