The Ral/exocyst effector complex counters c-Jun N-terminal kinase-dependent apoptosis in Drosophila melanogaster.
Ral GTPase activity is a crucial cell-autonomous factor supporting tumor initiation and progression. To decipher pathways impacted by Ral, we have generated null and hypomorph alleles of the Drosophila melanogaster Ral gene. Ral null animals were not viable. Reduced Ral expression in cells of the sensory organ lineage had no effect on cell division but led to postmitotic cell-specific apoptosis. Genetic epistasis and immunofluorescence in differentiating sensory organs suggested that Ral activity suppresses c-Jun N-terminal kinase (JNK) activation and induces p38 mitogen-activated protein (MAP) kinase activation. HPK1/GCK-like kinase (HGK), a MAP kinase kinase kinase kinase that can drive JNK activation, was found as an exocyst-associated protein in vivo. The exocyst is a Ral effector, and the epistasis between mutants of Ral and of msn, the fly ortholog of HGK, suggest the functional relevance of an exocyst/HGK interaction. Genetic analysis also showed that the exocyst is required for the execution of Ral function in apoptosis. We conclude that in Drosophila Ral counters apoptotic programs to support cell fate determination by acting as a negative regulator of JNK activity and a positive activator of p38 MAP kinase. We propose that the exocyst complex is Ral executioner in the JNK pathway and that a cascade from Ral to the exocyst to HGK would be a molecular basis of Ral action on JNK.
Balakireva
Maria
M
Institut Curie, INSERM U528, Groupe d'Analyse des Réseaux de Transduction (ART), 26 rue d'Ulm, 75248 Paris cedex 05, France.
Rossé
Carine
C
Langevin
Johanna
J
Chien
Yu-chen
YC
Gho
Michel
M
Gonzy-Treboul
Geneviève
G
Voegeling-Lemaire
Stéphanie
S
Aresta
Sandra
S
Lepesant
Jean-Antoine
JA
Bellaiche
Yohanns
Y
White
Michael
M
Camonis
Jacques
J
D000483:Alleles; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D019070:Cell Lineage; D004331:Drosophila melanogaster / Q000166:cytology* / Q000196:embryology* / Q000201:enzymology / Q000235:genetics; D004625:Embryo, Nonmammalian; D004789:Enzyme Activation; D004843:Epistasis, Genetic; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D020043:Genes, Essential; D017344:Genes, Insect; D007150:Immunohistochemistry; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D018715:Microscopy, Video; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012679:Sense Organs / Q000196:embryology / Q000254:growth & development; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C102102:hematopoietic progenitor kinase 1; D048056:Mitogen-Activated Protein Kinase 9; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D019204:GTP-Binding Proteins