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, Zong Zhong 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 OstaninDean Y. Li

Research output: Contribution to journalArticle

59 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)889-904
Number of pages16
JournalCancer Cell
Volume29
Issue number6
DOIs
StatePublished - Jun 13 2016

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Yoo, J. H., Shi, D. S., Grossmann, A. H., Sorensen, L. K., Tong, Z. Z., Mleynek, T. M., Rogers, A., Zhu, W., Richards, J. R., Winter, J. M., Zhu, J., Dunn, C., Bajji, A., Shenderovich, M., Mueller, A. L., Woodman, S. E., Harbour, J. W., Thomas, K. R., Odelberg, S. J., ... Li, D. Y. (2016). ARF6 Is an Actionable Node that Orchestrates Oncogenic GNAQ Signaling in Uveal Melanoma. Cancer Cell, 29(6), 889-904. https://doi.org/10.1016/j.ccell.2016.04.015