Insulin induces insulin receptor degradation in the liver through EphB4

The tyrosine kinase receptor EphB4 is shown to interact with the insulin receptor to facilitate its endocytosis and degradation, thereby decreasing insulin signaling and promoting insulin resistance. Insulin signaling is essential for glucose metabolism, and insulin decreases insulin receptor (InsR) levels in a dose-dependent and time-dependent manner. However, the regulatory mechanisms of InsR reduction upon insulin stimulation remain poorly understood. Here, we show that Eph receptor B4 (EphB4), a tyrosine kinase receptor that modulates cell adhesion and migration, can bind directly to InsR, and this interaction is markedly enhanced by insulin. Due to the adaptor protein 2 (Ap2) complex binding motif in EphB4, the interaction of EphB4 and InsR facilitates clathrin-mediated InsR endocytosis and degradation in lysosomes. Hepatic overexpression of EphB4 decreases InsR and increases hepatic and systemic insulin resistance in chow-fed mice, whereas genetic or pharmacological inhibition of EphB4 improve insulin resistance and glucose intolerance in obese mice. These observations elucidate a role for EphB4 in insulin signaling, suggesting that EphB4 might represent a therapeutic target for the treatment of insulin resistance and type 2 diabetes.

Automated summary

The tyrosine kinase receptor EphB4 interacts with the insulin receptor to promote its endocytosis and degradation, leading to decreased insulin signaling and insulin resistance. Inhibition of EphB4 can improve insulin resistance and glucose intolerance.