Regulation and function of the Hippo pathway in growth control

Hippo 通路在生长控制中的调节和功能

• 批准号: 10584267
• 负责人: Wenqi Wang
• 金额: $ 32.34万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584267
• 关键词: Adaptor Signaling Protein; Autophagocytosis; Autophagosome; Basic Science; Binding; Binding Proteins; Cancer Cell Growth; Cell Nucleus; Cell Survival; Cells; Complex; Cytoplasm; Data; Development; Drosophila genus; Event; Family; Foundations; Genetic Transcription; Glucose; Goals; Grant; Growth; Growth Factor; Head and Neck Cancer; Head and Neck Neoplasms; Homeostasis; Human; Lipids; Lysosomes; Malignant Neoplasms; Mammals; Mediating; Metabolic Pathway; Modeling; Molecular; Natural regeneration; Nuclear; Nuclear Translocation; Oncogenic; Organ Size; Pathway interactions; Phosphatidic Acid; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological Processes; Physiology; Play; Process; Protein Phosphatase 2A Regulatory Subunit PR53; Proteins; Proteomics; Recycling; Regulation; Role; Series; Signal Transduction; Site; Starvation; Stimulus; Stress; Testing; Tissues; Translational Research; biological adaptation to stress; cancer therapy; comparative; human disease; insight; interest; mechanical signal; novel; novel therapeutic intervention; programs; response; transcription factor; tumor growth; tumor metabolism; tumor xenograft; upstream kinase

PROJECT SUMMARY The Hippo pathway is a key regulator of development, regeneration, tissue homeostasis and organ size, whose dysregulations have been frequently observed in human diseases like cancer. In mammals, the Hippo pathway is composed of a core kinase cascade that comprises two Ser/Thr kinases MST and LATS as well as their adaptor proteins SAV1 and MOB1, respectively, downstream effector protein YAP, and nuclear transcription factor TEAD. Upon Hippo pathway activation, MST phosphorylates and activates LATS, which in turn phosphorylates YAP, resulting in its cytoplasmic retention and degradation. Un-phosphorylated YAP is translocated into the nucleus, where it binds TEAD to drive the transcription of genes involved in various growth-related events. Recent studies in both Drosophila and mammals have further revealed MAP4K-family kinases (MAP4Ks) and PP2A phosphatase complex STRIPAK as additional components of the Hippo pathway, where MAP4Ks act in parallel to MST to phosphorylate and activate LATS, while STRIPAK inhibits MST and MAP4Ks to control the Hippo core kinase cascade. Multiple growth-related signaling events, such as growth factors, glucose/energy homeostasis, cell-cell contact, mechanical cues and a series of stress signals, have been uncovered to regulate the Hippo pathway and its downstream YAP-dependent transcriptional program. However, precisely how these upstream signaling stimuli feed into the Hippo pathway core components has not been fully understood. In the past grant period, we shed light on this long-standing question by characterizing phosphatidic acid and its-associated lipid metabolic pathway in transducing the Hippo pathway upstream signaling events to the Hippo pathway kinase LATS. In the current grant period, we propose to re-examine the Hippo pathway in energy stress response that was discovered by us a few years ago. Specifically, we will elucidate the molecular mechanisms underlying the energy stress-induced Hippo pathway activation by characterizing the role of the AMPK-STRIPAK-MAP4Ks axis in this process (Aim 1). In addition, we will investigate a YAP-independent function of the Hippo pathway in promoting cell survival against energy stress (Aim 2). Collectively, completion of this project will reveal mechanistically how energy stress activates the Hippo pathway and provide functional insights into the Hippo pathway in growth control and cancer development.

项目总结 河马途径是发育、再生、组织动态平衡和器官大小的关键调节因子， 它的失调在癌症等人类疾病中经常被观察到。在哺乳动物中，河马 途径由两个Ser/Thr激酶、MST和LATS以及 它们的接头蛋白分别是SAV1和MOB1，下游的效应蛋白YAP，以及核 转录因子Tead。在河马通路激活后，MST磷酸化并激活LATS，LATS在 TURN使YAP磷酸化，导致其胞质滞留和降解。非磷酸化的YAP是 转位到细胞核，在那里它结合tead来驱动参与各种基因转录的各种 与增长相关的事件。最近对果蝇和哺乳动物的研究进一步揭示了MAP4K家族 作为河马附加成分的激酶(MAP4K)和PP2A磷酸酶复合体STRIPAK 途径，其中MAP4K与MST平行地作用于磷酸化并激活LATS，而STRIPAK抑制 MST和MAP4Ks控制河马核心激酶级联。多个与增长相关的信号事件，例如 生长因子、葡萄糖/能量动态平衡、细胞-细胞接触、机械信号和一系列压力信号， 已被发现调节河马途径及其下游依赖YAP的转录 程序。然而，这些上游信号刺激究竟是如何进入河马通路核心的 人们还没有完全了解这些组件。在过去的赠款期间，我们阐明了这个由来已久的 通过表征磷脂酸及其相关的脂代谢途径在转导 河马途径上游信号传递到河马途径激酶LATS。在目前的授权期内，我们 建议重新研究我们几年前发现的能量应激反应中的河马途径 那是以前的事了。具体地说，我们将阐明能量应激诱导河马的分子机制 通过表征AMPK-STRIPAK-MAP4Ks轴在这一过程中的作用来激活通路(目标1)。在……里面 此外，我们将研究河马通路在促进细胞存活方面的YAP不依赖的功能。 对抗能量压力(目标2)。总而言之，这个项目的完成将从机械上揭示能源 应激激活河马通路并提供河马通路在生长控制中的功能洞察力 和癌症的发展。