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Molecular and Cellular Biology, September 2001, p. 5857-5868, Vol. 21, No. 17
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.17.5857-5868.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Oncogenic Mutants of RON and MET Receptor Tyrosine Kinases Cause Activation of the beta -Catenin Pathway

Alla Danilkovitch-Miagkova,1,* Alexei Miagkov,2 Alison Skeel,1 Noboru Nakaigawa,1,dagger Berton Zbar,1 and Edward J. Leonard1

Laboratory of Immunobiology, National Cancer Institute, Frederick Cancer Research and Development Center, Fort Detrick, Frederick, Maryland 21702,1 and Neuromuscular Division, Department of Neurology, Johns Hopkins University, School of Medicine, Baltimore, Maryland 212312

Received 2 November 2000/Returned for modification 26 December 2000/Accepted 8 June 2001

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.

* Corresponding author. Mailing address: Laboratory of Immunobiology, National Cancer Institute, Frederick Cancer Research and Development Center, Fort Detrick, Frederick, MD 21702. Phone: (301) 846-1560. Fax: (301) 846-6145. E-mail: danilkovitch{at}mail.ncifcrf.gov.

dagger Present address: Department of Urology, Yokohama City University Medical School, Kanazawa-ku, Yokohama, Japan.

Molecular and Cellular Biology, September 2001, p. 5857-5868, Vol. 21, No. 17
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.17.5857-5868.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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