@article{494ab7f4985c48ee99e056e39c7f1f70,
title = "N-glycosylated GPNMB ligand independently activates mutated EGFR signaling and promotes metastasis in NSCLC",
abstract = "Lung cancer is the leading cause of cancer-related death worldwide. As well as the identified role of epidermal growth factor receptor (EGFR), its association with driver mutations has improved the therapeutics for patients with lung cancer harboring EGFR mutations. These patients usually display shorter overall survival and a higher tendency to develop distant metastasis compared with those carrying the wild-type EGFR. Nevertheless, the way to control mutated EGFR signaling remains unclear. Here, we performed membrane proteomic analysis to determine potential components that may act with EGFR mutations to promote lung cancer malignancy. Expression of transmembrane glycoprotein non-metastatic melanoma protein B (GPNMB) was positively correlated with the status of mutated EGFR in non-small-cell lung cancer (NSCLC). This protein was not only overexpressed but also highly glycosylated in EGFR-mutated, especially EGFR-L858R mutated, NSCLC cells. Further examination showed that GPNMB could activate mutated EGFR without ligand stimulation and could bind to the C-terminus of EGFR, assist phosphorylation at Y845, turn on downstream STAT3 signaling, and promote cancer metastasis. Moreover, we also found that Asn134 (N134) glycosylation of GPNMB played a crucial role in this ligand-independent regulation. Depleting N134-glycosylation on GPNMB could dramatically inhibit binding of GPNMB to mutated EGFR, blocking its downstream signaling, and ultimately inhibiting cancer metastasis in NSCLC. Clarifying the role of N-glycosylated GPNMB in regulating the ligand-independent activation of mutated EGFR may soon give new insight into the development of novel therapeutics for NSCLC.",
keywords = "EGFR mutation, GPNMB, metastasis, N-glycosylation, NSCLC",
author = "Han, {Chia Li} and Chen, {Xuan Ren} and Albert Lan and Hsu, {Yuan Ling} and Wu, {Pei Shan} and Hung, {Pei Fang} and Hung, {Chung Lieh} and Pan, {Szu Hua}",
note = "Funding Information: The authors thank the following individuals for material and technical supports: Dr. Pan-Chyr Yang, Dr. Chih-Hsin Yang (Department of Medicine, College of Medicine, National Taiwan University), Dr. Kay-Hooi Khoo (Institute of Biological Chemistry, Academia Sinica), Dr. Yu-Ju Chen (Institute of Chemistry, Academia Sinica), Dr. Chia-Yi Lin (Institute of Biomedical Sciences, Academia Sinica) and Ms Tzu-Yu Chen (Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University). This research was funded by National Taiwan University (NTU-105R7879) and the Ministry of Science and Technology (Taiwan) (MOST 105-2628-B-002-007-MY3, 108-3114-Y-001-002, 108-2314-B-002-191-MY3, 109-2113-M-038-002). Funding Information: The authors thank the following individuals for material and technical supports: Dr. Pan‐Chyr Yang, Dr. Chih‐Hsin Yang (Department of Medicine, College of Medicine, National Taiwan University), Dr. Kay‐Hooi Khoo (Institute of Biological Chemistry, Academia Sinica), Dr. Yu‐Ju Chen (Institute of Chemistry, Academia Sinica), Dr. Chia‐Yi Lin (Institute of Biomedical Sciences, Academia Sinica) and Ms Tzu‐Yu Chen (Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University). This research was funded by National Taiwan University (NTU‐105R7879) and the Ministry of Science and Technology (Taiwan) (MOST 105‐2628‐B‐002‐007‐MY3, 108‐3114‐Y‐001‐002, 108‐2314‐B‐002‐191‐MY3, 109‐2113‐M‐038‐002). Publisher Copyright: {\textcopyright} 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.",
year = "2021",
month = may,
doi = "10.1111/cas.14872",
language = "English",
volume = "112",
pages = "1911--1923",
journal = "Cancer Science",
issn = "1347-9032",
publisher = "Wiley-Blackwell",
number = "5",
}