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Vol. 15, Issue 4, 1591-1599, April 2004

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The FAM Deubiquitylating Enzyme Localizes to Multiple Points of Protein Trafficking in Epithelia, where It Associates with E-cadherin and -catenin

Rachael Z. Murray ^* , Lachlan A. Jolly ^*, and Stephen A. Wood ^*  

^* Child Health Research Institute, North Adelaide, SA 5006, Australia; Centre for the Molecular Genetics of Development, University of Adelaide, SA 5005, Australia

Submitted August 29, 2003; Revised December 11, 2003; Accepted December 31, 2003
Monitoring Editor: Keith Mostov

Ubiquitylation is a necessary step in the endocytosis and lysosomal trafficking of many plasma membrane proteins and can also influence protein trafficking in the biosynthetic pathway. Although a molecular understanding of ubiquitylation in these processes is beginning to emerge, very little is known about the role deubiquitylation may play. Fat Facets in mouse (FAM) is substrate-specific deubiquitylating enzyme highly expressed in epithelia where it interacts with its substrate, -catenin. Here we show, in the polarized intestinal epithelial cell line T84, FAM localized to multiple points of protein trafficking. FAM interacted with -catenin and E-cadherin in T84 cells but only in subconfluent cultures. FAM extensively colocalized with -catenin in cytoplasmic puncta but not at sites of cell-cell contact as well as immunoprecipitating with -catenin and E-cadherin from a higher molecular weight complex (500 kDa). At confluence FAM neither colocalized with, nor immunoprecipitated, -catenin or E-cadherin, which were predominantly in a larger molecular weight complex (2 MDa) at the cell surface. Overexpression of FAM in MCF-7 epithelial cells resulted in increased -catenin levels, which localized to the plasma membrane. Expression of E-cadherin in L-cell fibroblasts resulted in the relocalization of FAM from the Golgi to cytoplasmic puncta. These data strongly suggest that FAM associates with E-cadherin and -catenin during trafficking to the plasma membrane.

Abbreviations used: DUB, deubiquitylating enzyme; UBP, ubiquitin-specific protease; TGN, trans-Golgi Network; ER, endoplasmic reticulum; MDCK, Madin-Darby canine kidney; MVB, multivesicular body.

Corresponding author. E-mail address: stephen.wood{at}adelaide.eduau.

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