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Sci. Signal., 5 March 2013
Vol. 6, Issue 265, p. ra14
[DOI: 10.1126/scisignal.2003398]

RESEARCH ARTICLES

The Small GTPase ARF6 Stimulates β-Catenin Transcriptional Activity During WNT5A-Mediated Melanoma Invasion and Metastasis

Allie H. Grossmann1,2,3*, Jae Hyuk Yoo3,4*, James Clancy5, Lise K. Sorensen3, Alanna Sedgwick5, Zongzhong Tong6, Kirill Ostanin6, Aaron Rogers1, Kenneth F. Grossmann7,8, Sheryl R. Tripp9, Kirk R. Thomas3,7, Crislyn D’Souza-Schorey5, Shannon J. Odelberg3,6,7{dagger}, and Dean Y. Li3,4,7,10,11{dagger}

1 Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
2 ARUP Laboratories, University of Utah, Salt Lake City, UT 84108, USA.
3 Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112, USA.
4 Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA.
5 Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA.
6 Navigen Inc., Salt Lake City, UT 84108, USA.
7 Department of Medicine, University of Utah, Salt Lake City, UT 84132, USA.
8 Division of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84132, USA.
9 ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT 84112, USA.
10 Cardiology Section, VA Salt Lake City Health Care System, Salt Lake City, UT 84112, USA.
11 The Key Laboratory for Human Disease Gene Study of Sichuan Province, Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, Sichuan 610072, China.

* These authors contributed equally to this work.

Abstract: β-Catenin has a dual function in cells: fortifying cadherin-based adhesion at the plasma membrane and activating transcription in the nucleus. We found that in melanoma cells, WNT5A stimulated the disruption of N-cadherin and β-catenin complexes by activating the guanosine triphosphatase adenosine diphosphate ribosylation factor 6 (ARF6). Binding of WNT5A to the Frizzled 4–LRP6 (low-density lipoprotein receptor–related protein 6) receptor complex activated ARF6, which liberated β-catenin from N-cadherin, thus increasing the pool of free β-catenin, enhancing β-catenin–mediated transcription, and stimulating invasion. In contrast to WNT5A, the guidance cue SLIT2 and its receptor ROBO1 inhibited ARF6 activation and, accordingly, stabilized the interaction of N-cadherin with β-catenin and reduced transcription and invasion. Thus, ARF6 integrated competing signals in melanoma cells, thereby enabling plasticity in the response to external cues. Moreover, small-molecule inhibition of ARF6 stabilized adherens junctions, blocked β-catenin signaling and invasiveness of melanoma cells in culture, and reduced spontaneous pulmonary metastasis in mice, suggesting that targeting ARF6 may provide a means of inhibiting WNT/β-catenin signaling in cancer.

{dagger} To whom correspondence should be addressed. E-mail: dean.li{at}u2m2.utah.edu (D.Y.L.); sodelber{at}genetics.utah.edu (S.J.O.)

Citation: A. H. Grossmann, J. H. Yoo, J. Clancy, L. K. Sorensen, A. Sedgwick, Z. Tong, K. Ostanin, A. Rogers, K. F. Grossmann, S. R. Tripp, K. R. Thomas, C. D’Souza-Schorey, S. J. Odelberg, D. Y. Li, The Small GTPase ARF6 Stimulates β-Catenin Transcriptional Activity During WNT5A-Mediated Melanoma Invasion and Metastasis. Sci. Signal. 6, ra14 (2013).

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