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

doi:10.1083/jcb.153.5.1023

Published online 29 May 2001. doi:10.1083/jcb.153.5.1023

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© The Rockefeller University Press, 0021-9525/2001/5/1023/ $5.00
The Journal of Cell Biology, Volume 153, Number 5, May 28, 2001 1023-1034

Original Article

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

Rong Wang^a, Linda D. Ferrell^b, Saadia Faouzi^c, Jacquelyn J. Maher^c, and J. Michael Bishop^a
^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

Correspondence to: Rong Wang, Department of Surgery, Vascular Biology Laboratories, University of California at San Francisco, San Francisco, CA 94143-0522. Tel:(415) 476-6855 Fax:(415) 476-6470 E-mail:rwang{at}cgl.ucsf.edu.

Overexpression is the most common abnormality of receptor tyrosinekinases (RTKs) in human tumors. It is presumed that overexpressionleads to constitutive activation of RTKs, but the mechanismof that activation has been uncertain. Here we show that overexpressionof the Met RTK allows activation of the receptor by cell attachmentand that this form of activation can be tumorigenic. Transgenicmice that overexpressed Met in hepatocytes developed hepatocellularcarcinoma (HCC), one of the human tumors in which Met has beenimplicated previously. The tumorigenic Met was activated bycell attachment rather than by ligand. Inactivation of the transgeneled to regression of even highly advanced tumors, apparentlymediated by apoptosis and cessation of cellular proliferation.These results reveal a previously unappreciated mechanism bywhich the tumorigenic action of RTKs can be mediated, provideevidence that Met may play a role in both the genesis and maintenanceof HCC, and suggest that Met may be a beneficial therapeutictarget in tumors that overexpress the receptor.

Key Words: Met, receptor tyrosine kinase signaling, tumorigenesis, transgenicmouse, cell adhesion

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