N-glycosylated GPNMB ligand independently activates mutated EGFR signaling and promotes metastasis in NSCLC
Journal
Cancer Science
Journal Volume
112
Journal Issue
5
Pages
1911-1923
Date Issued
2021
Author(s)
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. ? 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
Subjects
EGFR mutation; GPNMB; metastasis; N-glycosylation; NSCLC
SDGs
Other Subjects
asparagine; carcinoembryonic antigen related cell adhesion molecule 5; epidermal growth factor receptor; glycoprotein; glycoprotein non metastatic melanoma protein b; glycosylated protein; intercellular adhesion molecule 1; lectin galactoside-binding soluble 3; membrane protein; mucin 1; protein A; protein tyrosine phosphatase; protein tyrosine phosphatase receptor type j; STAT3 protein; unclassified drug; uvomorulin; EGFR protein, human; epidermal growth factor receptor; GPNMB protein, human; ligand; membrane protein; STAT3 protein; STAT3 protein, human; tumor protein; adult; Article; carboxy terminal sequence; CL1-0 cell line; CL1-5 cell line; controlled study; disease association; distant metastasis; enzyme activity; female; gene mutation; genetic association; glycosylation; human; human cell; major clinical study; male; microscopy; middle aged; non small cell lung cancer; priority journal; protein analysis; protein binding; protein expression; protein phosphorylation; proteomics; signal transduction; animal; cell motion; genetics; glycosylation; lung tumor; metabolism; mouse; mutation; non small cell lung cancer; pathology; phosphorylation; SCID mouse; tumor cell line; tumor invasion; Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; ErbB Receptors; Female; Glycosylation; Humans; Ligands; Lung Neoplasms; Male; Membrane Glycoproteins; Membrane Proteins; Mice; Mice, SCID; Middle Aged; Mutation; Neoplasm Invasiveness; Neoplasm Proteins; Phosphorylation; Signal Transduction; STAT3 Transcription Factor
Publisher
Blackwell Publishing Ltd
Type
journal article