| http://purl.uniprot.org/citations/30018141 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/30018141 | http://www.w3.org/2000/01/rdf-schema#comment | "The immune system includes abundant examples of biologically-relevant cross-regulation of signaling pathways by the T cell antigen receptor (TCR) and the G protein-coupled chemokine receptor, CXCR4. TCR ligation induces transactivation of CXCR4 and TCR-CXCR4 complex formation, permitting the TCR to signal via CXCR4 to activate a phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein (PREX1)-dependent signaling pathway that drives robust cytokine secretion by T cells. To understand this receptor heterodimer and its regulation, we characterized the molecular mechanisms required for TCR-mediated TCR-CXCR4 complex formation. We found that the cytoplasmic C-terminal domain of CXCR4 and specifically phosphorylation of Ser-339 within this region were required for TCR-CXCR4 complex formation. Interestingly, siRNA-mediated depletion of G protein-coupled receptor kinase-2 (GRK2) or inhibition by the GRK2-specific inhibitor, paroxetine, inhibited TCR-induced phosphorylation of CXCR4-Ser-339 and TCR-CXCR4 complex formation. Either GRK2 siRNA or paroxetine treatment of human T cells significantly reduced T cell cytokine production. Upstream, TCR-activated tyrosine kinases caused inducible tyrosine phosphorylation of GRK2 and were required for the GRK2-dependent events of CXCR4-Ser-339 phosphorylation and TCR-CXCR4 complex formation. Downstream of TCR-CXCR4 complex formation, we found that GRK2 and phosphatidylinositol 3-kinase γ (PI3Kγ) were required for TCR-stimulated membrane recruitment of PREX1 and for stabilization of cytokine mRNAs and robust cytokine secretion. Together, our results identify a novel role for GRK2 as a target of TCR signaling that is responsible for TCR-induced transactivation of CXCR4 and TCR-CXCR4 complex formation that signals via PI3Kγ/PREX1 to mediate cytokine production. Therapeutic regulation of GRK2 or PI3Kγ may therefore be useful for limiting cytokines produced by T cell malignancies or autoimmune diseases."xsd:string |
| http://purl.uniprot.org/citations/30018141 | http://purl.org/dc/terms/identifier | "doi:10.1074/jbc.ra118.003097"xsd:string |
| http://purl.uniprot.org/citations/30018141 | http://purl.uniprot.org/core/author | "Hedin K.E."xsd:string |
| http://purl.uniprot.org/citations/30018141 | http://purl.uniprot.org/core/author | "Kremer K.N."xsd:string |
| http://purl.uniprot.org/citations/30018141 | http://purl.uniprot.org/core/author | "Rollins M.R."xsd:string |
| http://purl.uniprot.org/citations/30018141 | http://purl.uniprot.org/core/author | "Dinkel B.A."xsd:string |
| http://purl.uniprot.org/citations/30018141 | http://purl.uniprot.org/core/author | "Medlyn M.J."xsd:string |
| http://purl.uniprot.org/citations/30018141 | http://purl.uniprot.org/core/date | "2018"xsd:gYear |
| http://purl.uniprot.org/citations/30018141 | http://purl.uniprot.org/core/name | "J Biol Chem"xsd:string |
| http://purl.uniprot.org/citations/30018141 | http://purl.uniprot.org/core/pages | "14022-14039"xsd:string |
| http://purl.uniprot.org/citations/30018141 | http://purl.uniprot.org/core/title | "GRK2 mediates TCR-induced transactivation of CXCR4 and TCR-CXCR4 complex formation that drives PI3Kgamma/PREX1 signaling and T cell cytokine secretion."xsd:string |
| http://purl.uniprot.org/citations/30018141 | http://purl.uniprot.org/core/volume | "293"xsd:string |
| http://purl.uniprot.org/citations/30018141 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/30018141 |
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