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PMID: 9826708 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Uncoupling signal transducers from oncogenic MET mutants abrogates cell transformation and inhibits invasive growth.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 95 ·No. 24 ·1998-11-24 ·Pages 14379-83

Bardelli A, Longati P, Gramaglia D, Basilico C, Tamagnone L, Giordano S, Ballinari D, Michieli P, Comoglio PM

Abstract

The assumption that genes encoding tyrosine kinase receptors could play a role in human cancers has been confirmed by the identification of oncogenic mutations in the kinase domain of RET and KIT. Recently, homologous residues were found mutated in MET, in papillary renal carcinomas (PRCs). The link coupling these genetic lesions to cellular transformation is still unclear. METPRC mutations result in increased kinase activity and-in some instances, i.e., M1250T substitution-in changes in substrate specificity. A direct correlation occurs between the transforming potential of METPRC mutants and their ability to constitutively associate with signal transducers through two phosphorylated tyrosines (Y1349VHVNATY1356VNV) located in the receptor tail. Substitution of these "docking tyrosines" with phenylalanines leaves unaffected the altered properties of the kinase but abrogates transformation and invasiveness in vitro. Uncoupling the receptor from signal transducers with a tyrosine-phosphorylated peptide derivative (YpVNV) inhibits invasive growth induced by METPRC mutants. These data indicate that constitutive receptor coupling to downstream signal transducers is a key mechanism in neoplastic transformation driven by mutated MET and suggest a therapeutic strategy to target neoplastic diseases associated with this oncogene.

MeSH Terms
Amino Acid Sequence Amino Acid Substitution Animals COS Cells Carcinoma, Papillary/genetics Carcinoma, Renal Cell/genetics Cell Division Cell Transformation, Neoplastic/drug effects Cloning, Molecular Humans Kidney Neoplasms/genetics Kinetics Mutagenesis, Site-Directed Neoplasm Invasiveness Oncogenes Peptide Fragments/chemistry,pharmacology Phosphorylation Phosphotyrosine Point Mutation Polymerase Chain Reaction Proto-Oncogene Proteins c-met/chemistry,genetics Recombinant Fusion Proteins/chemistry Signal Transduction Transfection
Chemicals
Peptide Fragments Recombinant Fusion Proteins Phosphotyrosine Proto-Oncogene Proteins c-met
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Bardelli A
Institute for Cancer Research and Treatment, University of Torino, School of Medicine 10060, Candiolo, Italy. abardelli@ircc.unito.it
Longati P
Gramaglia D
Basilico C
Tamagnone L
Giordano S
Ballinari D
Michieli P
Comoglio P M
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.95.24.14379
Email
abardelli@ircc.unito.it
Published
1998-11-24
Pages
14379-83
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC24381
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.95.24.14379 PMC Full Text View journal details
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