Negative feedback regulation of Met-dependent invasive growth by Notch.
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.
Stella
M Cristina
MC
Institute for Cancer Research and Treatment, University of Turin School of Medicine, Division of Molecular Oncology, IV Floor, Str. Prov. 142, Km. 3,95, 10060 Candiolo, Torino, Italy. mariacristina.stella@ircc.it
Trusolino
Livio
L
Pennacchietti
Selma
S
Comoglio
Paolo M
PM
D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D004285:Dogs; D015536:Down-Regulation / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000196:embryology / Q000235:genetics; D004789:Enzyme Activation; D025461:Feedback, Physiological / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014132:Trachea / Q000166:cytology* / Q000196:embryology / Q000378:metabolism*; D000072056:Transcription Factor HES-1; D014158:Transcription, Genetic / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D029721:Drosophila Proteins; D017228:Hepatocyte Growth Factor; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D019859:Proto-Oncogene Proteins c-met; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger; D020794:Receptor Protein-Tyrosine Kinases; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; C497759:N protein, Drosophila; C078493:HES1 protein, human; C080148:tor protein, Drosophila; C501009:HRAS protein, human