Format

Send to

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

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

Author information

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.

PMID:
27265506
PMCID:
PMC5027844
DOI:
10.1016/j.ccell.2016.04.015
[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Substances, Supplementary concept, Grant support

Publication type

MeSH terms

Substances

Supplementary concept

Grant support

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center