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Vol. 19, Issue 3, 822-832, March 2008

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Fbx8 Makes Arf6 Refractory to Function via Ubiquitination

Hajime Yano^*, Itaru Kobayashi^*,, Yasuhito Onodera^*, Frédéric Luton, Michel Franco, Yuichi Mazaki^*, Shigeru Hashimoto^*, Kazuhiro Iwai, Ze'ev Ronai^||, and Hisataka Sabe^*,

*Department of Molecular Biology, Osaka Bioscience Institute, Osaka 565-0874, Japan; Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan; Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique-Unité Mixte de Recherche 6097, 06560 Valbonne, France; Department of Molecular Cell Biology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan; and ^||Signal Transduction Program, The Burnham Institute, La Jolla, CA 92037

Submitted August 10, 2007; Revised November 28, 2007; Accepted December 11, 2007
Monitoring Editor: Sandra Schmid

The small GTP-binding protein Arf6 regulates membrane remodeling at cell peripheries and plays crucial roles in higher orders of cellular functions including tumor invasion. Here we show that Fbx8, an F-box protein bearing the Sec7 domain, mediates ubiquitination of Arf6. This ubiquitination did not appear to be linked to immediate proteasomal degradation of Arf6, whereas Fbx8 knockdown caused hyperactivation of Arf6. Expression of Fbx8 protein was substantially lost in several breast tumor cell lines, in which Arf6 activity is pivotal for their invasion. Forced expression of Fbx8 in these cells suppressed their Arf6 activities and invasive activities, in which the F-box and Sec7 domains of Fbx8 are required. Together with the possible mechanism as to how Fbx8-mediated ubiquitination interferes with the functions of Arf6, we propose that Fbx8 provides a novel suppressive control of Arf6 activity through noncanonical ubiquitination. Our results indicate that dysfunction of Fbx8 expression may contribute to the invasiveness of some breast cancer cells.

Address correspondence to: Hisataka Sabe (sabe{at}obi.or.jp)

Abbreviations used: Arf6, ADP ribosylation factor 6; GEF, guanine nucleotide exchange factor; GAP, GTPase-activating protein; SCF complex, Skp1/Cul1/F-box complex; GGA, Golgi-localizing, -adaptin ear homology domain, Arf-binding protein; ARNO, ADP ribosylation factor nucleotide binding site opener; AMAP1, a multidomain Arf GAP protein.