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The deubiquitinating enzyme USP17 is essential for GTPase subcellular localization and cell motility.

ABSTRACT: Deubiquitinating enzymes are now emerging as potential therapeutic targets that control many cellular processes, but few have been demonstrated to control cell motility. Here, we show that ubiquitin-specific protease 17 (USP17) is rapidly and transiently induced in response to chemokines SDF-1/CXCL12 and IL-8/CXCL8 in both primary cells and cell lines, and that its depletion completely blocks chemokine-induced cell migration and cytoskeletal rearrangements. Using live cell imaging, we demonstrate that USP17 is required for both elongated and amoeboid motility, in addition to chemotaxis. USP17 has previously been reported to disrupt Ras localization and we now find that USP17 depletion blocks chemokine-induced subcellular relocalization of GTPases Cdc42, Rac and RhoA, which are GTPases essential for cell motility. Collectively, these results demonstrate that USP17 has a critical role in cell migration and may be a useful drug target for both inflammatory and metastatic disease.

SUBMITTER: de la Vega M

PROVIDER: S-EPMC3072070 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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The deubiquitinating enzyme USP17 is essential for GTPase subcellular localization and cell motility.

de la Vega Michelle M Kelvin Alyson A AA Dunican Dara J DJ McFarlane Cheryl C Burrows James F JF Jaworski Jakub J Stevenson Nigel J NJ Dib Karim K Rappoport Joshua Z JZ Scott Christopher J CJ Long Aideen A Johnston James A JA

Nature communications 20110329

Deubiquitinating enzymes are now emerging as potential therapeutic targets that control many cellular processes, but few have been demonstrated to control cell motility. Here, we show that ubiquitin-specific protease 17 (USP17) is rapidly and transiently induced in response to chemokines SDF-1/CXCL12 and IL-8/CXCL8 in both primary cells and cell lines, and that its depletion completely blocks chemokine-induced cell migration and cytoskeletal rearrangements. Using live cell imaging, we demonstrat ...[more]

PMID: 21448158

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Project description:The post?translational modification of proteins by ubiquitinating enzymes plays a central role in a number of cellular functions, such as cell proteolysis, DNA repair, and cell signaling and communication. Deubiquitinating enzymes (DUBs) disassemble ubiquitin chains and remove ubiquitin moieties from proteins. Targeting DUBs in cancer models has revealed an important role for these enzymes in tumorigenesis, and they therefore have emerged as attractive therapeutic targets. In the present study, the effects of three DUB inhibitors, PR?619, RA?9 and LDN?91946, on a non?small cell lung cancer cell line (A549) and a mesothelioma cell line (H2373) were investigated. PR?619 significantly inhibited cell adhesion and the proliferation of both cell lines. RA?9 exerted an inhibitory effect on the adhesion and proliferation of H2373 cells, whereas it had no effect on A549 cells. Notably, however, while PR?619 attenuated the proliferation of both cell lines, it exerted an opposite effect on cell motility; in the case of A549 cells, there was a significant increase in cell motility, while for the H2373 cells, there was a significant decrease. Furthermore, protein phosphorylation kinetic analyses revealed that the effects were cell line?specific. In H2373 cells, the phosphorylation of only one peptide corresponding to the P85A protein was significantly affected, and while LDN?91946 treatment increased phosphorylation, treatment with RA?9 or PR?619 decreased its phosphorylation compared to the DMSO control. By contrast, in the case of A549 cells, the phosphorylation of 21 peptides was significantly affected by the same compounds. In light of the potential for the negative side?effects of DUB inhibition, such as increased cancer cell motility, the data presented herein underscore the dire need for the development of specific DUB inhibitors and to elucidate the individual role of DUB family members in cancer biology before they can be specifically pharmacologically targeted.

Dataset Information

The deubiquitinating enzyme USP17 is essential for GTPase subcellular localization and cell motility.

Publications

The deubiquitinating enzyme USP17 is essential for GTPase subcellular localization and cell motility.

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