The Small GTPase ARF6 Stimulates {beta}-Catenin Transcriptional Activity During WNT5A-Mediated Melanoma Invasion and Metastasis
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la petite GTPase ARF6 régule les processus invasif et métastatique d'un mélanome
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.