The mutationally activated Met receptor mediates motility and metastasis

The mutationally activated Met receptor mediates motility and metastasis

^*Advanced BioScience Laboratories–Basic Research Program, ^†Science Applications International Corporation, and ^‡National Institutes of Health, Division of Basic Sciences, Frederick Cancer Research and Development Center, National Cancer Institute, P.O. Box B, Frederick, MD 21702

Edited by Owen N. Witte, University of California, Los Angeles, CA, and approved September 28, 1998 (received for review August 6, 1998)

Abstract

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.

Footnotes

↵ § To whom reprint requests should be addressed. e-mail: woude{at}ncifcrf.gov.
This paper was submitted directly (Track II) to the Proceedings Office.
ABBREVIATIONS:

MDCK,

Madin-Darby canine kidney;

NGF,

nerve growth factor;

HGF/SF,

hepatocyte growth factor/scatter factor