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A novel germ line juxtamembrane Met mutation in human gastric cancer.

Authors
Lee, JH; Han, SU; Cho, H; Jennings, B; Gerrard, B; Dean, M; Schmidt, L; Zbar, B; Vande Woude, GF
Citation
Oncogene, 19(43):4947-4953, 2000
Journal Title
Oncogene
ISSN
0950-92321476-5594
Abstract
Activating mutations in the Met receptor tyrosine kinase, both germline and somatic, have been identified in human papillary renal cancer. Here we report a novel germline missense Met mutation, P1009S, in a patient with primary gastric cancer. The dosage of the mutant Met DNA was elevated in the tumor when compared to its matched normal DNA. Therefore, as with hereditary renal papillary cancer, the mutant Met allele may also be selectively duplicated in the tumor. Different from previously reported Met mutations, which occur in the tyrosine kinase domain, this missense mutation is located at the juxtamembrane domain, and is not constitutively activated. However, following treatment with HGF/SF, the P1009S mutant Met protein, expressed in NIH3T3 cells, displays increased and persistent tyrosine phosphorylation compared to the wild-type Met. Importantly, these cells also form colonies in soft agar, and are highly tumorigenic in athymic nude mice. A second nucleotide change in this region of Met, T1010I, was found in a breast cancer biopsy and a large cell lung cancer cell line. Although this previously reported 'polymorphism' did not stimulate NIH3T3 cell growth in soft agar, it was more active than the wild-type Met in the athymic nude mice tumorigenesis assay, suggesting that it may have effects on tumorigenesis. Met has been shown to be highly expressed in human gastric carcinoma cell lines, and our results raise the possibility that activating missense Met mutations could contribute to tumorigenesis of gastric cancer.
MeSH terms
3T3 Cells/metabolismAdenocarcinoma/*geneticsAmino Acid SequenceAnimalsCell Membrane/metabolismDNA, Neoplasm/geneticsExonsFemaleGene AmplificationGene Expression Regulation, Neoplastic/geneticsGerm-Line MutationHepatocyte Growth Factor/pharmacologyHumansMiceMice, NudeMolecular Sequence DataMutation, MissensePhosphorylation/drug effectsProtein Structure, TertiaryProto-Oncogene Proteins c-met/*genetics/metabolismStomach Neoplasms/*geneticsTyrosine/metabolism
DOI
10.1038/sj.onc.1203874
PMID
11042681
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
Journal Papers > School of Medicine / Graduate School of Medicine > Surgery
AJOU Authors
이, 재호한, 상욱조, 혜성
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