ACAPs Are Arf6 GTPase-activating Proteins That Function in the Cell Periphery

doi:10.1083/jcb.151.3.627

Published online 30 October 2000. doi:10.1083/jcb.151.3.627

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© The Rockefeller University Press, 0021-9525/2000/10/627/ $5.00
The Journal of Cell Biology, Volume 151, Number 3, October 30, 2000 627-638

Original Article

ACAPs Are Arf6 GTPase-activating Proteins That Function in the Cell Periphery

Trevor R. Jackson^c, Fraser D. Brown^b, Zhongzhen Nie^a, Koichi Miura^a, Letizia Foroni^c, Jianlan Sun^d, Victor W. Hsu^d, Julie G. Donaldson^b, and Paul A. Randazzo^a
^a Laboratory of Cellular Oncology, Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland 20892-4255
^b Laboratory of Cell Biology, National Heart, Lung and Blood Institute, Bethesda, Maryland 20892-0301
^c Department of Hematology, Royal Free and University College, London Medical School, Royal Free Campus, London, England, NW32AF
^d Brigham and Women's Hospital, Harvard Medical School, Boston, Massachussetts 02115

Correspondence to: Paul A. Randazzo, Laboratory of Cellular Oncology, Division of Basic Sciences, NCI, 37 Convent Dr. MSC 4255, Bethesda, MD 20892-4255. Tel:(301) 496-3788 Fax:(301) 496-5839

The GTP-binding protein ADP-ribosylation factor 6 (Arf6) regulatesendosomal membrane trafficking and the actin cytoskeleton inthe cell periphery. GTPase-activating proteins (GAPs) are criticalregulators of Arf function, controlling the return of Arf tothe inactive GDP-bound state. Here, we report the identificationand characterization of two Arf6 GAPs, ACAP1 and ACAP2. Togetherwith two previously described Arf GAPs, ASAP1 and PAP, theycan be grouped into a protein family defined by several commonstructural motifs including coiled coil, pleckstrin homology,Arf GAP, and three complete ankyrin-repeat domains. All containphosphoinositide-dependent GAP activity. ACAP1 and ACAP2 arewidely expressed and occur together in the various culturedcell lines we examined. Similar to ASAP1, ACAP1 and ACAP2 wererecruited to and, when overexpressed, inhibited the formationof platelet-derived growth factor (PDGF)–induced dorsalmembrane ruffles in NIH 3T3 fibroblasts. However, in contrastwith ASAP1, ACAP1 and ACAP2 functioned as Arf6 GAPs. In vitro,ACAP1 and ACAP2 preferred Arf6 as a substrate, rather than Arf1and Arf5, more so than did ASAP1. In HeLa cells, overexpressionof either ACAP blocked the formation of Arf6-dependent protrusions.In addition, ACAP1 and ACAP2 were recruited to peripheral, tubularmembranes, where activation of Arf6 occurs to allow membranerecycling back to the plasma membrane. ASAP1 did not inhibitArf6-dependent protrusions and was not recruited by Arf6 totubular membranes. The additional effects of ASAP1 on PDGF-inducedruffling in fibroblasts suggest that multiple Arf GAPs functioncoordinately in the cell periphery.

Key Words: actin, ADP-ribosylation factor, GTPase-activating proteins,membrane traffic, pleckstrin homology domain

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