The Ral/exocyst effector complex counters c-Jun N-terminal kinase-dependent apoptosis in Drosophila melanogaster
The Ral/exocyst effector complex counters c-Jun N-terminal kinase-dependent apoptosis in Drosophila melanogaster
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DOI：
10.1128/mcb.00506-06
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发表时间：
2006-12-01
影响因子：
5.3
通讯作者：
Camonis, Jacques
中科院分区：
文献类型：
--
作者：
Balakireva, Maria;Rosse, Carine;Camonis, Jacques
Rai GTPase活性是支持肿瘤发生和发展的关键细胞自主因子。为了破译受Rai影响的途径，我们生成了果蝇黑腹鼠Ral基因的零等位基因和低变形等位基因。有些动物无法存活。Rai在感觉器官系细胞中的表达减少对细胞分裂没有影响，但导致有丝分裂后细胞特异性凋亡。分化感觉器官的遗传上位性和免疫荧光表明，Rai活性抑制c-Jun n-末端激酶（JNK）的激活，诱导p38丝裂原活化蛋白（MAP）激酶的激活。HPK1/ gck样激酶（HGK）是一种可以驱动JNK活化的MAP激酶激酶激酶激酶，在体内被发现是一种囊泡相关蛋白。胞囊是一种Rai效应物，而Ral和HGK的蝇同源物msn突变体之间的上位性表明胞囊/HGK相互作用的功能相关性。遗传分析还表明，胞囊是细胞凋亡中Rai功能发挥的必要条件。我们得出结论，在果蝇中，Rai通过作为JNK活性的负调节因子和p38 MAP激酶的正激活因子来对抗凋亡程序以支持细胞命运的决定。我们认为，在JNK通路中，胞囊复合物是Rai的刽子手，从Rai到胞囊再到HGK的级联反应可能是Rai作用于JNK的分子基础。
Rai GTPase activity is a crucial cell-autonomous factor supporting tumor initiation and progression. To decipher pathways impacted by Rai, we have generated null and hypomorph alleles of the Drosophild melanogaster Ral gene. Ral null animals were not viable. Reduced Rai 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 Rai 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 Rai 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 Rai function in apoptosis. We conclude that in Drosophila Rai 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 Rai executioner in the JNK pathway and that a cascade from Rai to the exocyst to HGK would be a molecular basis of Rai action on JNK.