Mitotic regulators and the SHP2-MAPK pathway promote IR endocytosis and feedback regulation of insulin signaling
Mitotic regulators and the SHP2-MAPK pathway promote IR endocytosis and feedback regulation of insulin signaling
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DOI：
10.1038/s41467-019-09318-3
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发表时间：
2019-04-01
影响因子：
16.6
通讯作者：
Yu, Hongtao
中科院分区：
文献类型：
--
作者：
Choi, Eunhee;Kikuchi, Sotaro;Yu, Hongtao
胰岛素通过分叉的信号通路控制葡萄糖稳态和细胞生长。胰岛素信号的失调与糖尿病和癌症有关。纺锤体检查点控制着有丝分裂期间染色体分离的保真度。在这里，我们证明了胰岛素受体底物1和2(IRS1/2)与纺锤体检查点蛋白合作，通过将笼状蛋白适配器复合体AP2重新招募到IR来促进胰岛素受体(IR)的内吞作用。由细胞外信号调节蛋白1和2(ERK1/2)和Src同源磷酸酶2(SHP2)调控的IRS1/2的磷酸化开关保证了激活的IR的选择性内化。Shp2的抑制阻断了这种反馈调节和促进生长的IR信号，延长了胰岛素对代谢的作用，并改善了小鼠的胰岛素敏感性。我们认为，有丝分裂调节剂和SHP2促进了对IR的反馈抑制，从而限制了胰岛素信号的持续时间。针对这种反馈抑制可以改善胰岛素敏感性。
Insulin controls glucose homeostasis and cell growth through bifurcated signaling pathways. Dysregulation of insulin signaling is linked to diabetes and cancer. The spindle checkpoint controls the fidelity of chromosome segregation during mitosis. Here, we show that insulin receptor substrate 1 and 2 (IRS1/2) cooperate with spindle checkpoint proteins to promote insulin receptor (IR) endocytosis through recruiting the clathrin adaptor complex AP2 to IR. A phosphorylation switch of IRS1/2 orchestrated by extracellular signal-regulated kinase 1 and 2 (ERK1/2) and Src homology phosphatase 2 (SHP2) ensures selective internalization of activated IR. SHP2 inhibition blocks this feedback regulation and growth-promoting IR signaling, prolongs insulin action on metabolism, and improves insulin sensitivity in mice. We propose that mitotic regulators and SHP2 promote feedback inhibition of IR, thereby limiting the duration of insulin signaling. Targeting this feedback inhibition can improve insulin sensitivity.