MAPK, phosphatidylinositol 3-kinase, and mammalian target of rapamycin pathways converge at the level of ribosomal protein S6 phosphorylation to control metabolic signaling in CD8 T cells.
Ribosomal protein S6 (rpS6) is a key component of the translational machinery in eukaryotic cells and is essential for ribosome biogenesis. rpS6 is phosphorylated on evolutionarily conserved serine residues, and data indicate that rpS6 phosphorylation might regulate cell growth and protein synthesis. Studies in cell lines have shown an important role for the serine kinase mammalian target of rapamycin (mTOR) in rpS6 phosphorylation, further linking rpS6 to control of cellular metabolism. rpS6 is essential in T cells because its deletion in mouse double-positive thymocyte cells results in a complete block in T cell development; however, the signaling pathway leading to rpS6 phosphorylation downstream of TCR stimulation has yet to be fully characterized. We show that maximal TCR-induced rpS6 phosphorylation in CD8 T cells requires both Lck and Fyn activity and downstream activation of PI3K, mTOR, and MEK/ERK MAPK pathways. We demonstrate that there is cross-talk between the PI3K and MAPK pathways as well as PI3K-independent mTOR activity, which result in differential phosphorylation of specific rpS6 serine residues. These results place rpS6 phosphorylation as a point of convergence for multiple crucial signaling pathways downstream of TCR triggering.
Salmond
Robert J
RJ
Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom.
Emery
Juliet
J
Okkenhaug
Klaus
K
Zamoyska
Rose
R
D000818:Animals; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002352:Carrier Proteins / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000276:immunology* / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000276:immunology / Q000378:metabolism; D020239:Receptor Cross-Talk; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D019893:Ribosomal Protein S6 Kinases / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases
D002352:Carrier Proteins; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D051076:Proto-Oncogene Proteins c-fyn; D011948:Receptors, Antigen, T-Cell; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; C546843:mTOR protein, mouse; C494960:Fyn protein, mouse