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N-glycosylation regulates MET processing and signaling
Atsushi Saitou1,2, Yoshihiro Hasegawa1,2, Naoki Fujitani1
1Department of Biochemistry, Sapporo Medical University School of Medicine, Sapporo, Japan.
Cancer Science
|January 29, 2022
Summary
N-glycans on the MET receptor play a crucial, site-specific role in regulating its processing and signaling pathways. Understanding these N-glycans offers new insights into non-small cell lung cancer treatment resistance.
Area of Science:
- Molecular Biology
- Cancer Research
- Glycobiology
Background:
- MET receptor tyrosine kinase is linked to resistance against tyrosine kinase inhibitors in non-small cell lung cancer.
- The functional roles of MET's 11 potential N-glycosylation sites remain largely uncharacterized.
Purpose of the Study:
- To elucidate the site-specific functions of N-glycans in regulating MET processing and signaling.
- To investigate the impact of N-glycosylation on MET function in cancer cells.
Main Methods:
- Treatment of cancer cells with N-glycosylation inhibitors.
- Purification and mass spectrometry analysis of recombinant MET extracellular domain.
- Generation of MET knockout cells and N-glycan-deletion mutants for functional studies.
Main Results:
- N-glycosylation inhibitors reduced MET processing and trafficking in lung cancer cells.
- Mass spectrometry identified complex-type N-glycans as dominant on MET.
- Site-specific N-glycans differentially regulate MET processing and HGF-induced signaling, with SEMA domain glycans being positive regulators and others negative.
Conclusions:
- N-glycans are critical regulators of MET receptor processing, trafficking, and signaling in a site-specific manner.
- These findings highlight the importance of N-glycosylation in MET function and suggest potential therapeutic avenues for overcoming resistance in non-small cell lung cancer.
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