Metabolic regulation of cellular junction proteins

描述（由申请人提供）：Hippo信号传导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。Hippo信号传导抑制转录共激活因子Yes相关蛋白（雅普），这是一种在多种癌症（包括肝细胞癌、结肠癌和卵巢癌）中扩增的癌基因。雅普促进细胞增殖、上皮-间充质转化（EMT）、存活和化学抗性。因此，了解雅普活性是如何调节的对于开发新的癌症治疗剂是重要的。我们最近发现，细胞能量水平是一个新的上游信号调节Hippo通路，通过中央代谢传感器LKB 1和AMP激活的蛋白激酶（AMPK）。一致地，AMPK的小分子激活剂抑制雅普活性;并且雅普在LKB 1缺陷型癌症中被激活。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雅普癌基因。我们的具体目标包括：（1）确定紧密连接和Hippo信号的代谢调节机制。(2)探讨紧密连接蛋白在雅普调控中的作用，以及雅普在LKB 1缺陷型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雅普;并使用YAP-TEAD相互作用的小分子抑制剂在体外和体内靶向LKB 1缺陷型肺癌细胞。

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.