Regulation and function of the YAP transcription co-activator oncoprotein

描述(申请人提供)：河马肿瘤抑制途径的功能是通过抑制增殖和诱导细胞凋亡来限制组织生长和器官大小。河马途径的失调导致了肿瘤的发生。河马途径的关键下游效应物是转录共激活因子Yap，它被磷酸化并被河马途径激酶LATS抑制。在人类癌症中发现了YAP的过度表达和过度激活。广泛的研究已经确定了许多调节河马途径的细胞内蛋白。然而，有关河马途径的细胞外信号和细胞表面受体的关键问题尚未得到解决。我们最近发现G蛋白偶联受体(GPCR)及其同源配体调节河马通路。GPCR调控多种细胞内信号分子，包括蛋白激酶A(PKA)和蛋白激酶C(PKC)。PKA由cAMP激活，cAMP是第二信使，通过Gs偶联受体的刺激而升高。二酰甘油也是GQ/11偶联受体上调的第二信使，它激活了PKC。PKA和PKC都参与了广泛的细胞调控，包括基因表达和细胞生长。我们的初步研究表明，PKA和PKC对YAP有很强的调节作用。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。本项目的长期目标是阐明PKA和PKC对YAP的调控机制，了解Hippo-YAP通路在细胞生长、器官大小、肿瘤发生和肿瘤转移中的调控和功能，为癌症治疗提供潜在的治疗靶点。

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.