Src tyrosine kinase signaling antagonizes nuclear localization of FOXO and inhibits its transcription factor activity

Abstract

Biochemical experiments in mammalian cells have linked Src family kinase activity to the insulin signaling pathway. To explore the physiological link between Src and a central insulin pathway effector, we investigated the effect of different Src signaling levels on the Drosophila transcription factor dFOXO in vivo. Ectopic activation of Src42A in the starved larval fatbody was sufficient to drive dFOXO out of the nucleus. When Src signaling levels were lowered by means of loss-of-function mutations or pharmacological inhibition, dFOXO localization was shifted to the nucleus in growing animals, and transcription of the dFOXO target genes d4E-BP and dInR was induced. dFOXO loss-of-function mutations rescued the induction of dFOXO target gene expression and the body size reduction of Src42A mutant larvae, establishing dFOXO as a critical downstream effector of Src signaling. Furthermore, we provide evidence that the regulation of FOXO transcription factors by Src is evolutionarily conserved in mammalian cells.

Resveratrol Prevents Oxidative Stress-Induced Senescence and Proliferative Dysfunction by Activating the AMPK-FOXO3 Cascade in Cultured Primary Human Keratinocytes

“…One such target is the FOXO family of transcription factors. Increased FOXO activity initiates stress as well as insulin signaling responses [ 33 , 34 ]. Unlike human umbilical vein endothelial cells that we are studying in another line of research; keratinocytes express more FOXO3 than FOXO1 ( Fig.…”

CDCP1 overexpression drives prostate cancer progression and can be targeted in vivo

“…Note that both CDCP1 isoforms localized at the cell membrane of the salivary gland of the fly, as assessed by costaining of E-cadherin, and presented similar expression levels (Supplemental Figure 3, A-C, arrows). Interestingly, loss of 1 allele (50% reduction) of src42A and src64B (35,38,39), the 2 Src homologs in Drosophila, suppressed extra macrochaetae formation driven by the overexpression of CDCP1-WT, demonstrating that this phenotype is Src-dependent (Supplemental Figure 3D). Collectively, this cross-species genetic approach demonstrates that CDCP1 overexpression in vivo initiates tumorigenesis.…”

Kinome Screen Identifies PFKFB3 and Glucose Metabolism as Important Regulators of the Insulin/Insulin-like Growth Factor (IGF)-1 Signaling Pathway

“…Insulin triggers GLUT4 translocation via the PI3K/Akt pathway, resulting in phosphorylation of downstream substrates including the Akt substrate AS160. In addition, a number of other protein kinases have been implicated in insulin action including Cdk5 (2,3), the G protein-coupled receptor kinase 2 (GRK2) (4,5), Src family kinases (6,7), members of the PKC family (8), and JNK (9). To understand the role of protein kinases and phosphorylation in insulin action we recently performed global analysis of insulin-regulated protein phosphorylation in 3T3-L1 adipocytes.…”

“…4. These candidates include a number of kinases that have previously been implicated in insulin signaling: connector enhancer of kinase suppressor of Ras 1 (CNKSR1) (34), death-associated protein kinase 3 (DAPK3)/ myosin light chain kinase (35,36), microtubule-associated serine/threonine-protein kinase 2 (MAST2) (37), TP53 regulating kinase (TP53RK) (38 -41), the Src adaptor protein phosphoprotein associated with glycosphingolipid microdomains (PAG) (6,7,42,43), and STK6 (44) (Fig. 4 and Table 1).…”