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MBC in Press, published online ahead of print September 5, 2007
Mol. Biol. Cell 10.1091/mbc.E07-02-0149

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Submitted on February 20, 2007
Revised on August 21, 2007
Accepted on August 27, 2007

ARL4D Recruits Cytohesin-2/ARNO to Modulate Actin Remodeling

Chun-Chun Li,* Tsai-Chen Chiang,* Tsung-Sheng Wu,* Gustavo Pacheco-Rodriguez,{dagger} Joel Moss,{dagger} and Fang-Jen S. Lee*

*Institute of Molecular Medicine, College of Medicine, National Taiwan University, and Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; {dagger}Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1434

Monitoring Editor: Francis Barr

ARL4D is a developmentally regulated member of the ARF/ARL family of Ras-related GTPases. Although the primary structure of ARL4D is very similar to that of other ARF/ARL molecules, its function remains unclear. Cytohesin-2/ARNO is a guanine nucleotide-exchange factor (GEF) for ARF and, at the plasma membrane, it can activate ARF6 to regulate actin reorganization and membrane ruffling. We show here that ARL4D interacts with the C-terminal pleckstrin homology (PH) and polybasic c domains of cytohesin-2/ARNO in a GTP-dependent manner. Localization of ARL4D at the plasma membrane is GTP- and N-terminal myristoylation-dependent. ARL4D(Q80L), a putative active form of ARL4D, induced accumulation of cytohesin-2/ARNO at the plasma membrane. Consistent with a known action of cytohesin-2/ARNO, ARL4D(Q80L) increased GTP-bound ARF6 and induced disassembly of actin stress fibers. Expression of inactive cytohesin-2/ARNO(E156K) or siRNA knockdown of cytohesin-2/ARNO blocked ARL4D-mediated disassembly of actin stress fibers. Similar to the results with cytohesin-2/ARNO or ARF6, reduction of ARL4D suppressed cell migration activity. Furthermore, ARL4D-induced translocation of cytohesin-2/ARNO did not require phosphoinositide 3-kinase activation. Together, these data demonstrate that ARL4D acts as a novel upstream regulator of cytohesin-2/ARNO to promote ARF6 activation and modulate actin remodeling.

Address correspondence to: Fang-Jen S. Lee (fangjen{at}ha.mc.ntu.edu.tw)






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