Insulin induces insulin receptor degradation in the liver through EphB4
© 2022. The Author(s), under exclusive licence to Springer Nature Limited..
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.
| Errataetall: |
CommentIn: Nat Metab. 2022 Sep;4(9):1093-1094. - PMID 36131206 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:4 |
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| Enthalten in: |
Nature metabolism - 4(2022), 9 vom: 21. Sept., Seite 1202-1213 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Liu, Xingfeng [VerfasserIn] |
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| Links: |
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| Themen: |
Clathrin |
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| Anmerkungen: |
Date Completed 26.09.2022 Date Revised 22.11.2022 published: Print-Electronic CommentIn: Nat Metab. 2022 Sep;4(9):1093-1094. - PMID 36131206 Citation Status MEDLINE |
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| doi: |
10.1038/s42255-022-00634-5 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM346476259 |
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| 245 | 1 | 0 | |a Insulin induces insulin receptor degradation in the liver through EphB4 |
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| 500 | |a CommentIn: Nat Metab. 2022 Sep;4(9):1093-1094. - PMID 36131206 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022. The Author(s), under exclusive licence to Springer Nature Limited. | ||
| 520 | |a 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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| 650 | 7 | |a Insulin |2 NLM | |
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| 700 | 1 | |a Wang, Kai |e verfasserin |4 aut | |
| 700 | 1 | |a Hou, Shaocong |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Qian |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Chunxiao |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Qijin |e verfasserin |4 aut | |
| 700 | 1 | |a Kong, Lijuan |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Jingwen |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Zhenhe |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Huabing |e verfasserin |4 aut | |
| 700 | 1 | |a Yuan, Tao |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yuxiu |e verfasserin |4 aut | |
| 700 | 1 | |a Huan, Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Zhufang |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Zhuowei |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Zhifeng |e verfasserin |4 aut | |
| 700 | 1 | |a Cui, Bing |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Pingping |e verfasserin |4 aut | |
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