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Molecular and Cellular Biology, March 2000, p. 2055-2065, Vol. 20, No. 6
0270-7306/00/$04.00+0

Disassociation of Met-Mediated Biological Responses In Vivo: the Natural Hepatocyte Growth Factor/Scatter Factor Splice Variant NK2 Antagonizes Growth but Facilitates Metastasis

Toshiyuki Otsuka,1 John Jakubczak,1 Wilfred Vieira,2 Donald P. Bottaro,3 Diane Breckenridge,3 William J. Larochelle,3 and Glenn Merlino1,*

Laboratories of Molecular Biology,1 Cell Biology,2 and Cellular and Molecular Biology,3 National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

Received 27 September 1999/Returned for modification 30 November 1999/Accepted 17 December 1999

Hepatocyte growth factor/scatter factor (HGF/SF) stimulates numerous cellular activities capable of contributing to the metastatic phenotype, including growth, motility, invasiveness, and morphogenetic transformation. When inappropriately expressed in vivo, an HGF/SF transgene induces numerous hyperplastic and neoplastic lesions. NK1 and NK2 are natural splice variants of HGF/SF; all interact with a common receptor, Met. Although both agonistic and antagonistic properties have been ascribed to each isoform in vitro, NK1 retains the full spectrum of HGF/SF-like activities when expressed as a transgene in vivo. Here we report that transgenic mice broadly expressing NK2 exhibit none of the phenotypes characteristic of HGF/SF or NK1 transgenic mice. Instead, when coexpressed in NK2-HGF/SF bitransgenic mice, NK2 antagonizes the pathological consequences of HGF/SF and discourages the subcutaneous growth of transplanted Met-containing melanoma cells. Remarkably, the metastatic efficiency of these same melanoma cells is dramatically enhanced in NK2 transgenic host mice relative to wild-type recipients, rivaling levels achieved in HGF/SF and NK1 transgenic hosts. Considered in conjunction with reports that in vitro NK2 induces scatter, but not other activities, these data strongly suggest that cellular motility is a critical determinant of metastasis. Moreover, our results demonstrate how alternatively structured ligands can be exploited in vivo to functionally dissociate Met-mediated activities and their downstream pathways.

* Corresponding author. Mailing address: Molecular Genetics Section, Laboratory of Molecular Biology, National Cancer Institute, NIH, Building 37, Room 2E24, Bethesda, MD 20892-4255. Phone: (301) 496-4270. Fax: (301) 480-7618. E-mail: gmerlino{at}helix.nih.gov.

Molecular and Cellular Biology, March 2000, p. 2055-2065, Vol. 20, No. 6
0270-7306/00/$04.00+0


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