Negative Feedback Regulation of Met-Dependent Invasive Growth by Notch

Abstract

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.

ACKNOWLEDGMENTS

P. Larghero and E. Laguzzi were of invaluable help during the early stages of this work. We thank T. Sudo, S. Herzig, S. Roth, M. Affolter, and F. Sprenger for sharing reagents, all the colleagues and especially the “Lilla's group,” and E. Audero and L. Primo for helpful discussions and comments. We acknowledge N. Azpiazu for critical reading of the manuscript. We are grateful to A. Cignetto for secretarial assistance. The excellent technical assistance of L. Palmas, R. Albano, F. Grasso, and S. Tyenga is acknowledged.

This work was supported by research grants of AIRC, CNR-MIUR, FIRB-MIUR, MIUR-PRIN, and the Foundation Compagnia di San Paolo to P.M.C.