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

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-acetylglucosamine (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 signaltransducing 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. Furthermore, HGS glycosylation is demonstrated to promote tumor growth in the xenograft study and chemoresistance in liver carcinoma cells. Thus, our study reveals a role of O-GlcNAcylation in regulating receptor tyrosine kinase endocytic trafficking and signaling.

Automated summary

The O-GlcNAc modification plays a crucial role in regulating the intracellular trafficking and degradation of EGFR. It inhibits the interaction between HGS and STAM, impairing the formation of ESCRT-0 and leading to the accumulation and prolonged signaling of EGFR in cells. Additionally, glycosylation of HGS promotes tumor growth and chemoresistance in liver carcinoma cells.