The PIKE homolog Centaurin gamma regulates developmental timing in Drosophila.
The PIKE homolog Centaurin gamma regulates developmental timing in Drosophila.
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DOI：
10.1371/journal.pone.0097332
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Hoch M
中科院分区：
文献类型：
--
作者：
Gündner AL;Hahn I;Sendscheid O;Aberle H;Hoch M
由PIKE/CENTG1基因编码的磷酸肌苷-3激酶增强子（PIKE）蛋白是半人马座小gtpase超家族γ亚群的成员。它们的特征在于其嵌合蛋白结构域，包括pleckstrin同源性（PH）结构域、GTPase激活（GAP）结构域、锚定蛋白重复序列以及固有的GTPase结构域。在哺乳动物中，三种具有蛋白质结构和亚细胞定位变化的PIKE亚型由PIKE位点编码。在小鼠中，PIKE失活会导致广泛的缺陷，包括大脑发育过程中的神经元细胞死亡和乳腺发育的失调。PIKE -/-突变小鼠体型更小，白色脂肪组织更少，由于amp活化蛋白激酶（AMPK）和胰岛素受体/Akt信号失调而表现出胰岛素抵抗。在这里，我们研究了PIKE蛋白在果蝇代谢调节中的作用。我们发现果蝇PIKE同源基因ceng1A编码功能性GTPase，其内部GAP结构域催化其GTPase活性。为了阐明果蝇中ceng1A的生物学功能，我们通过同源重组在ceng1A基因中引入了一个缺失，删除了所有预测的功能性PIKE结构域。我们发现纯合子的ceng1A突变动物存活到成年。与PIKE -/-小鼠突变体相比，果蝇ceng1A的基因消融不会导致生长缺陷或体重减轻。尽管代谢途径，如胰岛素信号，对饥饿的敏感性和高摄食条件下的脂质动员在ceng1A突变体中没有受到干扰，但纯合子ceng1A突变体在二龄幼虫阶段表现出较长的发育，导致蛹期延迟。与这些结果一致，我们发现蜕皮激素诱导基因的表达在ceng1A突变体中减少。总之，我们提出了果蝇Ceng1A在调节依赖于蜕皮激素信号的二到三龄幼虫转变中的新作用。
Phosphoinositide-3-kinase enhancer (PIKE) proteins encoded by the PIKE/CENTG1 gene are members of the gamma subgroup of the Centaurin superfamily of small GTPases. They are characterized by their chimeric protein domain architecture consisting of a pleckstrin homology (PH) domain, a GTPase-activating (GAP) domain, Ankyrin repeats as well as an intrinsic GTPase domain. In mammals, three PIKE isoforms with variations in protein structure and subcellular localization are encoded by the PIKE locus. PIKE inactivation in mice results in a broad range of defects, including neuronal cell death during brain development and misregulation of mammary gland development. PIKE -/- mutant mice are smaller, contain less white adipose tissue, and show insulin resistance due to misregulation of AMP-activated protein kinase (AMPK) and insulin receptor/Akt signaling. here, we have studied the role of PIKE proteins in metabolic regulation in the fly. We show that the Drosophila PIKE homolog, ceng1A, encodes functional GTPases whose internal GAP domains catalyze their GTPase activity. To elucidate the biological function of ceng1A in flies, we introduced a deletion in the ceng1A gene by homologous recombination that removes all predicted functional PIKE domains. We found that homozygous ceng1A mutant animals survive to adulthood. In contrast to PIKE -/- mouse mutants, genetic ablation of Drosophila ceng1A does not result in growth defects or weight reduction. Although metabolic pathways such as insulin signaling, sensitivity towards starvation and mobilization of lipids under high fed conditions are not perturbed in ceng1A mutants, homozygous ceng1A mutants show a prolonged development in second instar larval stage, leading to a late onset of pupariation. In line with these results we found that expression of ecdysone inducible genes is reduced in ceng1A mutants. Together, we propose a novel role for Drosophila Ceng1A in regulating ecdysone signaling-dependent second to third instar larval transition.
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