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Deubiquitinating enzyme USP33VDU1 is required for.pdf

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Deubiquitinating enzyme USP33VDU1 is required for

Deubiquitinating enzyme USP33/VDU1 is required for Slit signaling in inhibiting breast cancer cell migration Junichi Yuasa-Kawadaa,b,1, Mariko Kinoshita-Kawadaa,b,1, Yi Raoa,c, and Jane Y. Wua,b,2 aDepartment of Neurology, Lurie Cancer Center, Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; bDepartment of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232; and cPeking University School of Life Sciences, Beijing 100871, China Edited by Lily Y. Jan, University of California School of Medicine, San Francisco, CA, and approved July 7, 2009 (received for review February 17, 2008) Slit regulates migration of not only neurons, but also nonneuronal cells, such as leukocytes and cancer cells. Slit effect on cancer cell migration has not been well-characterized. In this study, we used several different assays to examine Slit effect on breast cancer cell migration in vitro. We show that ubiquitin-specific protease 33 (USP33)/VDU1, originally identified as a von Hippel–Lindau tumor suppressor (VHL) protein-interacting deubiquitinating enzyme, binds to the Robo1 receptor, and that USP33 is required for Slit responsiveness in breast cancer cells. Slit induces redistribution of Robo1 from intracellular compartments to the plasma membrane in a USP33-dependent manner. Slit impairs directional migration of breast cancer cells without affecting their migration speed. This inhibitory effect is Robo-mediated and USP33-dependent. These data uncover a previously unknown function of USP33 and reveal a new player in Slit-Robo signaling in cancer cell migration. cell migration and motility metastasis Slit-Robo signaling Cell migration is a fundamental process critical for not onlyembryonic development but also homeostasis in adult ani- mals. A number of molecular cues guide axons and migrating neurons (1–4). Recent studies suggest that molecular mecha- nisms modulating migration of cells in different tissues/organs a