Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Graduate School of the Chinese Academy of Sciences, Shanghai, China.
Mol Cell Biol. 2012 Sep;32(18):3610-23. doi: 10.1128/MCB.00592-12. Epub 2012 Jul 9.
The Cbl family proteins function as both E3 ubiquitin ligases and adaptor proteins to regulate various cellular signaling events, including the insulin/insulin-like growth factor 1 (IGF1) and epidermal growth factor (EGF) pathways. These pathways play essential roles in growth, development, metabolism, and survival. Here we show that in Drosophila melanogaster, Drosophila Cbl (dCbl) regulates longevity and carbohydrate metabolism through downregulating the production of Drosophila insulin-like peptides (dILPs) in the brain. We found that dCbl was highly expressed in the brain and knockdown of the expression of dCbl specifically in neurons by RNA interference increased sensitivity to oxidative stress or starvation, decreased carbohydrate levels, and shortened life span. Insulin-producing neuron-specific knockdown of dCbl resulted in similar phenotypes. dCbl deficiency in either the brain or insulin-producing cells upregulated the expression of dilp genes, resulting in elevated activation of the dILP pathway, including phosphorylation of Drosophila Akt and Drosophila extracellular signal-regulated kinase (dERK). Genetic interaction analyses revealed that blocking Drosophila epidermal growth factor receptor (dEGFR)-dERK signaling in pan-neurons or insulin-producing cells by overexpressing a dominant-negative form of dEGFR abolished the effect of dCbl deficiency on the upregulation of dilp genes. Furthermore, knockdown of c-Cbl in INS-1 cells, a rat β-cell line, also increased insulin biosynthesis and glucose-stimulated secretion in an ERK-dependent manner. Collectively, these results suggest that neuronal dCbl regulates life span, stress responses, and metabolism by suppressing dILP production and the EGFR-ERK pathway mediates the dCbl action. Cbl suppression of insulin biosynthesis is evolutionarily conserved, raising the possibility that Cbl may similarly exert its physiological actions through regulating insulin production in β cells.
Cbl 家族蛋白作为 E3 泛素连接酶和衔接蛋白发挥作用，调节包括胰岛素/胰岛素样生长因子 1（IGF1）和表皮生长因子（EGF）途径在内的各种细胞信号事件。这些途径在生长、发育、代谢和存活中发挥着重要作用。在这里，我们表明在果蝇中，果蝇 Cbl（dCbl）通过下调脑中果蝇胰岛素样肽（dILP）的产生来调节寿命和碳水化合物代谢。我们发现 dCbl 在脑中高度表达，并且通过 RNA 干扰特异性敲低神经元中的 dCbl 表达会增加对氧化应激或饥饿的敏感性、降低碳水化合物水平并缩短寿命。胰岛素产生神经元特异性敲低 dCbl 会导致类似的表型。脑或胰岛素产生细胞中的 dCbl 缺失会上调 dilp 基因的表达，导致 dILP 途径的激活增加，包括果蝇 Akt 和果蝇细胞外信号调节激酶（dERK）的磷酸化。遗传相互作用分析表明，通过过表达显性负形式的 dEGFR 在泛神经元或胰岛素产生细胞中阻断果蝇表皮生长因子受体（dEGFR）-dERK 信号会消除 dCbl 缺失对 dilp 基因上调的影响。此外，在大鼠β细胞系 INS-1 细胞中敲低 c-Cbl 也以 ERK 依赖的方式增加胰岛素生物合成和葡萄糖刺激的分泌。总之，这些结果表明神经元 dCbl 通过抑制 dILP 的产生和 EGFR-ERK 途径来调节寿命、应激反应和代谢，而 EGFR-ERK 途径介导了 dCbl 的作用。Cbl 对胰岛素生物合成的抑制作用在进化上是保守的，这增加了 Cbl 可能通过调节β细胞中的胰岛素产生来发挥其生理作用的可能性。
