Stress-Activated Protein Kinases (SAPKs) in IGF-I Mediated Cell Survival

Abstract

INTRODUCTION. The IGF-I receptor is a potent mediator of cell survival in response to diverse death stimuli in different tissues. Several signalling pathways can be activated by the IGF-IR including the PI-3 kinase/AKT pathways leading to cell death regulators. However, there is also evidence for IGF-I-mediated survival signalling that is not dependent on PI-3 kinase and AKT activation. Here, we investigated the stress activated protein kinases (SAPKs) including Jun Nterminal kinase (JNK) and p38 as candidate mediators of PI-3 kinase independent survival signalling. RESULTS. Initial experiments demonstrated that IGF-I elicits transient phosphorylation of JNK and c-Jun in FL5.12/IGF-IR cells (1) even in the presence of the PI-3 kinase inhibitor LY294002. To determine if JNK contributes to IGF-I-mediated survival signalling we used the quinone reductase inhibitor dicoumarol, which inhibits JNK activation (2). Dicoumarol suppressed IGF-I-induced phosphorylation of c-Jun and caused a dose-responsive abrogation of IGF-I-mediated protection from IL-3 withdrawal, but did not affect AKT activation (Fig. 1).