ArticleOncogene2000
Two mutations affecting conserved residues in the Met receptor operate via different mechanisms.
Article in Oncogene, 2000. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 28 citations in OpenAlex.
- MET variants with activating N-lobe mutations identified in hereditary papillary renal cell carcinomas still require ligand stimulation.Molecular oncology · 2025Article
- Review
- Removal of substrate inhibition ofFood chemistry: X · 2023Article
- Advances in Renal Cell Carcinoma Drug Resistance Models.Frontiers in oncology · 2022Review
- When the MET receptor kicks in to resist targeted therapies.Oncogene · 2021Review
- Review
- Electrostatic explanation of D1228V/H/N-induced c-Met resistance and sensitivity to type I and type II kinase inhibitors in targeted gastric cancer therapy.Journal of molecular modeling · 2019Article
- Hypoxia leads to decreased autophosphorylation of the MET receptor but promotes its resistance to tyrosine kinase inhibitors.Oncotarget · 2018Article
- NPS-1034, a novel MET inhibitor, inhibits the activated MET receptor and its constitutively active mutants.Investigational new drugs · 2014Article
- Initial clinical sensitivity and acquired resistance to MET inhibition in MET-mutated papillary renal cell carcinoma.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2013Article
- Article
- Cancer driver mutations in protein kinase genes.Cancer letters · 2009Review
- Computational modeling of structurally conserved cancer mutations in the RET and MET kinases: the impact on protein structure, dynamics, and stability.Biophysical journal · 2009Article
- Biological role of the HGF/MET ligand/receptor couple in bovine mammary epithelial cells.Veterinary research communications · 2007Article
- Structural characterization of autoinhibited c-Met kinase produced by coexpression in bacteria with phosphatase.Proceedings of the National Academy of Sciences of the United States of America · 2006Article
- RNAi technology and lentiviral delivery as a powerful tool to suppress Tpr-Met-mediated tumorigenesis.Cancer gene therapy · 2005Article
- Gain of function mutations of RTK conserved residues display differential effects on NTRK1 kinase activity.Oncogene · 2002Article
- Article
- Differential requirement of the last C-terminal tail of Met receptor for cell transformation and invasiveness.Oncogene · 2001Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We have investigated the mechanism by which two oncogenic mutations (M1268T and D1246H/N; Amino-acids are numbered according to Schmidt et al., 1999) affecting conserved residues in the catalytic domain of the Met receptor, activate its transforming potential. Both mutations were previously found in tumorigenic forms of the Ret and Kit receptors, respectively. The mutated residues are located either in the P+1 loop (M) or within the activation loop (A-loop) (D), which in a number of receptor tyrosine kinases harbors a pair of tandem tyrosines (Y1252-1253 in Met). Ligand-induced dimerization promotes their phosphorylation, and locks the A-loop into an open conformation. When unphosphorylated, the tandem tyrosines inhibit enzymatic activity by blocking the active site. Upon Y-->F mutation of Y1252-1253, neither ligand binding nor Tpr-mediated dimerization can release this block. Here we show that the M1268T mutation partially rescues the kinase activity (and the transforming ability) of the Y1252-1253F Tpr-Met mutant, but is completely dependent on dimerization for its effect. In contrast, the two D1246H/N mutants strictly depend on Y1252-1253 for activity. Surprisingly, however, they constitutively activate the isolated cytoplasmic TK domain of Met (Cyto-Met). These data indicate that the two mutations operate via distinct mechanisms.
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