@article{4a8bc2adaa814045a1c9c3dd08a19c89,
title = "ARF6 Is an Actionable Node that Orchestrates Oncogenic GNAQ Signaling in Uveal Melanoma",
abstract = "Activating mutations in Gαq proteins, which form the α 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 Gαq signaling to induce all of these downstream pathways as well as β-catenin signaling. ARF6 activates these diverse pathways through a common mechanism: the trafficking of GNAQ and β-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 Gα-mediated diseases.",
author = "Yoo, {Jae Hyuk} and Shi, {Dallas S.} and Grossmann, {Allie H.} and Sorensen, {Lise K.} and Tong, {Zong Zhong} and Mleynek, {Tara M.} and Aaron Rogers and Weiquan Zhu and Richards, {Jackson R.} and Winter, {Jacob M.} and Jie Zhu and Christine Dunn and Ashok Bajji and Mark Shenderovich and Mueller, {Alan L.} and Woodman, {Scott E.} and Harbour, {J. William} and Thomas, {Kirk R.} and Odelberg, {Shannon J.} and Kirill Ostanin and Li, {Dean Y.}",
note = "Funding Information: We thank S. Holmen, T. Oliver, C. Murtaugh, J. Christian, A. Bild, W. Sundquist, C. Hill, J. Kaplan, D. Ward, M. Babst, E. Jorgensen, M. Sanguinetti, and M. E. Hartnett for critical reading of the manuscript, D. Ward for technical advice, and D.Y.L. laboratory members for critical discussion of the manuscript. We thank C. Rodesch and the Cell Imaging Core Facility at the University of Utah for technical assistance, B. Anderson and the Huntsman Cancer Institute Biorepository and Molecular Pathology Shared Resources facility for preparation of tissues for histology, and D. Lim for assistance with figures. This work was funded by grants to D.Y.L., K.O., J.W.H., W.Z., and A.H.G. from the NCI , NINDS , NHLBI , NIAMS , NEI , NCATS , Huntsman Cancer Institute Cell Response and Regulation Program , George S. and Dolores Dore Eccles Foundation , American Asthma Foundation , the Burroughs Wellcome Fund (Clinical Scientist Award in Translational Medicine), the Ben B. and Iris M. Margolis Foundation , the H. A. and Edna Benning Fund for Medical Research , and the Harold J. Lloyd Charitable Trust (Career Development Melanoma Research Grant). D.Y.L. is co-founder and Chief Scientific Officer of Navigen, Inc. K.O., Z.T., C.D, A.B., M.S., and A.L.M. are employees of Navigen, Inc. Funding Information: We thank S. Holmen, T. Oliver, C. Murtaugh, J. Christian, A. Bild, W. Sundquist, C. Hill, J. Kaplan, D. Ward, M. Babst, E. Jorgensen, M. Sanguinetti, and M. E. Hartnett for critical reading of the manuscript, D. Ward for technical advice, and D.Y.L. laboratory members for critical discussion of the manuscript. We thank C. Rodesch and the Cell Imaging Core Facility at the University of Utah for technical assistance, B. Anderson and the Huntsman Cancer Institute Biorepository and Molecular Pathology Shared Resources facility for preparation of tissues for histology, and D. Lim for assistance with figures. This work was funded by grants to D.Y.L., K.O., J.W.H., W.Z., and A.H.G. from the NCI, NINDS, NHLBI, NIAMS, NEI, NCATS, Huntsman Cancer Institute Cell Response and Regulation Program, George S. and Dolores Dore Eccles Foundation, American Asthma Foundation, the Burroughs Wellcome Fund (Clinical Scientist Award in Translational Medicine), the Ben B. and Iris M. Margolis Foundation, the H. A. and Edna Benning Fund for Medical Research, and the Harold J. Lloyd Charitable Trust (Career Development Melanoma Research Grant). D.Y.L. is co-founder and Chief Scientific Officer of Navigen, Inc. K.O., Z.T., C.D, A.B., M.S., and A.L.M. are employees of Navigen, Inc. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",
year = "2016",
month = jun,
day = "13",
doi = "10.1016/j.ccell.2016.04.015",
language = "English (US)",
volume = "29",
pages = "889--904",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "6",
}