Michael J Clague

University of Liverpool, Liverpool, England, United Kingdom

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Publications (127)913.88 Total impact

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    Full-text · Dataset · Jan 2016
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    Daniel J Klionsky · Kotb Abdelmohsen · Akihisa Abe · Md Joynal Abedin · Hagai Abeliovich · Abraham Acevedo Arozena · Hiroaki Adachi · Christopher M Adams · Peter D Adams · Khosrow Adeli · [...] · Xiao-Feng Zhu · Yuhua Zhu · Shi-Mei Zhuang · Xiaohong Zhuang · Elio Ziparo · Christos E Zois · Teresa Zoladek · Wei-Xing Zong · Antonio Zorzano · Susu M Zughaier ·
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    ABSTRACT: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.
    Full-text · Article · Jan 2016 · Autophagy
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    ABSTRACT: Ras proteins are important signalling hubs situated near the top of networks controlling cell proliferation, differentiation and survival. Three almost identical isoforms, HRAS, KRAS and NRAS, are ubiquitously expressed yet have differing biological and oncogenic properties. In order to help understand the relative biological contributions of each isoform we have optimised a quantitative proteomics method for accurately measuring Ras isoform protein copy number per cell. The use of isotopic protein standards together with selected reaction monitoring for diagnostic peptides is sensitive, robust and suitable for application to sub-milligram quantities of lysates. We find that in a panel of isogenic SW48 colorectal cancer cells, endogenous Ras proteins are highly abundant with ≥260,000 total Ras protein copies per cell and the rank order of isoform abundance is KRAS>NRAS≥HRAS. A subset of oncogenic KRAS mutants exhibit increased total cellular Ras abundance and altered the ratio of mutant versus wild type KRAS protein. These data and methodology are significant because Ras protein copy number is required to parameterise models of signalling networks and informs interpretation of isoform-specific Ras functional data.
    Full-text · Article · Nov 2015 · PLoS ONE
  • Viktor Malec · Judy M Coulson · Sylvie Urbé · Michael J Clague
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    ABSTRACT: The loss of function of Von Hippel-Lindau (VHL) tumor suppressor leads to the development of hyper-vascular tumours, exemplified by clear cell type renal cell carcinoma (RCC). VHL governs the adaptive responses to fluctuation of oxygen levels largely through the regulated suppression of hypoxia inducible factors (HIFs). Here, we combine proteome and phospho-proteomic analysis of isogenic 786-O RCC (± VHL) cells, to compare signatures that reflect hypoxia and/or loss of VHL. VHL-independent hypoxic responses, notably include up-regulation of phosphorylation at Ser232 on pyruvate dehydrogenase α sub-unit that is known to promote glycolysis. Hypoxic responses governed by VHL include up-regulation of known biomarkers of RCC (e.g. GLUT1, NDRG1) and the signaling adaptor molecule IRS-2. Notably we also observe down-regulation of linked-components associated with the Jacobs-Stewart cycle, including the intracellular carbonic anhydrase II (CA2) which governs cellular response to CO2 fluctuations that often accompany hypoxia in tumours. Further studies indicate an unusual mechanism of control for CA2 expression, that at least in part, reflects enhanced activity of the NFκB pathway, that is associated with loss of VHL.
    No preview · Article · Oct 2015 · Journal of Proteome Research
  • Joseph J Sacco · Michael J Clague
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    ABSTRACT: The receptor tyrosine kinase, Met, orchestrates a complex signalling network that physiologically drives a programme of 'invasive growth'. In cancer however, this process may be co-opted to promote proliferation, survival and metastasis of cancer cells. Met is thus a key therapeutic target, not least in non-small cell lung cancer (NSCLC) where it is one of the most commonly dysregulated driver oncogenes. Identifying robust biomarkers that allow the selection of patients most likely to respond to Met targeted therapies will however be essential to realising their potential. This has been underlined recently by the early termination of three pivotal phase III trials investigating Met targeted agents in NSCLC, all of which failed to show clinical benefit. In contrast to these trials, which were relatively unselective, a couple of early phase trials have recently been instigated that select patients on the basis of Met amplification. While still at an early stage, interim results are relatively encouraging and strengthen the rationale for using Met amplifaction as a biomarker. Here we will discuss this and other aberrations in Met signalling in relation to their significance in the therapeutic targeting of Met.
