Research ArticleCancer

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

Sci. Signal.  05 Mar 2013:
Vol. 6, Issue 265, pp. ra14
DOI: 10.1126/scisignal.2003398

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Releasing β-Catenin for Melanoma Metastasis

Signaling through the Wnt pathway stimulates gene transcription mediated by β-catenin, and nuclear β-catenin is associated with a poor prognosis in cancer. The amount of β-catenin that is available to transcriptionally activate Wnt target genes may depend on the amount that is bound by cadherin in cell-cell adhesion structures called adherens junctions. Grossmann et al. found that WNT5A, which was produced by various melanoma cell lines, activated the small guanosine triphosphatase ARF6, triggered the release of β-catenin from N-cadherin, and increased the transcriptional activity of β-catenin. Pharmacological inhibition of ARF6 reduced β-catenin activity and invasive activity of melanoma cells in culture and decreased pulmonary metastasis in mice with tumors formed from melanoma cells. Thus, ARF6 may be a viable therapeutic target for reducing the invasiveness and metastasis of melanomas.