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PMID: 11486025 Published · ppublish English Journal Article

Oncogenic mutants of RON and MET receptor tyrosine kinases cause activation of the beta-catenin pathway.

Molecular and cellular biology ·Vol. 21 ·No. 17 ·2001-09-00 ·Pages 5857-68

Danilkovitch-Miagkova A, Miagkov A, Skeel A, Nakaigawa N, Zbar B, Leonard EJ

Abstract

beta-Catenin is an oncogenic protein involved in regulation of cell-cell adhesion and gene expression. Accumulation of cellular beta-catenin occurs in many types of human cancers. Four mechanisms are known to cause increases in beta-catenin: mutations of beta-catenin, adenomatous polyposis coli, or axin genes and activation of Wnt signaling. We report a new cause of beta-catenin accumulation involving oncogenic mutants of RON and MET receptor tyrosine kinases (RTKs). Cells transfected with oncogenic RON or MET were characterized by beta-catenin tyrosine phosphorylation and accumulation; constitutive activation of a Tcf transcriptional factor; and increased levels of beta-catenin/Tcf target oncogene proteins c-myc and cyclin D1. Interference with the beta-catenin pathway reduced the transforming potential of mutated RON and MET. Activation of beta-catenin by oncogenic RON and MET constitutes a new pathway, which might lead to cell transformation by these and other mutant growth factor RTKs.

MeSH Terms
3T3 Cells Animals Axin Protein Calcium-Calmodulin-Dependent Protein Kinases/metabolism Cell Line Cell Transformation, Neoplastic Cyclin D1/biosynthesis Cytoskeletal Proteins/metabolism Dogs Glycogen Synthase Kinase 3 Mice Mutagenesis, Site-Directed Phosphorylation Proteins/metabolism Proto-Oncogene Proteins c-met/genetics,metabolism Proto-Oncogene Proteins c-myc/biosynthesis,genetics Receptor Protein-Tyrosine Kinases/genetics,metabolism Receptors, Cell Surface/genetics,metabolism Repressor Proteins Signal Transduction TCF Transcription Factors Trans-Activators Transcription Factor 7-Like 2 Protein Transcription Factors/genetics Transcriptional Activation Tyrosine/metabolism beta Catenin
Chemicals
Axin Protein CTNNB1 protein, mouse Cytoskeletal Proteins Proteins Proto-Oncogene Proteins c-myc Receptors, Cell Surface Repressor Proteins TCF Transcription Factors TCF7L2 protein, human Tcf7l2 protein, mouse Trans-Activators Transcription Factor 7-Like 2 Protein Transcription Factors beta Catenin Cyclin D1 Tyrosine Proto-Oncogene Proteins c-met RON protein Receptor Protein-Tyrosine Kinases Calcium-Calmodulin-Dependent Protein Kinases Glycogen Synthase Kinase 3
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Danilkovitch-Miagkova A
Laboratory of Immunobiology, National Cancer Institute, Frederick Cancer Research and Development Center, Fort Detrick, Frederick, MD 21702, USA. danilkovitch@mail.ncifcrf.gov
Miagkov A
Skeel A
Nakaigawa N
Zbar B
Leonard E J
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.21.17.5857-5868.2001
Email
danilkovitch@mail.ncifcrf.gov
Published
2001-09-00
Pages
5857-68
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC87305
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.21.17.5857-5868.2001 PMC Full Text View journal details
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