Elucidating a Novel Mechanism for LATS1/2 in Suppressing Tumorigenesis

摘要： 河马途径是一个进化上保守的信号级联，调节着许多生物过程， 包括细胞生长和命运决定、器官大小控制和再生。河马途径的核心是 哺乳动物包括一个KK级联，LATS1/2和MST1/2，通过以下途径控制各种细胞过程 协调下游底物的磷酸化，包括YAP和TAZ。为了与一个 河马信号通路可能的抑瘤作用，已发现河马信号通路 调节失调在许多人类肿瘤中很常见，包括乳腺癌、胶质瘤、肺癌、结直肠癌和 子宫内膜癌。然而，尽管少数上游调节剂和下游底物是 确定了上游信号通路控制LATS1/2的确切分子机制 目前，乳腺癌中的蛋白激酶活性及其生理功能尚未完全阐明。因此， 这项提议的主要目标是探索LATS1/2的上游调控因子，以及发现一种新的肿瘤 LATS1/2在控制乳腺癌发生中的抑制作用。为此，我已经 获得的初步数据表明，脱泛素酶OTUD3，而不是其他OTUD家族 成员，具体相互作用和去泛素化LATS1。更重要的是，我确定了猛禽，核心之一 调节细胞代谢的中枢细胞生长调节因子mTORC1的成分作为一种新的 LATS1/2的磷酸化底物。在这个提议中，我计划：1)将OTUD3表征为一个新的上游 主要通过LATS1/2去泛素化来积极调节LATS1/2激酶活性的调节因子；2) 确定LATS1/2在抑制乳腺肿瘤发生中的生理作用主要通过 Ser606位的磷酸化Raptor，进而抑制mTORC1的激酶活性；3)确定 LATS1/2在Ser606处的Raptor磷酸化是否以及如何调节体内乳腺癌的发展。 我职业生涯的长期目标是将分子和细胞生物学研究的洞察力应用于 了解重要的河马/mTORC1信号通路的生理意义 在人类恶性肿瘤的发展过程中，特别是在乳腺癌中，并寻找合适的药物 更好的抗乳腺癌治疗的目标。这个K99/R00奖将为我提供保护时间 追求这个提议的新假设，获得新的技能集来执行实验和解决问题。 此外，K99奖将使我能够专注于独立进行基本和 转译研究，并培养未来癌症生物学领域的年轻科学家。

Abstract: The Hippo pathway is an evolutionarily conserved signaling cascade regulating numerous biological processes, including cell growth and fate decision, organ size control, and regeneration. The core of the Hippo pathway in mammals consists of a kinase cascade, LATS1/2 and MST1/2 that controls various cellular processes through orchestrating the phosphorylation of downstream substrates including YAP and TAZ. In keeping with a possible tumor suppressive role of the Hippo signaling pathway, it has been found that Hippo pathway dysregulation is common in many human tumors including breast, glioma, lung, colorectal cancer, and endometrial cancer. However, although a few of upstream regulators and downstream substrates were identified, the exact molecular mechanisms underlying how upstream signaling pathways control LATS1/2 kinase activity and its physiological functions in breast cancer have not yet been fully elucidated. Hence, the major goal of this proposal is to explore the upstream regulator of LATS1/2 as well as to uncover a novel tumor suppressor role of LATS1/2 in controlling tumorigenesis in the breast cancer setting. To this end, I have obtained preliminary data showing that the deubiquitinating enzyme OTUD3, but not other OTUD family member, specifically interacts and deubiquitinates LATS1. More importantly, I identified Raptor, one of the core components of mTORC1 which is a central cell growth regulator governing cellular metabolism, as a novel phosphorylation substrate of LATS1/2. In this proposal, I plan to: 1) characterize OTUD3 as a novel upstream regulator that positively regulates LATS1/2 kinase activity largely through deubiquitination of LATS1/2; 2) determine the physiological role of LATS1/2 in suppressing breast tumorigenesis largely through phosphorylating Raptor at Ser606 site, which in turn inhibits the kinase activity of mTORC1; 3) determine whether and how Raptor phosphorylation at Ser606 by LATS1/2 regulates breast cancer development in vivo. The long-term goals of my career are to apply the insights of molecular and cellular biology studies to understand the physiological significance of deregulated Hippo/mTORC1 signaling pathways that are important in the development of human malignancies, especially in breast cancer, and to search for proper druggable targets for better anti-breast cancer treatment. This K99/R00 award will provide protected time for me to pursue the novel hypotheses of this proposal, obtain new skill sets to execute experiments and solve problems. In addition, the K99 award will allow me to focus my efforts on independently conducting basic and translational research, and to train future young scientists in the cancer biology field.