The mutationally activated Met receptor mediates motility and metastasis.
Mutations in Met have been identified in human papillary renal carcinomas. We have shown previously that these mutations deregulate the enzymatic activity of Met and that NIH 3T3 cells expressing mutationally activated Met are transformed in vitro and are tumorigenic in vivo. In the present investigation, we find that mutant Met induces the motility of Madin-Darby canine kidney cells in vitro and experimental metastasis of NIH 3T3 cells in vivo, and that the Ras-Raf-MEK-ERK signaling pathway, which has been implicated previously in cellular motility and metastasis, is constitutively activated by the Met mutants. We also report that transgenic mice harboring mutationally activated Met develop metastatic mammary carcinoma. These data confirm the tumorigenic activity of mutant Met molecules and demonstrate their ability to induce the metastatic phenotype.
Jeffers
M
M
Advanced BioScience Laboratories-Basic Research Program, Division of Basic Sciences, Frederick Cancer Research and Development Center, National Cancer Institute, P.O. Box B, Frederick, MD 21702, USA.
Fiscella
M
M
Webb
C P
CP
Anver
M
M
Koochekpour
S
S
Vande Woude
G F
GF
D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004285:Dogs; D005260:Female; D006801:Humans; D007668:Kidney; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology*; D008668:Metallothionein / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D009362:Neoplasm Metastasis; D017354:Point Mutation; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014162:Transfection
D011993:Recombinant Fusion Proteins; D008668:Metallothionein; D019859:Proto-Oncogene Proteins c-met