LKB1/AMPK signaling and Peutz-Jeghers syndrome

编码丝氨酸/苏氨酸蛋白激酶的STK11功能突变缺失，LKB1导致家族性错构瘤综合征，Peutz Jeghers综合征(PJS)。重要的是，最近的研究发现，STK11在包括肺腺癌在内的各种人类癌症中存在孢子性突变。LKB1磷酸化并激活AMP依赖的蛋白激酶以响应能量应激，从而在能量平衡中起关键作用。指导这一提议的假设是，LKB1-AMPK信号轴进化为在能量应激条件下限制细胞生长，遗传或表观遗传异常，以及抑制LKBI功能的转录和转录后事件，允许肿瘤细胞推翻通常在能量应激条件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控制的信号和代谢网络，并利用这些信息确定对缺乏LKB1的肿瘤进行治疗干预的靶点。具体目标是：1)利用在前一个授权期内开发的技术来确定LKB1/AMPK信号网络中的可用药下游靶点；2)利用质谱学代谢组学来确定由于LKB1丢失而导致癌症中代谢途径改变的代谢途径；以及3)在观察到的人类肺癌的其他遗传变异的背景下，使用由于LKBI丢失而发生癌症的基因工程小鼠来评估根据目标1和2中的体外研究预测的药物或药物组合。

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.