2. Academic Validation
  3. Insulin induces insulin receptor degradation in the liver through EphB4

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

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. lipp@imm.ac.cn.
  • 8 Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, China. lipp@imm.ac.cn.
  • 9 CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, China. lipp@imm.ac.cn.
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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