The Drosophila sterile-20 kinase slik controls cell proliferation and apoptosis during imaginal disc development.
Cell proliferation and programmed cell death are closely controlled during animal development. Proliferative stimuli generally also induce apoptosis, and anti-apoptotic factors are required to allow net cell proliferation. Genetic studies in Drosophila have led to identification of a number of genes that control both processes, providing new insights into the mechanisms that coordinate cell growth, proliferation, and death during development and that fail to do so in diseases of cell proliferation. We present evidence that the Drosophila Sterile-20 kinase Slik promotes cell proliferation and controls cell survival. At normal levels, Slik provides survival cues that prevent apoptosis. Cells deprived of Slik activity can grow, divide, and differentiate, but have an intrinsic survival defect and undergo apoptosis even under conditions in which they are not competing with normal cells for survival cues. Like some oncogenes, excess Slik activity stimulates cell proliferation, but this is compensated for by increased cell death. Tumor-like tissue overgrowth results when apoptosis is prevented. We present evidence that Slik acts via Raf, but not via the canonical ERK pathway. Activation of Raf can compensate for the lack of Slik and support cell survival, but activation of ERK cannot. We suggest that Slik mediates growth and survival cues to promote cell proliferation and control cell survival during Drosophila development.
Hipfner
David R
DR
European Molecular Biology Laboratory, Heidelberg, Germany.
Cohen
Stephen M
SM
D000483:Alleles; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002470:Cell Survival; D029721:Drosophila Proteins / Q000235:genetics* / Q000502:physiology*; D004331:Drosophila melanogaster; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D047468:Immunoprecipitation; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D019076:Transgenes; D014921:Wings, Animal / Q000196:embryology* / Q000378:metabolism
D029721:Drosophila Proteins; D051034:Inhibitor of Apoptosis Proteins; D012333:RNA, Messenger; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; C492662:Slik protein, Drosophila; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4