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J. Biol. Chem., Vol. 283, Issue 22, 14915-14926, May 30, 2008

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ASAP3 Is a Focal Adhesion-associated Arf GAP That Functions in Cell Migration and Invasion^*

Vi Luan Ha, Sanita Bharti, Hiroki Inoue, William C. Vass, Fanny Campa, Zhongzhen Nie¹, Armand de Gramont^¶, Yvona Ward^||, and Paul A. Randazzo²

From the Laboratory of Cellular and Molecular Biology and Laboratory of Cellular Oncology, ^||Cell and Cancer Biology Branch, Center for Cancer Research, NCI and ^¶NIDDK, National Institutes of Health, Bethesda, Maryland 20892

ASAP3, an Arf GTPase-activating protein previously called DDEFL1 and ACAP4, has been implicated in the pathogenesis of hepatocellular carcinoma. We have examined in vitro and in vivo functions of ASAP3 and compared it to the related Arf GAP ASAP1 that has also been implicated in oncogenesis. ASAP3 was biochemically similar to ASAP1: the pleckstrin homology domain affected function of the catalytic domain by more than 100-fold; catalysis was stimulated by phosphatidylinositol 4,5-bisphosphate; and Arf1, Arf5, and Arf6 were used as substrates in vitro. Like ASAP1, ASAP3 associated with focal adhesions and circular dorsal ruffles. Different than ASAP1, ASAP3 did not localize to invadopodia or podosomes. Cells, derived from a mammary carcinoma and from a glioblastoma, with reduced ASAP3 expression had fewer actin stress fiber, reduced levels of phosphomyosin, and migrated more slowly than control cells. Reducing ASAP3 expression also slowed invasion of mammary carcinoma cells. In contrast, reduction of ASAP1 expression had no effect on migration or invasion. We propose that ASAP3 functions nonredundantly with ASAP1 to control cell movement and may have a role in cancer cell invasion. In comparing ASAP1 and ASAP3, we also found that invadopodia are dispensable for the invasive behavior of cells derived from a mammary carcinoma.

Received for publication, November 28, 2007 Accepted for publication April 1, 2008.

^* This work was supported, in whole or in part, by a National Institutes of Health grant from the Intramural Research Program (NCI), Department of Health and Human Services. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Current address: Dept. of Pathology, Medical College of Georgia, 1120 15th St., Augusta, GA 30912.

² To whom correspondence should be addressed: Bldg. 37, Rm. 2042, Bethesda, MD 20892. Tel.: 301-496-3788; Fax: 301-480-1260; E-mail: Randazzo{at}helix.nih.gov.

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