Insulin induces insulin receptor degradation in the liver through EphB4

  • Nat Metab. 2022 Sep;4(9):1202-1213. doi: 10.1038/s42255-022-00634-5.
Xingfeng Liu  1  2  3 ,  Kai Wang  1  2  3 ,  Shaocong Hou  1  2  3 ,  Qian Jiang  1  2  3 ,  Chunxiao Ma  1  2  3 ,  Qijin Zhao  1  2  3 ,  Lijuan Kong  1  2  3 ,  Jingwen Chen  1  2  3 ,  Zhenhe Wang  1 ,  Huabing Zhang  2  4 ,  Tao Yuan  2  4 ,  Yuxiu Li  2  4 ,  Yi Huan  1  2  3 ,  Zhufang Shen  1  2  3 ,  Zhuowei Hu  1  5 ,  Zhifeng Huang  6 ,  Bing Cui  1 ,  Pingping Li  7  8  9
Affiliations
  • 1. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 2. Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, China.
  • 3. CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, China.
  • 4. Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing, China.
  • 5. The National Clinical Research Center for Metabolic Diseases, Department of Metabolism and Endocrinology, the Second Xiangya Hospital, Central Sothern University, Changsha, China.
  • 6. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
  • 7. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].
  • 8. Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, China. [email protected].
  • 9. CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, China. [email protected].
PMID: 36131205 DOI: 10.1038/s42255-022-00634-5
Abstract

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.

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