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Molecular and Cellular Biology, November 2004, p. 9752-9762, Vol. 24, No. 22
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.22.9752-9762.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The TBC (Tre-2/Bub2/Cdc16) Domain Protein TRE17 Regulates Plasma Membrane-Endosomal Trafficking through Activation of Arf6{dagger}

Lenka Martinu,1 Jeffrey M. Masuda-Robens ,1,{ddagger},§ Sarah E. Robertson,1,{ddagger} Lorraine C. Santy,2 James E. Casanova,2 and Margaret M. Chou1*

Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania,1 Department of Cell Biology, University of Virginia Health Sciences Center, Charlottesville, Virginia2

Received 21 April 2004/ Returned for modification 8 June 2004/ Accepted 17 August 2004

TBC (Tre-2/Bub2/Cdc16) domains are predicted to encode GTPase-activating proteins (GAPs) for Rab family G proteins. While approximately 50 TBC proteins are predicted to exist in humans, little is known about their substrate specificity. Here we show that TRE17 (also called Tre-2 and USP6), a founding member of the TBC family, targets the Arf family GTPase Arf6, which regulates plasma membrane-endosome trafficking. Surprisingly, TRE17 does not function as a GAP for Arf6 but rather promotes its activation in vivo. TRE17 associates directly with Arf6 in its GDP- but not GTP-bound state. Mapping experiments pinpoint the site of interaction to the TBC domain of TRE17. Forced expression of TRE17 promotes the localization of Arf6 to the plasma membrane, leading to Arf6 activation, presumably due to facilitated access to membrane-associated guanine nucleotide exchange factors (GEFs). Furthermore, TRE17 cooperates with Arf6 GEFs to induce GTP loading of Arf6 in vivo. Finally, short interfering RNA-mediated loss of TRE17 leads to attenuated Arf6 activation. These studies identify TRE17 as a novel regulator of the Arf6-regulated plasma membrane recycling system and reveal an unexpected function for TBC domains.

* Corresponding author. Mailing address: University of Pennsylvania School of Medicine, Department of Cell and Developmental Biology, 421 Curie Blvd., BRBII Room 1011, Philadelphia, PA 19104-6160. Phone: (215) 573-4126. Fax: (215) 898-9871. E-mail: mmc{at}mail.med.upenn.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org.

{ddagger} J.M.M.-R. and S.E.R. contributed equally to this work.

§ Present address: Glaxo-IMCB Group Institute for Molecular and Cell Biology, Singapore 117609, Singapore.

Molecular and Cellular Biology, November 2004, p. 9752-9762, Vol. 24, No. 22
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.22.9752-9762.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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