    No preview · Article · Jun 2015
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    ABSTRACT: Histone deacetylases are important targets for cancer therapeutics, but their regulation is poorly understood. Our data show coordinated transcription of HDAC1 and HDAC2 in lung cancer cell lines, but suggest HDAC2 protein expression is cell-context specific. Through an unbiased siRNA screen we found that BRCA1-associated protein 1 (BAP1) regulates their expression, with HDAC2 reduced and HDAC1 increased in BAP1 depleted cells. BAP1 loss-of-function is increasingly reported in cancers including thoracic malignancies, with frequent mutation in malignant pleural mesothelioma. Endogenous HDAC2 directly correlates with BAP1 across a panel of lung cancer cell lines, and is downregulated in mesothelioma cell lines with genetic BAP1 inactivation. We find that BAP1 regulates HDAC2 by increasing transcript abundance, rather than opposing its ubiquitylation. Importantly, although total cellular HDAC activity is unaffected by transient depletion of HDAC2 or of BAP1 due to HDAC1 compensation, this isoenzyme imbalance sensitizes MSTO-211H cells to HDAC inhibitors. However, other established mesothelioma cell lines with low endogenous HDAC2 have adapted to become more resistant to HDAC inhibition. Our work establishes a mechanism by which BAP1 loss alters sensitivity of cancer cells to HDAC inhibitors. Assessment of BAP1 and HDAC expression may ultimately help identify patients likely to respond to HDAC inhibitors.
    Full-text · Article · Apr 2015 · Oncotarget
  • Michael J Clague · Claire Heride · Sylvie Urbé
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    ABSTRACT: The ubiquitin system is a major coordinator of cellular physiology through regulation of both protein degradation and signalling pathways. A key building block of a systems-level understanding has been generated by global proteomic studies, which provide copy number estimates for each component. The aggregate of ubiquitin, conjugating enzymes (E1, E2, and E3s), and deubiquitylases (DUBs) represents ∼1.3% of total cellular protein. Complementary approaches have generated quantitative measurements of various ubiquitin pools and further subdivision into different ubiquitin chain topologies. Systematic studies aimed at associating specific enzymes (E2s and DUBs) with the dynamics of these different pools have also made significant progress. Here, we delineate the emerging picture of the most significant determinants of the cellular ubiquitin economy. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Apr 2015 · Trends in cell biology
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    ABSTRACT: Mitochondria play a pivotal role in the orchestration of cell death pathways. Here, we show that the control of ubiquitin dynamics at mitochondria contributes to the regulation of apoptotic cell death. The unique mitochondrial deubiquitylase, USP30, opposes Parkin-dependent ubiquitylation of TOM20, and its depletion enhances depolarization-induced cell death in Parkin-overexpressing cells. Importantly, USP30 also regulates BAX/BAK-dependent apoptosis, and its depletion sensitizes cancer cells to BH3-mimetics. These results provide the first evidence for a fundamental role of USP30 in determining the threshold for mitochondrial cell death and suggest USP30 as a potential target for combinatorial anti-cancer therapy. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.
    Full-text · Article · Mar 2015 · EMBO Reports
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    ABSTRACT: Oncogenic mutations of Ras at codons 12, 13 or 61, that render the protein constitutively active, are found in ~16% of all cancer cases. Amongst the three major Ras isoforms, KRAS is the most frequently mutated isoform in cancer. Each Ras isoform and tumour type displays a distinct pattern of codon-specific mutations. In colon cancer, KRAS is typically mutated at codon 12, but a significant fraction of patients have mutations at codon 13. Clinical data suggest different outcomes and responsiveness to treatment between these two groups. To investigate the differential effects upon cell status associated with KRAS mutations we performed a quantitative analysis of the proteome and phospho-proteome of isogenic SW48 colon cancer cell lines in which one allele of the endogenous gene has been edited to harbour specific KRAS mutations (G12V, G12D or G13D). Each mutation generates a distinct signature, with the most variability seen between G13D and the codon 12 KRAS mutants. One notable example of specific up-regulation in KRAS codon 12 mutant SW48 cells is provided by the short form of the colon cancer stem cell marker Double Cortin-Like Kinase 1 (DCLK1) that can be reversed by suppression of KRAS.
