Regulation of the Hippo pathway and its role in uveal melanoma

描述（申请人提供）：Hippo肿瘤抑制通路通过抑制细胞增殖和促进细胞凋亡，限制干细胞/祖细胞的自我更新和扩增，在调节器官大小方面发挥重要作用。YAP/TAZ转录共激活因子是Hippo通路的主要下游效应因子。尽管进行了广泛的研究，但调控Hippo通路的上游信号尚不清楚。目前，尚未发现调控哺乳动物Hippo-YAP的细胞外配体或细胞表面受体。我们的初步研究发现溶血磷脂酸（LPA）和鞘氨醇1-磷酸（S1P）是调控Hippo通路的重要信号分子。LPA和S1P通过各自的g蛋白偶联受体（gpcr）激活YAP。LPA和S1P都与癌症的发生和转移有关。值得注意的是，Gq/11的激活突变在葡萄膜黑色素瘤中很常见（83%），葡萄膜黑色素瘤是眼部最常见的眼内肿瘤，有很强的肝脏转移倾向。我们的初步研究表明活跃的Gq/11能有效刺激YAP活性。本课题的主要目的是研究GPCR对Hippo-YAP的调控机制，确定YAP/TAZ激活在LPA、S1P等胞外信号生物学中的功能意义。此外，我们将探讨YAP/TAZ激活在葡萄膜黑色素瘤发生发展中的病理生理功能，旨在为该疾病的治疗提供科学依据。

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.