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J. Biol. Chem., Vol. 279, Issue 36, 37677-37684, September 3, 2004

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A Novel Mode of Action of an ArfGAP, AMAP2/PAG3/Pap, in Arf6 Function^*

Shigeru Hashimoto, Ari Hashimoto, Atsuko Yamada, Chie Kojima, Hiroko Yamamoto, Tomonari Tsutsumi¶, Mikito Higashi¶, Akira Mizoguchi¶, Ryohei Yagi, and Hisataka Sabe||

From the Department of Molecular Biology, Osaka Bioscience Institute, Osaka 565-0874, Japan, the Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan, and the ^¶Department of Neural Regeneration and Cell Communication, Faculty of Medicine, Mie University, Mie 514-8507, Japan

Previously we reported that AMAP2/PAG3/Pap/KIAA0400, a GTPase-activating protein (GAP), acts to antagonize Arf6 function when overexpressed, whereas it was shown to exhibit efficient GAP activities for other Arf isoforms in vitro. Here, we found that AMAP2, through its ArfGAP domain, binds to GTP-Arf6 but not to GDP-Arf6 or other Arfs irrespective of nucleotide status. The majority of AMAP2 was localized to intracellular tubulovesicular structures and redistributed to Arf6-enriched membrane areas upon Arf6 activation. In HeLa cells, Arf6 has been shown to be involved in the clathrin-independent endocytosis of Tac, but not the clathrin-dependent endocytosis of transferrin. We found that Arf6 silencing inhibited the internalization of Tac, but not transferrin, in HeLa cells. Internalization of Tac, but not transferrin, was also significantly inhibited by AMAP2 silencing and overexpression. AMAP2 was moreover found to bind to amphiphysin IIm, a component of the endocytic machinery, via its proline-rich domain. We propose that AMAP2 has dual mechanisms for its function; it exhibits efficient catalytic GAP activity for the class I and II Arfs and yet is involved in the cellular function of the class III Arf without immediate GAP activity. These dual mechanisms of AMAP2 may be important for the cellular function of GTP-Arf6.

Received for publication, April 15, 2004 , and in revised form, June 7, 2004.

^* This work was supported in part by grants-in-aid from the Ministry of Education, Science, Sports, and Culture of Japan and grants from Takeda Pharmaceutical Co. and the Uehara Memorial Life Science Foundation. 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.

^|| To whom correspondence should be addressed: Dept. of Molecular Biology, Osaka Bioscience Institute, Osaka 565-0874, Japan. Tel.: 81-6-6872-4814; Fax: 81-6-6871-6686; E-mail: sabe{at}obi.or.jp.

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