The Ras Target AF-6 is a Substrate of the Fam Deubiquitinating Enzyme

doi:10.1083/jcb.142.4.1053

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© The Rockefeller University Press, 0021-9525/1998//1053 $5.00
The Journal of Cell Biology, Volume 142, Number 4, , 1998 1053-1062

Articles

The Ras Target AF-6 is a Substrate of the Fam Deubiquitinating Enzyme

Shinichiro Taya^*, Takaharu Yamamoto^*, Kyoko Kano^*, Yoji Kawano^*, Akihiro Iwamatsu, Tomoko Tsuchiya, Keiji Tanaka, Masami Kanai-Azuma^||, Stephen A. Wood^¶, John S. Mattick^||, and Kozo Kaibuchi^*

^* Division of Signal Transduction, Nara Institute of Science and Technology, Ikoma 630-0101, Japan; Central Laboratories for Key Technology, Kirin Brewery Company Limited, Kanazawa-ku, Yokohama 236-0004, Japan; Metropolitan Institute of Medical Science, Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Bunkyo-ku, Tokyo 113-0021, Japan; ^|| Centre for Molecular and Cellular Biology, University of Queensland, St. Lucia, Queensland 4072, Australia; and ^¶ Department of Biochemistry, University of Adelaide, Adelaide 5005, Australia

The Ras target AF-6 has been shown to serve as one of the peripheralcomponents of cell–cell adhesions, and is thought toparticipate in cell–cell adhesion regulation downstreamof Ras. We here purified an AF-6-interacting protein with amolecular mass of $~$ 220 kD (p220) to investigate the functionof AF-6 at cell–cell adhesions. The peptide sequencesof p220 were identical to the amino acid sequences of mouse Fam. Fam is homologous to a deubiquitinating enzyme in Drosophila,the product of the fat facets gene. Recent genetic analysesindicate that the deubiquitinating activity of the fat facetsproduct plays a critical role in controlling the cell fate.We found that Fam accumulated at the cell–cell contactsites of MDCKII cells, but not at free ends of plasma membranes.Fam was partially colocalized with AF-6 and interacted withAF-6 in vivo and in vitro. We also showed that AF-6 was ubiquitinatedin intact cells, and that Fam prevented the ubiquitination ofAF-6.

Key Words: AF-6 • Fam • deubiquitinating enzyme • ubiquitination • cell–cell adhesions

Abbreviations used in this paper: ALL-1, acute lymphoblastic leukemia-1; ALLM, N-acetyl-Leu-Leu-methional; ALLN, N-acetyl-Leu-Leu-norleucinal; HA-Ub, hemagglutinin-tagged ubiquitin; GST, glutathione-S-transferase; MAP, mitogen-activated protein; MBP, maltose-binding protein; p-APMSF, (p-amidino-phenyl)methanesulfonyl fluoride; SH3, src homology region 3; Ub, ubiquitin; Ubps, ubiquitin-specific proteases; Ub-PEST, ubiquitin- ${alpha}$ NH-MHISPPEPESEEEEEHYC; ZO-1, zonula occludens-1.

Address all correspondence and proofs to Kozo Kaibuchi, M.D.& Ph.D., Division of Signal Transduction, Nara Instituteof Science and Technology, 8916-5 Takayama, Ikoma 630-0101,Japan. Tel.: 81-743-72-5440. Fax: 81-743-72-5449. E-mail: kaibuchi{at}bs.aist-nara.ac.jp

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