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

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

Cancer Cell. 2016 Jun 13;29(6):889-904. doi: 10.1016/j.ccell.2016.04.015. Epub 2016 Jun 2.

Authors

Jae Hyuk Yoo¹, Dallas S Shi², Allie H Grossmann³, Lise K Sorensen⁴, ZongZhong Tong⁵, Tara M Mleynek⁴, Aaron Rogers⁶, Weiquan Zhu⁷, Jackson R Richards¹, Jacob M Winter⁴, Jie Zhu⁸, Christine Dunn⁹, Ashok Bajji¹⁰, Mark Shenderovich¹¹, Alan L Mueller⁹, Scott E Woodman¹², J William Harbour¹³, Kirk R Thomas¹⁴, Shannon J Odelberg¹⁵, Kirill Ostanin¹⁶, Dean Y Li¹⁷

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA.
⁵ 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.
⁶ Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
⁷ 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.
⁸ Department of Ophthalmology and Shiley Eye Institute, University of California, San Diego, La Jolla, CA 92093, USA.
⁹ Navigen Inc., 383 Colorow Drive, Salt Lake City, UT 84108, USA.
¹⁰ Navigen Inc., 383 Colorow Drive, Salt Lake City, UT 84108, USA; VioGen Biosciences LLC, Salt Lake City, UT 84119, USA.
¹¹ Navigen Inc., 383 Colorow Drive, Salt Lake City, UT 84108, USA; Mol3D Research LLC, Salt Lake City, UT 84124, USA.
¹² Department of Melanoma Medical Oncology, Department of Systems Biology, University of Texas, MD Anderson Cancer Center, Houston, TX 77054, USA.
¹³ Ocular Oncology Service, Bascom Palmer Eye Institute and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
¹⁴ 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.
¹⁵ 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.
¹⁶ Navigen Inc., 383 Colorow Drive, Salt Lake City, UT 84108, USA. Electronic address: kostanin@nvgn.com.
¹⁷ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ADP-Ribosylation Factor 6
ADP-Ribosylation Factors / antagonists & inhibitors
ADP-Ribosylation Factors / genetics
ADP-Ribosylation Factors / metabolism*
Animals
Cell Line, Tumor
Cell Membrane / metabolism
Cell Nucleus / metabolism
Cell Proliferation / drug effects
Cytoplasm / metabolism
GTP-Binding Protein alpha Subunits, Gq-G11 / genetics*
GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
Humans
Melanoma / drug therapy*
Melanoma / genetics
Melanoma / metabolism
Mice
Neoplasm Transplantation
Protein Transport / drug effects
Signal Transduction / drug effects
Small Molecule Libraries / administration & dosage*
Small Molecule Libraries / pharmacology
Uveal Neoplasms / drug therapy*
Uveal Neoplasms / genetics
Uveal Neoplasms / metabolism
beta Catenin / metabolism*

Substances

ADP-Ribosylation Factor 6
GNAQ protein, human
Small Molecule Libraries
beta Catenin
GTP-Binding Protein alpha Subunits, Gq-G11
ADP-Ribosylation Factors
ARF6 protein, human
Arf6 protein, mouse

Supplementary concepts

Uveal melanoma

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding