GRK2 mediates TCR-induced transactivation of CXCR4 and TCR–CXCR4 complex formation that drives PI3Kγ/PREX1 signaling and T cell cytokine secretion
| Autor: | Michael J. Medlyn, Brittney A. Dinkel, Kimberly N. Kremer, Karen E. Hedin, Meagan R. Rollins |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Transcriptional Activation
0301 basic medicine Receptors CXCR4 G-Protein-Coupled Receptor Kinase 2 T-Lymphocytes T cell Immunology Receptors Antigen T-Cell chemical and pharmacologic phenomena Biochemistry 03 medical and health sciences chemistry.chemical_compound Transactivation 0302 clinical medicine medicine Class Ib Phosphatidylinositol 3-Kinase Guanine Nucleotide Exchange Factors Humans Phosphorylation Molecular Biology Binding Sites T-cell receptor hemic and immune systems Tyrosine phosphorylation Cell Biology T cell cytokine production Cell biology Interleukin 10 030104 developmental biology medicine.anatomical_structure chemistry 030220 oncology & carcinogenesis Cytokines Cytokine secretion Signal transduction Signal Transduction |
| Zdroj: | Journal of Biological Chemistry. 293:14022-14039 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.ra118.003097 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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