title: Insulin-like growth factor-1 activates Akt and Jun N-terminal kinases (JNKs) in promoting the survival of T lymphocytes.
abstract: Insulin-like growth factor 1 receptor (IGF-1R) expression is augmented on T cells upon ligation of CD28, and this promotes IGF-1-mediated protection from Fas-induced cell death for up to 6 days. To determine the mechanism of action of IGF-1R in T-cell expansion, we investigated the signalling pathways activated by IGF-1 in T cells and in Jurkat cells. We found that IGF-1 transiently induces Akt, jun N-terminal kinases (JNK), and c-Jun phosphorylation in activated T cells, with JNK and c-Jun phosphorylation occurring faster than Akt phosphorylation. To mimic IGF-1R expression levels in CD28-stimulated Jurkat cells these cells were stably transfected to over-express the IGF-1R. Jurkat/IGF-1R cells exhibited enhanced constitutive Akt phosphorylation compared with mock-transfected controls, but IGF-1 induced transient phosphorylation of MKK4, JNKs, and c-Jun. Inhibition of PI-3 kinase activity and Akt phosphorylation with LY294002 totally suppressed IGF-1-mediated protection from Fas killing in activated T cells, but only partially suppressed IGF-1-mediated protection in Jurkat/IGF-1R cells. However, either dicumarol in T cells or a dominant negative JNK1 (APF) in Jurkat/IGF-1R cells greatly suppressed IGF-1-mediated protection from Fas killing. Together, these data demonstrate that IGF-1-mediated activation of JNKs and PI-3 kinase contributes to normal T-cell survival, whereas the JNK pathway may be more important in Jurkat leukaemia cells.
authors.affiliation: Department of Biochemistry and Biosciences Research Institute, National University of Ireland, Cork, Ireland.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Walsh
authors.forename: Loraine M
authors.initials: LM
authors.lastname: Smith
authors.forename: Rosemary
authors.initials: R
authors.lastname: O'Connor
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D015153:Blotting, Western; D002867:Chromones / Q000494:pharmacology; D001728:Dicumarol / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique / Q000379:methods; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000276:immunology*; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology*; D009025:Morpholines / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000276:immunology*; D051057:Proto-Oncogene Proteins c-akt; D017978:Receptors, Growth Factor / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D019014:fas Receptor; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D007334:Insulin-Like Growth Factor I; D001728:Dicumarol; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases