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

ABSTRACT: SignificanceEpidermal 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.

SUBMITTER: Wu L

PROVIDER: S-EPMC8915906 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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

Wu Liming L Cheng Yaxian Y Geng Didi D Fan Zhiya Z Lin Bingyi B Zhu Qiang Q Li Jingchao J Qin Weijie W Yi Wen W

Proceedings of the National Academy of Sciences of the United States of America 20220303 10

SignificanceEpidermal 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 ...[more]

PMID: 35239437

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

Project description:Ligand-stimulated epidermal growth factor receptor (EGFR) signaling plays fundamental roles in normal cell physiology, such as cell growth, cell proliferation, and cell survival. Deregulation of EGFR signaling contributes to the development and progression of diseases including cancer. Despite its essential role in biology, the mechanisms by which EGFR signaling is regulated in cells are still poorly understood. Here, we demonstrate that O-linked N-acetyl-glucosamine (O-GlcNAc) modification serves as an important regulator of EGFR intracellular trafficking and degradation. Mechanistically, O-GlcNAcylation of hepatocyte growth factor regulated tyrosine kinase substrate (HGS), a key protein in EGFR intraluminal sorting pathway, inhibits HGS interaction with signal-transducing adaptor molecule (STAM), thereby impairing the formation of endosomal sorting complex required for transport-0 (ESCRT-0). Moreover, O-GlcNAcylation increases HGS ubiquitination and decreases its protein stability in cells. Consequently, HGS O-GlcNAcylation inhibits EGFR intraluminal sorting and lysosomal degradation, leading to the accumulation of EGFR and prolonged EGFR signaling in cells.

2022-04-04 | PXD031700 | Pride

Cetuximab/C225-induced intracellular trafficking of epidermal growth factor receptor.

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Intravesicular epidermal growth factor receptor subject to retrograde trafficking drives epidermal growth factor-dependent migration.

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Endocytic Adaptor Protein HIP1R Controls Intracellular Trafficking of Epidermal Growth Factor Receptor in Neuronal Dendritic Development.

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Epidermal growth factor receptor signaling intensity determines intracellular protein interactions, ubiquitination, and internalization.

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Internalization, intracellular trafficking, and biodistribution of monoclonal antibody 806: a novel anti-epidermal growth factor receptor antibody.

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Diacylglycerol kinase delta regulates protein kinase C and epidermal growth factor receptor signaling.

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| S-EPMC1622849 | biostudies-literature

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