    Full-text · Article · Jan 2015 · Journal of Proteome Research

  • No preview · Article · Dec 2014 · Molecular Cancer Research
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    ABSTRACT: Defined signals that dictate the architecture of cellular boundaries in confluent cultures are poorly characterized. Here, we report dramatic remodeling, invoked by long-term epidermal growth factor (EGF) withdrawal from mammary-derived MCF10A cells. Such intervention generates an interdigitated, desmosome-rich monolayer, wherein cells project actin-containing protrusions deep into neighboring cells. These changes protect cellular sheets from mechanical disruption and dramatically restrict the freedom of cells to roam within the monolayer. Ectopic expression of activated Rac counteracts interdigitation and induces membrane ruffling, but cells remain confined by their interdigitated neighbors. Interdigitations are rapidly dissolved by acute EGF application in a process that is sensitive to actin depolymerization and myosin II inhibition. These assays for formation and dissolution of interdigitations provide a platform for the dissection of novel signaling pathways that are highly specific to EGF receptor (EGFR) activation.
    Full-text · Article · Sep 2014 · Cell Reports
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    ABSTRACT: DNA double-strand breaks (DSBs) are perhaps the most toxic of all DNA lesions, with defects in the DNA-damage response to DSBs being associated with various human diseases. Although it is known that DSB repair pathways are tightly regulated by ubiquitylation, we do not yet have a comprehensive understanding of how deubiquitylating enzymes (DUBs) function in DSB responses. Here, by carrying out a multidimensional screening strategy for human DUBs, we identify several with hitherto unknown links to DSB repair, the G2/M DNA-damage checkpoint and genome-integrity maintenance. Phylogenetic analyses reveal functional clustering within certain DUB subgroups, suggesting evolutionally conserved functions and/or related modes of action. Furthermore, we establish that the DUB UCHL5 regulates DSB resection and repair by homologous recombination through protecting its interactor, NFRKB, from degradation. Collectively, our findings extend the list of DUBs promoting the maintenance of genome integrity, and highlight their potential as therapeutic targets for cancer.
    Full-text · Article · Sep 2014 · Nature Cell Biology
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    ABSTRACT: Platinum-based chemotherapy is widely used to treat various cancers, but many patients ultimately relapse due to drug resistance. We employed phosphoproteomic analysis and functional assays of the response of SK-OV-3 ovarian cancer cells to cisplatin as a strategy to identify kinases as candidate "druggable" targets to sensitize cells to platinum. A SILAC-based approach combined with TiO2-based phosphopeptide enrichment allowed the direct identification of ERK1/2, p90RSK and ERBB2 as kinases whose phosphorylation is regulated by cisplatin. Bioinformatic analysis revealed enrichment in linear phosphorylation motifs predicted to be targets of p38MAPK, CDK2 and PIM2. All three PIM kinases were found expressed in a panel of 10 ovarian cancer cell lines, the oncogenic PIM2 being the most commonly induced by cisplatin. Targeting PIM2 kinase by either biochemical inhibitors or RNA interference impaired cell growth, decreased cisplatin-triggered BAD phosphorylation and sensitized ovarian cancer cells to drug-induced apoptosis. Over-expression of PIM2 triggered anchorage independent growth and resulted in increased BAD phosphorylation and cell resistance to DNA damaging agents. Data show that the PIM2 kinase plays a role in the response of ovarian cancer cells to platinum drugs and suggest that PIM inhibitors may find clinical application as an adjunct to platinum-based therapies.
    Full-text · Article · Aug 2014 · Journal of Proteome Research
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    ABSTRACT: Introduction Receptor tyrosine kinases (RTKs) are found on the surface of normal and cancerous cells. Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor 2 (HER2) are RTKs that are often overexpressed in breast cancer. RTK upregulation leads to enhanced activation of downstream signalling pathways that inhibit apoptosis and promote proliferation, migration and angiogenesis. Breast Cancer Associated gene 2 (BCA2) is a poorly studied E3 ligase that is overexpressed in over 50% of breast cancers. Depletion of BCA2 has been shown to reduce cell growth and invasion while overexpression increases proliferation. BCA2 has been implicated in EGFR endocytosis, however there is conflicting evidence regarding its influence on the biology of this receptor. This project aims to elucidate the role of BCA2 in RTK endocytosis, downregulation and breast cancer. Materials and Methods Immunodetection was used to analyse BCA2 and EGFR levels in the breast cancer cell lines MCF-7, MDA-MB-231, T47D and BT474 and in the non-cancerous MCF10A line. HeLa cervical carcinoma cells were also studied as EGFR trafficking in this cell line is very well characterised. Transient overexpression experiments were performed in HeLa cells using a vector for HA-tagged BCA2. EGFR levels and trafficking in BCA2 overexpressing cells were analysed by Western blotting and fluorescence microscopy. The effect of BCA2 overexpression on EGFR degradation was examined by treating HA-BCA2 or mock transfected HeLa cells with EGF for between 0 and 60 min. To explore the relationship between BCA2 expression and breast cancer outcome, Kaplan-Meier curves were generated with the KMPLOT biomarker analysis tool. Results