Genetic Elucidation of AMP-Activated Protein Kinase Signaling Mechanisms

摘要： AMP激活的蛋白激酶（AMPK）作为关键的能量传感器发挥作用， 代谢变阻器来维持细胞的能量需求，主要是通过维持ATP 程度. AMPK信号传导的破坏导致神经元死亡，而AMPK基因的突变导致神经元死亡。 人类AMPK亚单位导致致命的心脏疾病，沃尔夫-帕金森-白色 综合征我们正在使用果蝇的遗传模型来识别基因， 在体内调节AMPK信号传导。利用这种新的前向遗传筛选， 确定核苷二磷酸激酶（NDPK）作为潜在的修饰剂和靶点 AMPK信号我们发现了一种新的机制， NDPK的磷酸化将其关闭。此关闭开关位置对应于一个位置 在晚期人类神经母细胞瘤中发生了突变通过鉴定新基因 抑制AMPK RNAi致死性，并建立了一个突变的遗传模型， AMPK导致人类疾病，我们希望确定新的机制， 在体内调节AMPK功能的分子。

Abstract: AMP-activated protein kinase (AMPK) functions as a key energy sensor and metabolic rheostat to maintain cells' energy needs, largely through maintaining ATP levels. Disruption of AMPK signaling leads to neuronal death, while mutations in human AMPK subunits cause the fatal cardiac disorder, Wolff-Parkinson-White syndrome. We are using a genetic model in Drosophila to identify genes that modulate AMPK signaling in vivo. Using this novel forward genetic screen we have identified nucleoside diphosphate kinase (NDPK) as a potential modifier and target of AMPK signaling. We have found a new mechanism whereby AMPK-dependent phsphorylation of NDPK turns it off. This off switch site corresponds to a location mutated in advanced human neuroblastoma. Through identification of new genes that suppress AMPK RNAi lethality, and making a genetic model of mutations in AMPK that cause human disease, we hope to identify both new mechanisms and molecules that modulate AMPK function in vivo.