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Uncoupling signal transducers from oncogenic MET mutants abrogates cell transformation and inhibits invasive growth
A Bardelli1, P Longati, D Gramaglia
1Institute for Cancer Research and Treatment, University of Torino, School of Medicine 10060, Candiolo, Italy. abardelli@ircc.unito.it
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.
Insights
Mutations in the MET gene drive cancer by increasing its kinase activity and enabling constant signaling. Targeting this MET signaling pathway offers a new therapeutic strategy for MET-driven cancers.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Tyrosine kinase receptors, including RET and KIT, are implicated in human cancers.
- Oncogenic mutations in the MET gene are found in papillary renal carcinomas (PRCs).
Purpose of the Study:
- To elucidate the mechanism linking METPRC mutations to cellular transformation.
- To investigate the role of receptor-tail tyrosines in MET-driven neoplastic transformation.
Main Methods:
- Analysis of METPRC mutations, kinase activity, and substrate specificity.
- Investigating the association of mutated MET with signal transducers.
- Using phenylalanine substitution and peptide inhibitors to disrupt receptor-signal transducer interactions.
Main Results:
- METPRC mutations increase kinase activity and can alter substrate specificity.
- Constitutive association with signal transducers via specific tyrosines (Y1349, Y1356) correlates with transforming potential.
- Disrupting these "docking tyrosines" abrogates transformation and invasiveness.
- Inhibiting receptor-signal transducer coupling with a peptide derivative (YpVNV) blocks invasive growth.
Conclusions:
- Constitutive coupling of mutated MET to downstream signal transducers is crucial for neoplastic transformation.
- Targeting this aberrant signaling offers a potential therapeutic strategy for MET-driven cancers.