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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 Hippo 通路是发育、再生、组织稳态和器官大小的关键调节因子，在癌症等人类疾病中经常观察到其失调。在哺乳动物中，河马该途径由核心激酶级联组成，其中包括两种 Ser/Thr 激酶 MST 和 LATS 以及它们的衔接蛋白SAV1和MOB1分别是下游效应蛋白YAP和核转录因子TEAD。 Hippo 通路激活后，MST 磷酸化并激活 LATS，从而使 YAP 磷酸化，导致其细胞质滞留和降解。未磷酸化的 YAP 是易位到细胞核中，与 TEAD 结合，驱动参与多种基因的转录。与成长相关的事件。最近对果蝇和哺乳动物的研究进一步揭示了 MAP4K 家族激酶 (MAP4K) 和 PP2A 磷酸酶复合物 STRIPAK 作为 Hippo 的附加组件途径，其中 MAP4K 与 MST 并行作用，磷酸化并激活 LATS，而 STRIPAK 则抑制 MST 和 MAP4K 控制 Hippo 核心激酶级联。多种与生长相关的信号事件，例如生长因子、葡萄糖/能量稳态、细胞间接触、机械信号和一系列应激信号，已被发现可调节 Hippo 通路及其下游 YAP 依赖性转录程序。然而，这些上游信号刺激到底是如何进入 Hippo 通路核心的？组件尚未被完全理解。在过去的资助期内，我们阐明了这一长期存在的问题通过表征磷脂酸及其相关的脂质代谢途径来转导问题 Hippo 通路上游信号传导事件至 Hippo 通路激酶 LATS。在当前的资助期内，我们建议重新审视我们几年前发现的能量应激反应中的Hippo通路前。具体来说，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 轴在此过程中的作用来激活通路（目标 1）。在此外，我们将研究 Hippo 通路在促进细胞存活中的独立于 YAP 的功能对抗能源压力（目标 2）。总的来说，该项目的完成将机械地揭示能源如何压力激活 Hippo 通路并提供 Hippo 通路在生长控制中的功能见解和癌症的发展。