JNK and Insulin Converge at Foxo

Abstract

Insulin and insulin-like growth factor (IGF) signaling (IIS) promotes growth and energy storage but also shortens life span, whereas signaling by the Jun N-terminal kinase (JNK) pathway lengthens life span. One mechanism by which IIS decreases life span is by inhibition of the activity of the transcription factor Foxo. Increased Foxo activity is associated with tolerance to stress, such as oxidative stress, and oxidative stress is associated with stimulation of the JNK pathway, a mitogen-activated protein kinase (MAPK) cascade. Wang et al. provide evidence in Drosophila that JNK mediates its life span-lengthening effect by increasing the activity of Foxo and thereby antagonizing the IIS pathway. First, the long-lived phenotype of flies heterozygous for the JNK pathway negative regulator, puc (which encodes a JNK-specific MAPK phosphatase), was reversed when the flies were also heterozygous for dfoxo . Genetic interactions were also noted in the fly eye for dfoxo and hep , which encodes a JNK kinase, and for dfoxo and bsk , which encodes Drosophila JNK. Evidence for direct antagonism of IIS was provided by analysis of fat body cells overexpressing the insulin receptor InR with or without coexpression of an activated form of Hep. Overexpression of InR produces overgrowth of these cells, which have no detectable nuclear dFoxo, whereas coexpression of activated Hep results in suppression of overgrowth and the appearance of dFoxo in the nucleus. Activation of the JNK pathway also stimulated expression of dFoxo target genes, including the Drosophila homolog of eIF4E binding protein, an inhibitor of translation. JNK also influences life span by activity in the insulin-producing cells (IPCs) in the fly brain. JNK activity was high in the IPCs, and activation of the JNK pathway in genetically altered flies ( puc heterozygotes or flies overexpressing activated Hep) inhibited expression of dilp2 , the gene encoding Drosophila insulin-like peptide 2, and this inhibition required dFoxo. Thus, JNK signaling exerts two effects that contribute to life span: In individual cells, JNK antagonizes the IIS pathway, and in the IPCs, JNK antagonizes the expression of insulin-like peptide, thereby affecting life span at an organismal level. M. C. Wang, D. Bohmann, H. Jasper, JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling. Cell 121 , 115-125 (2005). [PubMed]