Neuronal dCbl downregulates the EGFR‐ERK pathway and controls the production of Insulin‐like Peptides in Drosophila

Abstract

The Cbl proteins are a family of E3 ubiquitin ligases and adaptor proteins that regulates a diversity of cellular signaling and play essential roles in growth, development and survival. To explore the mechanism by which Cbl exerts its regulatory actions in vivo, here we show that in the fruit fly Drosophila melanogaster, dCbl controls multiple aspects of physiological processes through downregulating the expression of insulin‐like peptides (dilps) in the brain. We found knockdown by RNA interference of the expression of dCbl in neurons or specifically in insulin‐producing cells led to increased sensitivity to oxidative or nutrient stresses, decreased carbohydrate storage, and shortened lifespan. Moreover, neuronal dCbl deficiency caused elevations in the p‐dAkt and p‐dERK, which was accompanied by increased expression of dilps. Interestingly, genetic interaction analysis showed blocking neuronal dEGFR‐dERK signaling abolished dCbl deficiency‐mediated upregulation of dilps. In parallel, suppression of c‐Cbl in rat insulin‐producing INS‐1 cells also increased the production of insulin in an ERK‐dependent manner. Collectively, these results reveal that Cbl downregulation of the EGFR pathway is coupled to the dynamic control of insulin biosynthesis, suggesting Cbl may act through an evolutionarily conserved mechanism to participate in systemic modulation of growth, metabolism and lifespan.