Regulation and function of the YAP transcription co-activator oncoprotein

YAP转录辅激活癌蛋白的调控和功能

• 批准号: 8627562
• 负责人: Kun-Liang Guan
• 金额: $ 30.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-08 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627562
• 关键词: 1,2-diacylglycerol; Address; Apoptosis; Biochemical; Cell Surface Receptors; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Diglycerides; Epithelial; G-Protein-Coupled Receptors; Gene Expression; Genetic Transcription; Goals; Growth; Human; Ligands; Malignant Neoplasms; Mesenchymal; Neoplasm Metastasis; Oncogene Proteins; Organ Size; Pathway interactions; Phosphorylation; Phosphotransferases; Physiological; Play; Protein Dephosphorylation; Protein Kinase C; Proteins; Regulation; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Signaling Molecule; Tumor Suppressor Proteins; cancer therapy; cell growth; cell growth regulation; extracellular; overexpression; public health relevance; receptor coupling; second messenger; therapeutic target; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The Hippo tumor suppressor pathway functions to limit tissue growth and organ size by inhibiting proliferation and inducing apoptosis. Dysregulation of the Hippo pathway contributes to tumorigenesis. The key downstream effectors of the Hippo pathway are the transcription co-activator YAP, which is phosphorylated and inhibited by the Hippo pathway kinase Lats. YAP overexpression and hyperactivation are found in human cancers. Extensive studies have identified many intracellular proteins that modulate the Hippo pathway. However, key questions regarding the extracellular signals and cell surface receptors for the Hippo pathway have not been addressed. We recently discovered that G-protein coupled receptors (GPCR) and their cognate ligands regulate the Hippo pathway. GPCR modulates many intracellular signaling molecules including protein kinase A (PKA) and protein kinase C (PKC). PKA is activated by cAMP, a second messenger that is elevated by stimulation of Gs-coupled receptor. PKC is activated by diacylglycerol that is also a second messenger elevated by Gq/11- coupled receptors. Both PKA and PKC are involved in a wide range of cellular regulation, including gene expression and cell growth. Our preliminary studies reveal that PKA and PKC potently modulate YAP. PKA inhibits YAP by increasing phosphorylation while PKC activates YAP by inducing dephosphorylation. The long- term goal of this project is to elucidate the mechanism of YAP regulation by PKA and PKC, to understand the regulation and function of the Hippo-YAP pathway in cell growth, organ size, tumorigenesis and cancer metastasis, and to provide potential therapeutic targets for cancer treatment.

描述（由申请人提供）：河马肿瘤抑制途径的功能可通过抑制增殖和诱导凋亡来限制组织生长和器官的大小。河马途径的失调会导致肿瘤发生。河马途径的关键下游效应子是转录共激活因子YAP，它被河马途径激酶LATS磷酸化和抑制。在人类癌症中发现了YAP的过表达和过度激活。广泛的研究已经确定了许多调节河马途径的细胞内蛋白质。但是，尚未解决有关河马途径的细胞外信号和细胞表面受体的关键问题。我们最近发现，G蛋白偶联受体（GPCR）及其同源配体调节河马途径。 GPCR调节许多细胞内信号分子，包括蛋白激酶A（PKA）和蛋白激酶C（PKC）。 PKA被CAMP激活，CAMP是由GS耦合受体刺激升高的第二个信使。 PKC被二酰基甘油激活，二酰基甘油也是由GQ/11-偶联受体升高的第二质体。 PKA和PKC都参与了广泛的细胞调节，包括基因表达和细胞生长。我们的初步研究表明，PKA和PKC有效调节YAP。 PKA通过增加磷酸化来抑制YAP，而PKC通过诱导去磷酸化来激活YAP。该项目的长期目标是阐明PKA和PKC调节YAP调节的机制，以了解河马-YAP途径在细胞生长，器官大小，肿瘤发生和癌症转移中的调节和功能，并为癌症治疗提供潜在的治疗靶点。