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 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

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

Melanoma Medical Oncology

Research output: Contribution to journal › Article › peer-review

109 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 language	English (US)
Pages (from-to)	889-904
Number of pages	16
Journal	Cancer cell
Volume	29
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2016.04.015
State	Published - Jun 13 2016

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

MD Anderson CCSG core facilities

Tissue Biospecimen and Pathology Resource
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10.1016/j.ccell.2016.04.015

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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

Yoo, JH, Shi, DS, Grossmann, AH, Sorensen, LK, Tong, ZZ, Mleynek, TM, Rogers, A, Zhu, W, Richards, JR, Winter, JM, Zhu, J, Dunn, C, Bajji, A, Shenderovich, M, Mueller, AL, Woodman, SE, Harbour, JW, Thomas, KR, Odelberg, SJ, Ostanin, K & Li, DY 2016, 'ARF6 Is an Actionable Node that Orchestrates Oncogenic GNAQ Signaling in Uveal Melanoma', Cancer cell, vol. 29, no. 6, pp. 889-904. https://doi.org/10.1016/j.ccell.2016.04.015

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title = "ARF6 Is an Actionable Node that Orchestrates Oncogenic GNAQ Signaling in Uveal Melanoma",

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.",

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

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year = "2016",

month = jun,

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doi = "10.1016/j.ccell.2016.04.015",

language = "English (US)",

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T1 - ARF6 Is an Actionable Node that Orchestrates Oncogenic GNAQ Signaling in Uveal Melanoma

AU - Yoo, Jae Hyuk

AU - Shi, Dallas S.

AU - Grossmann, Allie H.

AU - Sorensen, Lise K.

AU - Tong, Zong Zhong

AU - Mleynek, Tara M.

AU - Rogers, Aaron

AU - Zhu, Weiquan

AU - Richards, Jackson R.

AU - Winter, Jacob M.

AU - Zhu, Jie

AU - Dunn, Christine

AU - Bajji, Ashok

AU - Shenderovich, Mark

AU - Mueller, Alan L.

AU - Woodman, Scott E.

AU - Harbour, J. William

AU - Thomas, Kirk R.

AU - Odelberg, Shannon J.

AU - Ostanin, Kirill

AU - Li, Dean Y.

PY - 2016/6/13

Y1 - 2016/6/13

N2 - 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.

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

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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