and Discussion By immunodetection BCA2 manifests as two bands (34 and 37kDa) and we show high expression variability across a panel of breast-derived cell lines. We find that transient BCA2 overexpression significantly decreases EGFR levels in HeLa cells. In contrast to this we find that BCA2 overexpressing cells stimulated with EGF show reduced degradation of both receptor and ligand in lysosomal compartments. This is likely to reflect a role for BCA2 in the endolysosomal system and in agreement with this we show colocalisation between BCA2 and the late endosomal marker Rab7a. Levels of the non-RTK transferrin receptor and uptake of transferrin are unaffected by BCA2 overexpression suggesting the effects on trafficking may be confined to EGFR or a distinct class of receptor. Kaplan-Meier analyses show that high levels of BCA2 are associated with reduced relapse free survival (P<0.05) in HER2+ breast cancer subtypes. Conclusion Our findings present an interesting insight into BCA2-mediated EGFR regulation via altered endocytosis and suggest that BCA2 may affect inter-tumoural growth factor signalling and patient survival. The regulatory effect of BCA2 on different EGFR family members and on other oncogenic plasma membrane receptors remains to be determined.
    No preview · Conference Paper · Jul 2014
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    Ewan MacDonald · Sylvie Urbé · Michael J. Clague
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    ABSTRACT: The endosomal deubiquitylase USP8 has profound effects on endosomal morphology and organisation. Previous reports have proposed both positive (EGFR, MET) and negative roles in the down-regulation of receptors (Frizzled, Smoothened). Here we report an additional influence of USP8 on the retromer-dependent shuttling of ci-M6PR between the sorting endosome and biosynthetic pathway. Depletion of USP8 leads to a steady state redistribution of ci-M6PR from the Trans-Golgi Network (TGN) to endosomal compartments. Consequently we observe a defect in sorting of lysosomal enzymes, evidenced by increased levels of unprocessed Cathepsin D, which is secreted into the medium. The normal distribution of receptor can be restored by expression of siRNA-resistant USP8 but not by a catalytically inactive mutant or a truncated form, lacking a MIT domain required for endosomal localisation. We suggest that effects of USP8 depletion may reflect the loss of ESCRT-0 components which associate with retromer components Vps35 and SNX1, whilst failure to efficiently deliver lysosomal enzymes may also contribute to the observed block in receptor tyrosine kinase degradation.
    Full-text · Article · Jun 2014 · Traffic
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    Claire Heride · Sylvie Urbé · Michael J Clague
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    ABSTRACT: Ubiquitin, a 76 amino-acid polypeptide, presents a compact three-dimensional structure, utilising a fold that recurs within larger polypeptides and in other protein modifiers, such as NEDD8 and SUMO. Ubiquitylation was initially recognised as a signal for proteasome-mediated degradation. We shall consider here how this view has evolved to appreciate that the dynamic appendage of different types of ubiquitin chains represents a versatile, three-dimensional code, fundamental to the control of many cellular processes.
    Full-text · Article · Mar 2014 · Current biology: CB
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    ABSTRACT: Research in autophagy continues to accelerate,(1) and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.(2,3) There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.
    Full-text · Dataset · Dec 2013
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    J J Sacco · TY Yau · S Darling · V Patel · H Liu · S Urbé · M J Clague · J M Coulson
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    ABSTRACT: The phosphatidylinositol-3-kinase (PI3K) pathway is commonly hyperactivated in cancer. One mechanism by which this occurs is by silencing of the phosphatase and tensin homolog (PTEN), a tumor suppressor and major antagonist of the pathway, through genetic, epigenetic or posttranscriptional mechanisms. Here, we used an unbiased siRNA screen in non-small-cell lung cancer cells to identify deubiquitylases (DUBs) that have an impact on PI3K signaling by regulating the abundance of PTEN. We found that PTEN expression was induced by depleting any of three members of the Josephin family DUBs: ataxin 3 (ATXN3), ataxin 3-like (ATXN3L) and Josephin domain containing 1 (JOSD1). However, this effect is not mediated through altered PTEN protein stability. Instead, depletion of each DUB increases expression of both the PTEN transcript and its competing endogenous RNA, PTENP1. In ATXN3-depleted cells, under conditions of transcriptional inhibition, PTEN and PTENP1 mRNAs rapidly decay, suggesting that ATXN3 acts primarily by repressing their transcription. Importantly, the PTEN induction observed in response to ATXN3 siRNA is sufficient to downregulate Akt phosphorylation and hence PI3K signaling. Histone deacetylase inhibitors (HDACi) have been suggested as potential mediators of PTEN transcriptional reactivation in non-small-cell lung cancer. Although PTEN exhibits a very limited response to the broad-spectrum HDACi Vorinostat (SAHA) in A549 cells, we find that combination with ATXN3 depletion enhances PTEN induction in an additive manner. Similarly, these interventions additively decrease cell viability. Thus, ATXN3 provides an autonomous, complementary therapeutic target in cancers with epigenetic downregulation of PTEN.Oncogene advance online publication, 2 December 2013; doi:10.1038/onc.2013.512.
