LKB1/AMPK signaling and Peutz-Jeghers syndrome

编码Ser/Thr蛋白激酶的STK11功能突变丢失，LKB1是导致 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 STK11在包括肺腺癌在内的多种人类癌症中的孢子性突变。LKB1 磷酸化并激活AMP依赖的蛋白激酶以响应能量应激，从而发挥一种 在能量动态平衡中起关键作用。指导这一提议的假设是LKB1-AMPK信号轴 进化为在能量压力和遗传或表观遗传异常的条件下限制细胞的生长，如 以及抑制LKBI功能的转录和转录后事件，允许肿瘤细胞 超越通常在能量压力下限制细胞生长的代谢控制机制。总目标 该建议的目的是阐明由LKB，1-AMPK控制的信号和代谢网络，并使用 为缺乏LKB1的肿瘤确定治疗干预靶点的信息。具体目标是：1) 利用在前一个授权期内开发的技术来识别可用药下游 LKB1/AMPK信号网络中的靶点；2)利用质量谱代谢组学来鉴定代谢 由于失去LKB1而导致的癌症中的通路改变，以及，3)使用基因工程小鼠 由于失去LKBI而导致癌症，在人类肺中存在其他遗传异常的情况下 癌症，以评估药物或药物组合，根据AIMS 1和2的体外研究预测。

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 ofthe 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 aberrationslobserved in human lung cancers, to evaluate drugs or drug combinations, predicted on the basis of in vitro studies in Aims 1 and 2.