JNK pathway mediates apoptotic cell death induced by tumor suppressor LKB1 in Drosophila.
Although recent progresses have unveiled the diverse in vivo functions of LKB1, detailed molecular mechanisms governing these processes still remain enigmatic. Here, we showed that Drosophila LKB1 negatively regulates organ growth by caspase-dependent apoptosis, without affecting cell size and cell cycle progression. Through genetic screening for LKB1 modifiers, we discovered the JNK pathway as a novel component of LKB1 signaling; the JNK pathway was activated by LKB1 and mediated the LKB1-dependent apoptosis. Consistently, LKB1-null mutant was defective in embryonic apoptosis and displayed a drastic hyperplasia in the central nervous system; these phenotypes were fully rescued by ectopic JNK activation as well as wild-type LKB1 expression. Furthermore, inhibition of LKB1 resulted in epithelial morphogenesis failure, which was associated with a decrease in JNK activity. Collectively, our studies unprecedentedly elucidate JNK as the downstream mediator of the LKB1-dependent apoptosis, and provide a new paradigm for understanding the diverse LKB1 functions in vivo.
Lee
J H
JH
National Creative Research Initiatives Center for Cell Growth Regulation and Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 373-1 Kusong-dong, Yusong, Taejon, Korea.
Koh
H
H
Kim
M
M
Park
J
J
Lee
S Y
SY
Lee
S
S
Chung
J
J
D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004331:Drosophila melanogaster / Q000196:embryology / Q000254:growth & development / Q000502:physiology*; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology; D009154:Mutation; D009479:Neuropeptides / Q000502:physiology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D047990:TNF Receptor-Associated Factor 1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology
D029721:Drosophila Proteins; C108880:HID protein, Drosophila; D008565:Membrane Proteins; D009479:Neuropeptides; D047990:TNF Receptor-Associated Factor 1; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C464573:egr protein, Drosophila; C108881:grim protein, Drosophila; C474203:p53 protein, Drosophila; C086973:rpr protein, Drosophila; D011494:Protein Kinases; C495775:LKB1 protein, Drosophila; D048031:JNK Mitogen-Activated Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D020169:Caspases