| Literature DB >> 27265506 |
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.
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.Entities:
Mesh：
Substances：
Year: 2016 PMID： 27265506 PMCID： PMC5027844 DOI： 10.1016/j.ccell.2016.04.015
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743