c-Met function requires N-linked glycosylation modification of pro-Met.
c-Met, the receptor for hepatocyte growth factor (HGF), is cell surface tyrosine kinase that controls cancer cell growth, survival, invasion, and metastasis. Post-translational modification, such as glycosylation, plays an essential role in regulating the function of cell surface molecules. Whether glycosylation modification regulates the enzymatic properties of c-Met is unknown. In this study, we investigated the effect of glycosylation on the function of c-Met. We found that c-Met is an N-linked glycosylated protein. Both pro-Met and p145Met (the β subunit of mature c-Met) have N-linked glycosylation. Glycosylation inhibitor studies revealed that the N-glycosylation modification of p145Met is from pro-Met, but not due to the further modification of pro-Met. Importantly, blocking the N-glycosylation targets pro-Met to cytoplasm and initiates its phosphorylation independent of HGF engagement. Nonglycosylated pro-Met activates c-Met downstream pathways to a certain extent to compensate for the degradation of p145Met induced by glycosylation blocking-mediated endoplasmic reticulum (ER) stress.
Department of Public Health of Luzhou Medical College, Luzhou, Sichuan, China.
Run
R
Chen
Juan
J
Li
Chun-Hong
CH
Feng
Shao-Kun
SK
Chen
You-Ping
YP
Liu
Chun-Yan
CY
Duan
Hong
H
Li
Xian-Ming
XM
Xia
Tao
T
He
Mei
M
Wei
Rong-Yang
RY
Dai
D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D000077547:Crizotinib; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D005455:Fluorescent Antibody Technique; D006031:Glycosylation; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011720:Pyrazoles; D011725:Pyridines / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology
C066855:HGF protein, human; D010880:Piperidines; D011720:Pyrazoles; D011725:Pyridines; D014415:Tunicamycin; D000077547:Crizotinib; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met