O-GlcNAcylation regulates epidermal growth factor receptor intracellular trafficking and signaling

Author:

Wu Liming1,Cheng Yaxian2,Geng Didi2,Fan Zhiya3ORCID,Lin Bingyi1,Zhu Qiang2,Li Jingchao2,Qin Weijie3,Yi Wen12ORCID

Affiliation:

1. Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang Provincial Key Laboratory of Pancreatic Disease, School of Medicine, Zhejiang University, Hangzhou 310003, China

2. Ministry of Education Key Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China

3. National Center for Protein Sciences Beijing, State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing 102206, China

Abstract

Significance Epidermal growth factor receptor (EGFR) is one of the most important membrane receptors that transduce growth signals into cells to sustain cell growth, proliferation, and survival. EGFR signal termination is initiated by EGFR internalization, followed by trafficking through endosomes, and degradation in lysosomes. How this process is regulated is still poorly understood. Here, we show that hepatocyte growth factor regulated tyrosine kinase substrate (HGS), a key protein in the EGFR trafficking pathway, is dynamically modified by a single sugar N-acetylglucosamine. This modification inhibits EGFR trafficking from endosomes to lysosomes, leading to the accumulation of EGFR and prolonged signaling. This study provides an important insight into diseases with aberrant growth factor signaling, such as cancer, obesity, and diabetes.

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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