Elucidating a Novel Mechanism for LATS1/2 in Suppressing Tumorigenesis

阐明 LATS1/2 抑制肿瘤发生的新机制

• 批准号: 10191225
• 负责人: Xiaoming Dai
• 金额: $ 16.99万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10191225
• 关键词: Accounting; Automobile Driving; Award; Basic Science; Biochemical; Biological Assay; Biological Process; Breast; Breast Cancer Treatment; Cancer Biology; Cancer Diagnostics; Cell physiology; Colorectal; Colorectal Cancer; Data; Deubiquitinating Enzyme; Deubiquitination; Development; Drosophila genus; Ectopic Expression; Endometrial; Endometrial Carcinoma; Family; Family member; Female Breast Carcinoma; Future; Genetic Status; Genetically Engineered Mouse; Glioma; Goals; Growth; Human; In Vitro; Individual; Knock-in Mouse; LATS1 gene; Liver; Lung; Malignant Neoplasms; Mammals; Mammary Neoplasms; Mediating; Metabolism; Modification; Molecular; Molecular and Cellular Biology; Mouse Mammary Tumor Virus; Mus; Natural regeneration; Newly Diagnosed; Oncogenes; Organ Size; Orthologous Gene; Pathway interactions; Phase; Phosphorylation; Phosphotransferases; Physiological; Polyubiquitination; Problem Solving; Process; Protein-Serine-Threonine Kinases; Proteins; Raptors; Regulation; Role; Scientist; Signal Pathway; Signal Transduction; Site; Time; Tissues; Training; Transcription Coactivator; Translational Research; Tumor Suppressor Proteins; Ubiquitination; base; breast tumorigenesis; cancer therapy; career; cell growth; design; druggable target; experimental study; fly; in vivo; insight; malignant breast neoplasm; mammary; novel; novel therapeutic intervention; novel therapeutics; skills; targeted treatment; tumor; tumorigenesis

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.

抽象的： 河马途径是一种进化保守的信号级联，调节许多生物学过程， 包括细胞生长和命运决策，器官大小控制和再生。河马路径的核心 哺乳动物由激酶级联反应，LATS1/2和MST1/2组成，该级别通过控制各种细胞过程 编排包括YAP和TAZ在内的下游底物的磷酸化。与 河马信号通路可能抑制肿瘤的作用，已经发现河马途径 失调在许多人类肿瘤中很常见，包括乳腺癌，神经胶质瘤，肺，结直肠癌和 子宫内膜癌。但是，尽管上游调节器和下游基板是 确定，上游信号通路如何控制LATS1/2的确切分子机制 激酶活性及其在乳腺癌中的生理功能尚未完全阐明。因此， 该建议的主要目标是探索LATS1/2的上游调节器，并发现一种新型肿瘤 LATS1/2在控制乳腺癌的肿瘤发生中的抑制作用。为此，我有 获得了初步数据，表明去泛素化酶OTUD3，但没有其他Otud家族 成员，专门相互作用并去泛素化LATS1。更重要的是，我确定了Raptor，这是核心之一 MTORC1的组成部分，它是一种用于细胞代谢的中央细胞生长调节剂，作为一种新型 LATS1/2的磷酸化底物。在此提案中，我计划：1）将OTUD3描述为新颖的上游 通过LATS1/2的去泛素化，可以积极调节LATS1/2激酶活性的调节剂； 2） 确定LATS1/2在抑制乳腺肿瘤发生中的生理作用很大程度上通过 Ser606位点的磷酸化猛禽，进而抑制MTORC1的激酶活性； 3）确定 LATS1/2在Ser606处的猛禽磷酸化是否以及如何调节体内乳腺癌的发展。 我职业的长期目标是将分子和细胞生物学研究的见解应用于 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中，尤其是在乳腺癌中，并寻找适当的可药物 更好的抗北癌治疗的靶标。这个K99/R00奖将为我提供受保护的时间 追求该提议的新假设，获得新技能来执行实验并解决问题。 此外，K99奖将使我能够将自己的精力集中在独立进行基本和 转化研究，并在癌症生物学领域培训未来的年轻科学家。