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

Jae Hyuk Yoo; Dallas S Shi; Allie H Grossmann; Lise K Sorensen; ZongZhong Tong; Tara M Mleynek; Aaron Rogers; Weiquan Zhu; Jackson R Richards; Jacob M Winter; Jie Zhu; Christine Dunn; Ashok Bajji; Mark Shenderovich; Alan L Mueller; Scott E Woodman; J William Harbour; Kirk R Thomas; Shannon J Odelberg; Kirill Ostanin; Dean Y Li

doi:10.1016/j.ccell.2016.04.015

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

Journal article

Open access

Peer reviewed

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

Jae Hyuk Yoo, Dallas S Shi, Allie H Grossmann, Lise K Sorensen, ZongZhong Tong, Tara M Mleynek, Aaron Rogers, Weiquan Zhu, Jackson R Richards, Jacob M Winter, …

Cancer cell, Vol.29(6), pp.889-904

2016-06-13

DOI: https://doi.org/10.1016/j.ccell.2016.04.015

PMCID: PMC5027844

PMID: 27265506

Abstract

Neoplasm Transplantation

Small Molecule Libraries - pharmacology

Small Molecule Libraries - administration & dosage

Humans

Cytoplasm - metabolism

Protein Transport - drug effects

Cell Nucleus - metabolism

ADP-Ribosylation Factors - antagonists & inhibitors

Melanoma - genetics

Cell Membrane - metabolism

Uveal Neoplasms - metabolism

ADP-Ribosylation Factors - metabolism

GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism

ADP-Ribosylation Factors - genetics

Melanoma - metabolism

GTP-Binding Protein alpha Subunits, Gq-G11 - genetics

Uveal Neoplasms - genetics

beta Catenin - metabolism

Uveal Neoplasms - drug therapy

Animals

Signal Transduction - drug effects

Melanoma - drug therapy

Cell Line, Tumor

Cell Proliferation - drug effects

Mice

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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.36 Ophthalmology; 1.36.1414 Uveal Melanoma
Web Of Science research areas: Cell Biology; Oncology
ESI research areas: Molecular Biology & Genetics

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Title: ARF6 Is an Actionable Node that Orchestrates Oncogenic GNAQ Signaling in Uveal Melanoma
Creators: Jae Hyuk Yoo - Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA; Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA
Dallas S Shi - Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA; Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA
Allie H Grossmann - Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA; Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA; ARUP Laboratories, University of Utah, Salt Lake City, UT 84112, USA
Lise K Sorensen - Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA
ZongZhong Tong - Navigen Inc., 383 Colorow Drive, Salt Lake City, UT 84108, USA; Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, China
Tara M Mleynek - Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA
Aaron Rogers - Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA
Weiquan Zhu - Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA; Division of Cardiovascular Medicine, Department of Medicine, University of Utah, Salt Lake City, UT 84112, USA
Jackson R Richards - Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA; Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA
Jacob M Winter - Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA
Jie Zhu - Department of Ophthalmology and Shiley Eye Institute, University of California, San Diego, La Jolla, CA 92093, USA
Christine Dunn - Navigen Inc., 383 Colorow Drive, Salt Lake City, UT 84108, USA
Ashok Bajji - Navigen Inc., 383 Colorow Drive, Salt Lake City, UT 84108, USA; VioGen Biosciences LLC, Salt Lake City, UT 84119, USA
Mark Shenderovich - Navigen Inc., 383 Colorow Drive, Salt Lake City, UT 84108, USA; Mol3D Research LLC, Salt Lake City, UT 84124, USA
Alan L Mueller - Navigen Inc., 383 Colorow Drive, Salt Lake City, UT 84108, USA
Scott E Woodman - Department of Melanoma Medical Oncology, Department of Systems Biology, University of Texas, MD Anderson Cancer Center, Houston, TX 77054, USA
J William Harbour - Ocular Oncology Service, Bascom Palmer Eye Institute and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Kirk R Thomas - Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA; Division of Hematology, Department of Medicine, University of Utah, Salt Lake City, UT 84112, USA
Shannon J Odelberg - Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA; Division of Cardiovascular Medicine, Department of Medicine, University of Utah, Salt Lake City, UT 84112, USA; Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84112, USA
Kirill Ostanin - Navigen Inc., 383 Colorow Drive, Salt Lake City, UT 84108, USA. Electronic address: kostanin@nvgn.com
Dean Y Li - Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA; Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA; Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA; ARUP Laboratories, University of Utah, Salt Lake City, UT 84112, USA; Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, China; Division of Cardiovascular Medicine, Department of Medicine, University of Utah, Salt Lake City, UT 84112, USA; Department of Cardiology, VA Salt Lake City Health Care System, Salt Lake City, UT 84112, USA. Electronic address: dean.li@u2m2.utah.edu
Publication Details: Cancer cell, Vol.29(6), pp.889-904
Grant note: R01 NS080893 / NINDS NIH HHS R43 EY022516 / NEI NIH HHS T32 HL007576 / NHLBI NIH HHS R01 CA163970 / NCI NIH HHS R01 CA125970 / NCI NIH HHS R01 EY025342 / NEI NIH HHS U54 HL112311 / NHLBI NIH HHS R01 HL084516 / NHLBI NIH HHS R01 AR064788 / NIAMS NIH HHS U01 NS083573 / NINDS NIH HHS R01 HL077671 / NHLBI NIH HHS P30 CA016672 / NCI NIH HHS R01 CA202778 / NCI NIH HHS UL1 TR000105 / NCATS NIH HHS R43 AR063509 / NIAMS NIH HHS UL1 TR001067 / NCATS NIH HHS
Academic Unit: Miller School of Medicine; UMMG Department of Ophthalmology
Language: English
Resource Type: Journal article
PMID: 27265506
PMCID: PMC5027844
Record Identifier: 991031597032802976