Constitutively active protein kinase B enhances Lck and Erk activities and influences thymocyte selection and activation.
Protein kinase B (PKB), a serine threonine kinase is critically involved in cellular proliferation and survival. To characterize its role in T cell development in vivo, we have analyzed transgenic mice that express a membrane-targeted constitutively active version of PKB (myr PKB) in thymocytes and peripheral T cells. We report that myr PKB renders proliferative responses of thymocytes more sensitive to TCR signals by increased and sustained activation of Src kinase Lck and the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway. In addition, the proliferative response of myr PKB T cells is relatively independent of calcium mobilization and calcineurin activity. We also find that myr PKB enhances phosphorylation of glycogen synthase kinase 3, a negative regulator of NFAT and T cell activation, and the recruitment of the adapter protein Cbl-c. Interestingly, we demonstrate that upon TCR/CD3 stimulation of wild-type T cells PKB is translocated into lipid rafts, adding a new role for PKB in TCR-initiated signalosome formation in T cell activation. Localization of transgenic PKB in lipid rafts could contribute to the higher TCR sensitivity of myr PKB thymocytes which is reflected in an increase in positive selection toward the CD4 lineage and variable effects on negative selection depending on the model system analyzed. Thus, our observations clearly indicate a cross-talk between PKB and important signaling molecules downstream of TCR that modulate the thresholds of thymocyte selection and T cell activation.
Na
Shin-Young
SY
Institutes of Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
Patra
Amiya
A
Scheuring
Yvonne
Y
Marx
Alexander
A
Tolaini
Mauro
M
Kioussis
Dimitris
D
Hemmings
Brian A
BA
Hemmings
Brian
B
Hünig
Thomas
T
Bommhardt
Ursula
U
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D003433:Crosses, Genetic; D016572:Cyclosporine / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D021962:Membrane Microdomains / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019814:Myristic Acid / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology; D013950:Thymus Gland / Q000166:cytology* / Q000201:enzymology / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
D006131:Growth Inhibitors; D007527:Isoenzymes; D011518:Proto-Oncogene Proteins; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D019814:Myristic Acid; D003907:Dexamethasone; D016572:Cyclosporine; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases