Metabolic regulation of cellular junction proteins

描述(申请人提供)：河马信号是一种新兴的肿瘤抑制途径，在器官大小控制和肿瘤发生中发挥关键作用。河马信号抑制转录共激活因子YAP(YAP)，YAP是一种在多种癌症中扩增的癌基因，包括肝细胞癌、结肠癌和卵巢癌。YAP促进细胞增殖、上皮向间充质转化(EMT)、存活和化疗耐药。因此，了解YAP活性是如何调节的，对于开发新的癌症治疗药物是很重要的。我们最近发现，细胞能级是一种新的上游信号，通过中枢代谢传感器LKB1和AMP激活的蛋白激酶(AMPK)调节河马通路。AMPK的小分子激活剂始终抑制YAP的活性；而YAP在LKB1缺陷的癌症中被激活。进一步了解这一新的信号机制将有助于阐明细胞代谢如何调控YAP癌基因。本研究的具体目标包括：(1)确定紧密连接和河马信号代谢调控的机制(S)。(2)探讨紧密连接蛋白作为中枢信号转导节点在YAP调控中的作用，以及YAP在LKB1基因缺陷肺癌中作为下游致癌因子的作用。(3)确定AMPK的激活是否在体内抑制YAP，并利用YAP-tead相互作用的小分子抑制剂在体内外靶向LKB1缺陷的肺癌细胞。

DESCRIPTION (provided by applicant): Hippo signaling is an emerging tumor suppressor pathway that plays key roles in organ size control and tumorigenesis. Hippo signaling inhibits the transcription co-activator Yes-Associated Protein (YAP), an oncogene amplified in multiple cancers, including hepatocellular carcinoma, colon and ovarian cancer. YAP promotes cell proliferation, epithelial-to-mesenchymal transition (EMT), survival and chemoresistance. Therefore, it is important to understand how YAP activity is regulated for the development of novel cancer therapeutics. We recently discovered that cellular energy level is a novel upstream signal regulating Hippo pathway, through the central metabolic sensors LKB1 and AMP-activated protein kinase (AMPK). Consistently, small molecule activators of AMPK inhibit YAP activity; and YAP is activated in LKB1-deficient cancers. Further understanding this novel signaling mechanism will shed light on how cellular metabolism regulates YAP oncogene. Our specific aims of this proposal include: (1) To determine the mechanism(s) of metabolic regulation of tight junctions and Hippo signaling. (2) To investigate the roles of tight junction proteins as the central signaling node in regulation of YAP; and to investigate YAP as a downstream oncogenic factor in LKB1-deficient lung cancer. (3) To determine whether activation of AMPK inhibits YAP in vivo; and to target LKB1-deficient lung cancer cells in vitro and in vivo using small molecule inhibitor of YAP-TEAD interaction.