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Overexpression-mediated activation of MET in the Golgi promotes HER3/ERBB3 phosphorylation
- Source :
- Oncogene
- Publication Year :
- 2018
- Publisher :
- Springer Science and Business Media LLC, 2018.
-
Abstract
- Ligand-dependent oligomerization of receptor tyrosine kinases (RTKs) results in their activation through highly specific conformational changes in the extracellular and intracellular receptor domains. These conformational changes are unique for each RTK sub-family, limiting cross-activation between unrelated RTKs. The proto-oncogene MET receptor tyrosine kinase overcomes these structural constraints and phosphorylates unrelated RTKs in numerous cancer cell lines. The molecular basis for these interactions is unknown. We investigated the mechanism by which MET phosphorylates the human epidermal growth factor receptor-3 (HER3 or ERBB3), a catalytically impaired RTK whose phosphorylation by MET has been described as an essential component of drug resistance to inhibitors targeting EGFR and HER2. We find that in untransformed cells, HER3 is not phosphorylated by MET in response to ligand stimulation, but rather to increasing levels of MET expression, which results in MET activation in a ligand-independent manner. Phosphorylation of HER3 by its canonical dimerization partners, EGFR and HER2, is achieved by engaging an allosteric site on the HER3 kinase domain, but this site is not required when HER3 is phosphorylated by MET. We also observe that HER3 preferentially interacts with MET during its maturation along the secretory pathway, before MET is post-translationally processed by cleavage within its extracellular domain. This results in accumulation of phosphorylated HER3 in the Golgi apparatus. We further show that in addition to HER3, MET phosphorylates other RTKs in the Golgi, suggesting that this mechanism is not limited to HER3 phosphorylation. These data demonstrate a link between MET overexpression and its aberrant activation in the Golgi endomembranes and suggest that non-canonical interactions between MET and unrelated RTKs occur during maturation of receptors. Our study highlights a novel aspect of MET signaling in cancer that would not be accessible to inhibition by therapeutic antibodies.
- Subjects :
- 0301 basic medicine
Cancer Research
Receptor, ErbB-3
Allosteric regulation
Golgi Apparatus
Biology
Proto-Oncogene Mas
Article
Receptor tyrosine kinase
03 medical and health sciences
symbols.namesake
0302 clinical medicine
HER3
Neoplasms
Chlorocebus aethiops
Intracellular receptor
Golgi
Genetics
Animals
Humans
ERBB3
Phosphorylation
skin and connective tissue diseases
Molecular Biology
Cells, Cultured
Secretory pathway
non-canonical mechanism
Proto-Oncogene Proteins c-met
Golgi apparatus
RTK phosphorylation
Up-Regulation
3. Good health
Cell biology
Gene Expression Regulation, Neoplastic
body regions
030104 developmental biology
Protein kinase domain
030220 oncology & carcinogenesis
COS Cells
MET
symbols
biology.protein
Signal Transduction
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 38
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....ae9c56397edd43a021bfe8d0a96bf3da