Deubiquitinating enzyme USP33/VDU1 is required for Slit signaling in inhibiting breast cancer cell migration

Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14530-5. doi: 10.1073/pnas.0801262106. Epub 2009 Aug 12.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Movement / physiology*
  • Chemokine CXCL12 / metabolism
  • Chemotaxis
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Microtubule-Organizing Center / metabolism
  • Microtubules / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • RNA, Small Interfering / genetics
  • Receptors, CXCR4 / genetics
  • Receptors, CXCR4 / metabolism
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction*
  • Stress, Mechanical
  • Transfection
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism*

Substances

  • CXCR4 protein, human
  • Chemokine CXCL12
  • Intercellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • RNA, Small Interfering
  • Receptors, CXCR4
  • Receptors, Immunologic
  • roundabout protein
  • USP33 protein, human
  • Ubiquitin Thiolesterase
  • Slit homolog 2 protein