Regulation of the Hippo pathway and its role in uveal melanoma

Hippo通路的调节及其在葡萄膜黑色素瘤中的作用

• 批准号: 8340411
• 负责人: Kun-Liang Guan
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8340411
• 关键词: Apoptosis; Biochemical; Biology; Cell Count; Cell Proliferation; Cell Surface Receptors; Cutaneous Melanoma; Development; Disease; Eye; Frequencies; G-Protein-Coupled Receptors; Gene Expression; Genetic; Genetic Transcription; Goals; Human; Knowledge; Laboratories; Ligands; Liver; Lysophospholipids; Malignant Neoplasms; Mammalian Cell; Molecular; Mutate; Mutation; Neoplasm Metastasis; Organ Size; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Protein Dephosphorylation; Proteins; Ras/Raf; Regulation; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Sphingosine; Stem cells; Testing; Tumor Suppressor Proteins; Uveal Melanoma; base; cell motility; effective therapy; extracellular; insight; limitin; lysophosphatidic acid; self-renewal; sphingosine 1-phosphate; stem; therapeutic target; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The Hippo tumor suppressor pathway plays a crucial role in regulating organ size by inhibiting cell proliferation and promoting apoptosis, and limitin stem/progenitor cell self- renewal and expansion. The YAP/TAZ transcription co-activators are the major downstream effectors of the Hippo pathway. Despite extensive studies, upstream signals regulating the Hippo pathway are unknown. Currently, no extracellular ligand or cell surface receptor has been identified to regulate the mammalian Hippo-YAP. Our preliminary studies have discovered that lysophosphatidic acid (LPA) and sphingosine 1- phosphophate (S1P) are important signaling molecules that regulating the Hippo pathway. LPA and S1P act through their respective G-protein coupled receptors (GPCRs) to activate YAP. Both LPA and S1P have been implicated in cancer development and metastasis. Notably, activating mutations of Gq/11 are frequently found (83%) in uveal melanoma, which is the most common intraocular tumor in the eye with strong propensity of metastasis into the liver. Our preliminary study showed that active Gq/11 potently stimulates YAP activity. The major goals of this proposal are to investigate the mechanism of Hippo-YAP regulation by GPCR and to determine the functional significance of YAP/TAZ activation in the biology of LPA, S1P and other extracellular signals. Moreover, we will investigate the pathophysiological function of YAP/TAZ activation in the development of uveal melanoma and aim to provide scientific basis for treatment of this disease. PUBLIC HEALTH RELEVANCE: The Hippo signaling pathway plays a major role in organ size regulation by controlling cell number and has also been implicated in human cancer. Preliminary studies from the PI's laboratory have identified the first extracellular signals and cell surface receptors that regulate the Hippo pathway, and suggested a critical role of the Hippo pathway in uveal melanoma, which is the most common intraocular tumor in the eye. The goal of this proposal is to gain knowledge of Hippo-YAP pathway regulation and its role in uveal melanoma development.

描述（由申请人提供）：河马肿瘤抑制途径通过抑制细胞增殖和促进凋亡在调节器官大小中起着至关重要的作用，并限制了限制茎/祖细胞/祖细胞自我更新和扩张。 YAP/TAZ转录共激活因子是河马途径的主要下游效应子。尽管进行了广泛的研究，但调节河马途径的上游信号尚不清楚。目前，尚未鉴定出细胞外配体或细胞表面受体来调节哺乳动物的河马-YAP。我们的初步研究发现，溶物磷脂酸（LPA）和1-磷酸盐（S1P）是调节河马途径的重要信号分子。 LPA和S1P通过其各自的G蛋白偶联受体（GPCR）起作用以激活YAP。 LPA和S1P都与癌症的发展和转移有关。值得注意的是，在卵巢黑色素瘤中经常发现GQ/11的激活突变（83％），这是眼睛中最常见的眼内肿瘤，转移倾向很强。我们的初步研究表明，主动GQ/11有效刺激YAP活性。该提案的主要目标是研究GPCR通过GPCR调控的机理，并确定LPA，S1P和其他细胞外信号在生物学中YAP/TAZ激活的功能意义。此外，我们将研究YAP/TAZ激活在卵巢黑色素瘤发展中的病理生理功能，并旨在为治疗这种疾病提供科学基础。 公共卫生相关性：河马信号通路通过控制细胞数量在器官大小调节中起着重要作用，并且也与人类癌症有关。来自PI实验室的初步研究已经确定了调节河马途径的第一个细胞外信号和细胞表面受体，并提出了河马途径在卵巢黑色素瘤中的关键作用，这是眼睛中最常见的眼内肿瘤。该提议的目的是了解河马途径调节及其在紫菜素黑色素瘤发育中的作用。