Oncogenic mutants of RON and MET receptor tyrosine kinases cause activation of the beta-catenin pathway.
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.
Danilkovitch-Miagkova
A
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
A
Skeel
A
A
Nakaigawa
N
N
Zbar
B
B
Leonard
E J
EJ
D016475:3T3 Cells; D000818:Animals; D060466:Axin Protein; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D019938:Cyclin D1 / Q000096:biosynthesis; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004285:Dogs; D038362:Glycogen Synthase Kinase 3; D051379:Mice; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins; D015398:Signal Transduction; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation; D014443:Tyrosine / Q000378:metabolism; D051176:beta Catenin
D060466:Axin Protein; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin; D019938:Cyclin D1; D014443:Tyrosine; D019859:Proto-Oncogene Proteins c-met; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3