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Published online 28 May 2001. doi:10.1083/jcb.153.5.1023
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© The Rockefeller University Press, 0021-9525/2001//1023 $5.00
The Journal of Cell Biology, Volume 153, Number 5, , 2001 1023-1034

Original Article

Activation of the Met Receptor by Cell Attachment Induces and Sustains Hepatocellular Carcinomas in Transgenic Mice



Rong Wanga, Linda D. Ferrellb, Saadia Faouzic, Jacquelyn J. Maherc, and J. Michael Bishopa

a G.W. Hooper Foundation and Department of Microbiology and Immunology, University of California at San Francisco, San Francisco, California 94143
b Department of Pathology, University of California at San Francisco, San Francisco, California 94143
c Liver Center, University of California at San Francisco, San Francisco, California 94110
Department of Surgery, Vascular Biology Laboratories, University of California at San Francisco, San Francisco, CA 94143-0522.(415) 476-6470(415) 476-6855

rwang{at}cgl.ucsf.edu

Overexpression is the most common abnormality of receptor tyrosine kinases (RTKs) in human tumors. It is presumed that overexpression leads to constitutive activation of RTKs, but the mechanism of that activation has been uncertain. Here we show that overexpression of the Met RTK allows activation of the receptor by cell attachment and that this form of activation can be tumorigenic. Transgenic mice that overexpressed Met in hepatocytes developed hepatocellular carcinoma (HCC), one of the human tumors in which Met has been implicated previously. The tumorigenic Met was activated by cell attachment rather than by ligand. Inactivation of the transgene led to regression of even highly advanced tumors, apparently mediated by apoptosis and cessation of cellular proliferation. These results reveal a previously unappreciated mechanism by which the tumorigenic action of RTKs can be mediated, provide evidence that Met may play a role in both the genesis and maintenance of HCC, and suggest that Met may be a beneficial therapeutic target in tumors that overexpress the receptor.

Key Words: Met • receptor tyrosine kinase signaling • tumorigenesis • transgenic mouse • cell adhesion

© 2001 The Rockefeller University Press

Abbreviations used in this paper: HCC, hepatocellular carcinoma; HGF, hepatocyte growth factor; NHEM, normal human epidermal melanocyte; RTK, receptor tyrosine kinase; TRE, tetracycline-responsive element.


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