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Molecular and Cellular Biology, May 2005, p. 3982-3996, Vol. 25, No. 10
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.10.3982-3996.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Negative Feedback Regulation of Met-Dependent Invasive Growth by Notch

M. Cristina Stella,* Livio Trusolino, Selma Pennacchietti, and Paolo M. Comoglio

Division of Molecular Oncology, Institute for Cancer Research and Treatment (IRCC), University of Turin School of Medicine, Str. Prov. 142, Km. 3,95, 10060 Candiolo, Torino, Italy

Received 15 July 2004/ Returned for modification 8 October 2004/ Accepted 11 February 2005

The hepatocyte growth factor (HGF) receptor encoded by the Met oncogene controls a genetic program—known as "invasive growth"—responsible for several developmental processes and involved in cancer invasion and metastasis. This program functions through several regulatory gene products, as yet largely unknown, both upstream and downstream of Met. Here we show that activation of the Notch receptor results in transcriptional down-regulation of Met, suppression of HGF-dependent Ras signaling, and impairment of HGF-dependent cellular responses. In turn, Met activation leads to transcriptional induction of the Notch ligand Delta and the Notch effector HES-1, indicating that Met is able to self-tune its own protein levels and the ensuing biochemical and biological outputs through stimulation of the Notch pathway. By using branching morphogenesis of the tracheal system in Drosophila as a readout of invasive growth, we also show that exogenous expression of a constitutively active form of human Met induces enhanced sprouting of the tracheal tree, a phenotype that is further increased in embryos lacking Notch function. These results unravel an in-built mechanism of negative feedback regulation in which Met activation leads to transcriptional induction of Notch function, which in turn limits HGF activity through repression of the Met oncogene.

* Institute for Cancer Research and Treatment (IRCC), University of Turin School of Medicine, Division of Molecular Oncology, IV Floor, Str. Prov. 142, Km. 3,95, 10060 Candiolo, Torino, Italy. Phone: (39) 011 9933232. Fax: (39) 011 9933225. E-mail: mariacristina.stella{at}ircc.it.

Molecular and Cellular Biology, May 2005, p. 3982-3996, Vol. 25, No. 10
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.10.3982-3996.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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