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ARF6 Is an Actionable Node that Orchestrates Oncogenic GNAQ Signaling in Uveal Melanoma

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收录情况： ◇ SCIE ◇ 自然指数

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机构： [1]Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA [2]Department of Oncological Sciences,University of Utah, Salt Lake City, UT 84112, USA [3]Department of Human Genetics,University of Utah, Salt Lake City, UT 84112, USA [4]Department of Pathology,University of Utah, Salt Lake City, UT 84112, USA [5]ARUP Laboratories,University of Utah, Salt Lake City, UT 84112, USA [6]Navigen Inc., 383 Colorow Drive, Salt Lake City, UT 84108, USA [7]Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu 610072, China [8]Department of Ophthalmology and Shiley Eye Institute, University of California, San Diego, La Jolla, CA 92093, USA [9]VioGen Biosciences LLC, Salt Lake City, UT 84119, USA [10]Mol3D Research LLC, Salt Lake City, UT 84124, USA [11]Department of Melanoma Medical Oncology, Department of Systems Biology, University of Texas, MD Anderson Cancer Center, Houston, TX 77054, USA [12]Ocular Oncology Service, Bascom Palmer Eye Institute and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA [13]Division of Hematology,Department of Medicine, University of Utah, Salt Lake City, UT 84112, USA [14]Division of Cardiovascular Medicine,Department of Medicine, University of Utah, Salt Lake City, UT 84112, USA [15]Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84112, USA [16]Department of Cardiology, VA Salt Lake City Health Care System, Salt Lake City, UT 84112, USA

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Activating mutations in G alpha q proteins, which form the alpha subunit of certain heterotrimeric G proteins, drive uveal melanoma oncogenesis by triggering multiple downstream signaling pathways, including PLC/PKC, Rho/Rac, and YAP. Here we show that the small GTPase ARF6 acts as a proximal node of oncogenic G alpha q signaling to induce all of these downstream pathways as well as beta-catenin signaling. ARF6 activates these diverse pathways through a common mechanism: the trafficking of GNAQ and beta-catenin from the plasma membrane to cytoplasmic vesicles and the nucleus, respectively. Blocking ARF6 with a small-molecule inhibitor reduces uveal melanoma cell proliferation and tumorigenesis in a mouse model, confirming the functional relevance of this pathway and suggesting a therapeutic strategy for G alpha-mediated diseases.

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出版当年[2016]版：

大类 | 1 区

医学

小类 | 1 区细胞生物学 1 区肿瘤学

最新[2023]版：

大类 | 1 区

医学

小类 | 1 区细胞生物学 1 区肿瘤学

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出版当年[2016]版：

Q1 CELL BIOLOGY Q1 ONCOLOGY

最新[2023]版：

Q1 CELL BIOLOGY Q1 ONCOLOGY

影响因子： 48.8 最新[2023版] 42.1 最新五年平均 27.407 出版当年[2016版] 27.66 出版当年五年平均 23.214 出版前一年[2015版] 22.844 出版后一年[2017版]

第一作者：

第一作者机构： [1]Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA [2]Department of Oncological Sciences,University of Utah, Salt Lake City, UT 84112, USA

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通讯作者：

通讯机构： [1]Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA [2]Department of Oncological Sciences,University of Utah, Salt Lake City, UT 84112, USA [3]Department of Human Genetics,University of Utah, Salt Lake City, UT 84112, USA [5]ARUP Laboratories,University of Utah, Salt Lake City, UT 84112, USA [7]Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu 610072, China [14]Division of Cardiovascular Medicine,Department of Medicine, University of Utah, Salt Lake City, UT 84112, USA [16]Department of Cardiology, VA Salt Lake City Health Care System, Salt Lake City, UT 84112, USA

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