LKB1/AMPK signaling and Peutz-Jeghers syndrome

编码Ser/Thr蛋白激酶LKB 1的STK 11的功能缺失突变导致家族性错构瘤综合征Peutz Jeghers综合征（PJS）。重要的是，最近的研究揭示了STK 11在各种人类癌症中的孢子突变，包括肺腺癌。LKB 1在能量应激时磷酸化并激活AMP依赖性蛋白激酶，因此在能量稳态中起关键作用。指导该提议的假设是LKB 1-AMPK信号传导轴进化为在能量应激条件下限制细胞生长，并且遗传或表观遗传畸变以及抑制LKB 1功能的转录和转录后事件允许肿瘤细胞超越通常在能量应激下限制细胞生长的代谢控制机制。该提案的总体目标是阐明由LKB，1-AMPK控制的信号传导和代谢网络，并利用这些信息来确定缺乏LKB 1的肿瘤的治疗干预靶点。具体目标是：1）利用在前一个授权期间开发的技术来识别LKB 1/AMPK信令网络中的可下药下游目标; 2）利用质谱代谢组学来鉴定在由LKB 1缺失导致的癌症中改变的代谢途径，和3）在人肺癌中观察到的其他遗传畸变的背景下，使用由于LKB 1缺失而发展癌症的基因工程小鼠，根据目的1和2中的体外研究预测，评估药物或药物组合。

Loss of function mutations in STK11, encoding the Ser/Thr protein kinase, LKB1 are responsible for the familial hamartoma syndrome, Peutz Jeghers Syndrome (PJS). Importantly, recent studies have revealed sporatic mutations in STK11 in a variety of human cancers, including lung adenocarcinomas. LKB1 phosphorylates and activates AMP dependent protein kinase in response to energy stress and thus plays a key role in energy homeostasis. The hypothesis guiding this proposal is that the LKB1-AMPK signaling axis evolved to limit cell growth under conditions of energy stress and that genetic or epigenetic aberrations, as well as transcriptional and post-transcriptional events that suppress LKBI function, allow tumor cells to override metabolic control mechanisms that normally limit cell growth under energy stress. The overall goal of the proposal is to elucidate the signaling and metabolic network controlled by LKB,1-AMPK and use this information to identify targets for therapeutic intervention in tumors that lack LKB1. The specific aims are: 1) to utilize technologies developed during the previous granting period to identify druggable downstream targets in the LKB1/AMPK signaling network; 2) to utilize mass spec metabolomics to identify metabolic pathways that are altered in cancers that result from loss of LKB1 and, 3) to use genetically engineered mice that develop cancers due to loss of LKBI, in the context of other genetic aberrations observed in human lung cancers, to evaluate drugs or drug combinations, predicted on the basis of in vitro studies in Aims 1 and 2.