    Full-text · Article · Dec 2013 · Oncogene
  • Han Liu · Sylvie Urbé · Michael J. Clague
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    ABSTRACT: As the major route by which activated Receptor Tyrosine Kinases are degraded, the endolysosomal pathway may be seen as a tumour suppressor pathway. The appendage of ubiquitin chains to activated receptors provides a sorting signal for sorting into multivesicular bodies which go on to fuse directly with lysosomes. Deubiquitylating (DUB) activities, such as the endosome-localised AMSH and USP8, can favour recycling of receptors by reducing this active sorting into MVBs. These enzymes have an overlapping set of binding partners at the endosome, which include both early- and late-acting components of the Endosomal Sorting Complex Required for Transport (ESCRT) machinery. The exact interplay between these enzymes is still under debate. The consequences of depletion can be complex and need to be interpreted with care. Generically endosomal DUBs can influence receptor trafficking by direct deubiquitylation of receptors or associated proteins, by stabilisation of sorting factors or by contributing to free ubiquitin homeostasis by recycling ubiquitin once a MVB cargo molecule has been committed to degradation. We propose that a single endosomal DUB may carry out multiple functions depending on the suite of interactions being employed. Recent studies have provided further examples of DUBs which may associate with endosomes in a transient manner to influence the sorting of RTKs but also other types of receptors, such as GPCRs and various channels. © 2013 Springer Science+Business Media New York. All rights are reserved.
    No preview · Chapter · Jul 2013
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    ABSTRACT: Ubiquitylation is a major posttranslational modification that controls most complex aspects of cell physiology. It is reversed through the action of a large family of deubiquitylating enzymes (DUBs) that are emerging as attractive therapeutic targets for a number of disease conditions. Here, we provide a comprehensive analysis of the complement of human DUBs, indicating structural motifs, typical cellular copy numbers, and tissue expression profiles. We discuss the means by which specificity is achieved and how DUB activity may be regulated. Generically DUB catalytic activity may be used to 1) maintain free ubiquitin levels, 2) rescue proteins from ubiquitin-mediated degradation, and 3) control the dynamics of ubiquitin-mediated signaling events. Functional roles of individual DUBs from each of five subfamilies in specific cellular processes are highlighted with an emphasis on those linked to pathological conditions where the association is supported by whole organism models. We then specifically consider the role of DUBs associated with protein degradative machineries and the influence of specific DUBs upon expression of receptors and channels at the plasma membrane.
    Preview · Article · Jul 2013 · Physiological Reviews

Publication Stats

8k Citations
913.88 Total Impact Points


  • 1994-2015
    • University of Liverpool
      • Department of Cellular and Molecular Physiology
      Liverpool, England, United Kingdom
  • 2012
    • University of Michigan
      • Life Sciences Institute
      Ann Arbor, MI, United States
  • 2009
    • University of Cambridge
      • MRC Laboratory of Molecular Biology
      Cambridge, England, United Kingdom
  • 2006-2009
    • IBMS
      Londinium, England, United Kingdom
  • 2007
    • Miltenyi Biotec GmbH
      Bergisch Gladbach, North Rhine-Westphalia, Germany
  • 1990-2006
    • National Institutes of Health
      Maryland, United States
  • 2001
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 1992-1993
    • European Molecular Biology Laboratory
      • Cell Biology and Biophysics Unit (Heidelberg)
      Heidelburg, Baden-Württemberg, Germany
  • 1991
    • National Cancer Institute (USA)
      베서스다, Maryland, United States
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 1988-1990
    • University of Essex
      • School of Biological Sciences
      Colchester, England, United Kingdom