Insulin‐like growth factor‐1 activates Akt and Jun N‐terminal kinases (JNKs) in promoting the survival of T lymphocytes

PT Walsh, LM Smith, R O'Connor - Immunology, 2002 - Wiley Online Library
PT Walsh, LM Smith, R O'Connor
Immunology, 2002Wiley Online Library
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 …
Summary
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.
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