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Mol Cell Biol, March 1998, p. 1275-1283, Vol. 18, No. 3
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
NK1, a Natural Splice Variant of Hepatocyte Growth Factor/Scatter
Factor, Is a Partial Agonist In Vivo
John L.
Jakubczak,1,
William J.
Larochelle,2 and
Glenn
Merlino1,*
Laboratory of Molecular
Biology1 and
Laboratory of Cellular and
Molecular Biology,2 National Cancer
Institute, Bethesda, Maryland 20892
Received 29 September 1997/Returned for modification 13 November
1997/Accepted 3 December 1997
Hepatocyte growth factor/scatter factor (HGF/SF) is a potent
mitogen, motogen, and morphogen for epithelial cells expressing its
tyrosine kinase receptor, the c-met proto-oncogene product, and is required for normal development in the mouse. Inappropriate stimulation of Met signal transduction induces aberrant morphogenesis and oncogenesis in mice and has been implicated in human cancer. NK1 is
a naturally occurring HGF/SF splice variant composed of only the amino
terminus and first kringle domain. While the biological activities of
NK1 have been controversial, in vitro data suggest that it may have
therapeutic value as an HGF/SF antagonist. Here, we directly test this
hypothesis in vivo by expressing mouse NK1 in transgenic mice and
comparing the consequent effects with those observed for mice carrying
an HGF/SF transgene. Despite robust expression, NK1 did not behave as
an HGF/SF antagonist in vivo. Instead, NK1-transgenic mice displayed
most of the phenotypic characteristics associated with
HGF/SF-transgenic mice, including enlarged livers, ectopic
skeletal-muscle formation, progressive renal disease, aberrant pigment
cell localization, precocious mammary lobuloalveolar development, and
the appearance of mammary, hepatocellular, and melanocytic tumors. And
like HGF/SF-transgenic livers, NK1 livers had higher levels of
tyrosine-phosphorylated complexes associated with Met, suggesting that
the mechanistic basis for the effects of NK1 overexpression in vivo was
autocrine activation of Met. We conclude that NK1 acts in vivo as a
partial agonist. As such, the efficacy of NK1 as a therapeutic HGF/SF antagonist must be seriously questioned.
*
Corresponding author. Mailing address: Molecular
Genetics Section, Laboratory of Molecular Biology, National Cancer
Institute, National Institutes of Health, Building 37, Room 2E24, 37 Convent Dr., MSC 4255, Bethesda, MD 20892-4255. Phone: (301) 496-4270. Fax: (301) 480-7618. E-mail: gmerlino{at}helix.nih.gov.

Present address: Genetic Therapy, Inc., Gaithersburg, MD
20878.
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