14-3-3: Shc scaffolds integrate phosphoserine and phosphotyrosine signaling to regulate phosphatidylinositol 3-kinase activation and cell survival

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, Mark A. Guthridge

Research output: Contribution to journalArticlepeer-review

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 14-3-3ξ is phosphorylated on Tyr179 in response to granulocyte macrophage colony-stimulating factor. Importantly, 14-3-3ξ can function as an intermolecular bridge that couples to phosphoserine residues and also directly binds the SH2 domain of Shc via Tyr179. 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 14-3-3ξ-/- mice. We show that cytokine was able to promote Akt phosphorylation and viability of primary mast cells derived from 14-3-3ξ-/- mice when reconstituted with wild type 14-3-3ξ, 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.

Original languageEnglish
Pages (from-to)12080-12090
Number of pages11
JournalJournal of Biological Chemistry
Volume284
Issue number18
DOIs
Publication statusPublished - May 1 2009

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Fingerprint

Dive into the research topics of '14-3-3: Shc scaffolds integrate phosphoserine and phosphotyrosine signaling to regulate phosphatidylinositol 3-kinase activation and cell survival'. Together they form a unique fingerprint.

Cite this