title: Drosophila happyhour modulates JNK-dependent apoptosis.
abstract: Mitogen-activated protein kinase kinase kinase kinase-3 (MAP4K3) is a Ste20 kinase family member that modulates multiple signal transduction pathways. We recently identified MAP4K3 as proapoptotic kinase using an RNA interference screening approach. In mammalian cells, MAP4K3 enhances the mitochondrial apoptosis pathway through the post-transcriptional modulation of selected proapoptotic Bcl-2 homology domain 3-only proteins. Recent data suggest that MAP4K3 mutations contribute to pancreatic cancer, which highlights the importance of studying the in vivo function of this kinase. To determine whether the cell death function is conserved in vivo and which downstream signalling pathways are involved, we generated transgenic flies expressing happyhour (hppy), the Drosophila MAP4K3 orthologue. Here, we show that the overexpression of hppy promotes caspase-dependent apoptosis and that the hypothetical kinase domain is essential for inducing cell death. In addition, we show that hppy expression triggers the activation of both the c-Jun N-terminal kinase (JNK) and target of rapamycin (TOR) signalling pathways; however, only JNK signalling is required for apoptosis. Together, our results show that hppy has a JNK-dependent proapoptotic function in Drosophila, which reinforces the hypothesis that MAP4K3 might act as tumour suppressor by regulating apoptosis in higher eukaryotes.
authors.affiliation: Cell Death Regulation Laboratory, MRC Toxicology Unit, Leicester, UK.
authors.forename: D
authors.initials: D
authors.lastname: Lam
authors.forename: S
authors.initials: S
authors.lastname: Shah
authors.forename: I P
authors.initials: IP
authors.lastname: de Castro
authors.forename: S H Y
authors.initials: SH
authors.lastname: Loh
authors.forename: L M
authors.initials: LM
authors.lastname: Martins
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology* / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development; D004789:Enzyme Activation; D018507:Gene Expression Regulation, Developmental; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010641:Phenotype; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014921:Wings, Animal / Q000473:pathology
chemical_list: D029721:Drosophila Proteins; D011494:Protein Kinases; C416303:target of rapamycin protein, Drosophila; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C541347:hppy protein, Drosophila; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases