title: The small GTPase ARF6 stimulates β-catenin transcriptional activity during WNT5A-mediated melanoma invasion and metastasis.
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.
authors: Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
authors: Allie H
authors: AH
authors: Grossmann
authors: Jae Hyuk
authors: JH
authors: Yoo
authors: James
authors: J
authors: Clancy
authors: Lise K
authors: LK
authors: Sorensen
authors: Alanna
authors: A
authors: Sedgwick
authors: Zongzhong
authors: Z
authors: Tong
authors: Kirill
authors: K
authors: Ostanin
authors: Aaron
authors: A
authors: Rogers
authors: Kenneth F
authors: KF
authors: Grossmann
authors: Sheryl R
authors: SR
authors: Tripp
authors: Kirk R
authors: KR
authors: Thomas
authors: Crislyn
authors: C
authors: D'Souza-Schorey
authors: Shannon J
authors: SJ
authors: Odelberg
authors: Dean Y
authors: DY
authors: Li
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000502:physiology*; D020868:Gene Silencing; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000502:physiology*; D051153:Wnt Proteins / Q000502:physiology*; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000378:metabolism / Q000502:physiology*
chemical_list: D000089982:ADP-Ribosylation Factor 6; D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; C000715727:Arf6 protein, mouse