Toward understanding ubiquitin-modifying enzymes: from pharmacological targeting to proteomics.

Abstract:

:Ubiquitination is a highly conserved post-translational modification that regulates protein trafficking, function, and turnover. Ubiquitin ligases (E3s) conjugate ubiquitin polypeptides on substrates, whereas deubiquitnases (DUBs) reverse ubiquitination. Engineering of chemical antagonists and inhibitors of ubiquitin ligases and DUBs has considerably aided the study of enzymes that participate in ubiquitin modification of substrates. In addition, proteomic tools have been developed to characterize the enzymes, substrates, and modifications regulated by DUBs and E3s. Here we review inhibitors and antagonists that have been developed against DUBs and E3s, focusing on enzymes that participate in ubiquitin editing or in the reciprocal ubiquitin regulation of substrates. We outline the cellular biology that is regulated by these DUBs and E3s and highlight how the inhibitory compounds have improved our understanding of these pathways. Finally, we discuss the challenges and future directions for pharmacologically targeting ubiquitin-modifying enzymes, as well as the development of proteomic methods to evaluate ubiquitin modification of substrates.

journal_name

Trends Pharmacol Sci

authors

Lill JR,Wertz IE

doi

10.1016/j.tips.2014.01.005

subject

Has Abstract

pub_date

2014-04-01 00:00:00

pages

187-207

issue

4

eissn

0165-6147

issn

1873-3735

pii

S0165-6147(14)00017-0

journal_volume

35

pub_type

杂志文章,评审
  • Of mice and flies: commonalities among 5-HT receptors.

    abstract::Pharmacological studies as well as molecular cloning of 5-HT receptors have revealed a multiplicity of receptor subtypes, not only in mammals but, as discussed in this review by René Hen, also in molluscs and arthropods. Most of these receptors belong to the G protein-coupled receptor family, and their mechanism of ac...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/0165-6147(92)90054-a

    authors: Hen R

    更新日期:1992-04-01 00:00:00

  • Siglecs as targets for therapy in immune-cell-mediated disease.

    abstract::The sialic-acid-binding immunoglobulin-like lectins (siglecs) comprise a family of receptors that are differentially expressed on leukocytes and other immune cells. The restricted expression of several siglecs to one or a few cell types makes them attractive targets for cell-directed therapies. The anti-CD33 (also kno...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2009.02.005

    authors: O'Reilly MK,Paulson JC

    更新日期:2009-05-01 00:00:00

  • Cooperativity Has Empirical and Ultimate Levels of Explanation.

    abstract::Controversy over the meaning of pharmacological parameters often arises because of a lack of appreciation of different hierarchical levels of analysis. In a recent letter in Trends in Pharmacological Sciences, Zhang and Kavana [1] concluded that my two-state model for allosterism lacks cooperativity, even though Figur...

    journal_title:Trends in pharmacological sciences

    pub_type: 评论,信件

    doi:10.1016/j.tips.2016.06.001

    authors: Ehlert FJ

    更新日期:2016-08-01 00:00:00

  • FAAH and anandamide: is 2-AG really the odd one out?

    abstract::Fatty acid amide hydrolase (FAAH) is a hydrolytic enzyme that recognizes as substrates and inactivates the two most studied endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG). Following the observation that endocannabinoids produced by tissues during pathological conditions often have protective roles, FAA...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章

    doi:10.1016/j.tips.2008.03.001

    authors: Di Marzo V,Maccarrone M

    更新日期:2008-05-01 00:00:00

  • The history of pharmacology in Canada.

    abstract::Pharmacology training in Canada was initiated at McGill University in Montréal in 1824, and there are now 17 pharmacology departments in Canada offering graduate training to more than 500 students. In this article, Gerald Marks reviews the growth of pharmacology in Canada since the early 19th century in both academic ...

    journal_title:Trends in pharmacological sciences

    pub_type: 历史文章,杂志文章

    doi:10.1016/0165-6147(94)90312-3

    authors: Marks GS

    更新日期:1994-07-01 00:00:00

  • Hans Horst Meyer and the lipoid theory of narcosis.

    abstract::This year marks the 90th anniversary of the publication of Hans Horst Meyer's classic paper in which he proposed that the ability of a substance to produce narcosis or anesthesia is governed by its partition coefficient. In this article, Robert Lipnick describes the experiments carried out by Meyer and his colleagues ...

    journal_title:Trends in pharmacological sciences

    pub_type: 传,历史文章,杂志文章

    doi:10.1016/0165-6147(89)90025-4

    authors: Lipnick RL

    更新日期:1989-07-01 00:00:00

  • Allosteric modulation of muscarinic acetylcholine receptors.

    abstract::Five subtypes of muscarinic acetylcholine receptors have been identified in mammalian tissues, but the selectivity of ligands that are active at these receptors is low. It is possible, however, that selective compounds may be developed by targeting their allosteric site(s). Important new insights into the mechanism of...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/s0165-6147(00)89023-9

    authors: Tucek S,Proska J

    更新日期:1995-06-01 00:00:00

  • Do cannabinoids have a therapeutic role in transplantation?

    abstract::Cannabinoids have emerged as powerful drug candidates for the treatment of inflammatory and autoimmune diseases due to their immunosuppressive properties. Significant clinical and experimental data on the use of cannabinoids as anti-inflammatory agents exist in many autoimmune disease settings, but virtually no studie...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2010.05.006

    authors: Nagarkatti M,Rieder SA,Hegde VL,Kanada S,Nagarkatti P

    更新日期:2010-08-01 00:00:00

  • Sphingosine Kinase 2 in Autoimmune/Inflammatory Disease and the Development of Sphingosine Kinase 2 Inhibitors.

    abstract::The purpose of this Opinion is to present a case for targeting sphingosine kinase 2 (SK2) in autoimmune/inflammatory disease. Data obtained using Sphk2-/- mice suggest that SK2 is an anti-inflammatory enzyme, although this might be misleading because of a compensatory increase in the expression of a second isoform, sp...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2017.04.003

    authors: Pyne NJ,Adams DR,Pyne S

    更新日期:2017-07-01 00:00:00

  • Anxiety and alcohol abuse disorders: a common role for CREB and its target, the neuropeptide Y gene.

    abstract::It has been hypothesized that anxiety disorders play an important role in the initiation and maintenance of alcohol drinking behaviors. However, the molecular mechanisms for the association between anxiety and alcohol abuse are not well understood. Structures of the extended amygdala, particularly the central nucleus ...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/S0165-6147(03)00226-8

    authors: Pandey SC

    更新日期:2003-09-01 00:00:00

  • Computational studies to predict or explain G protein coupled receptor polypharmacology.

    abstract::Since G protein-coupled receptors (GPCRs) belong to a very large superfamily of evolutionarily related receptors (>800 members in humans), and due to the rapid progress on their structural biology, they are ideal candidates for polypharmacology studies. Broad screening and bioinformatics/chemoinformatics have been app...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章

    doi:10.1016/j.tips.2014.10.009

    authors: Jacobson KA,Costanzi S,Paoletta S

    更新日期:2014-12-01 00:00:00

  • Regulation of the expression and function of the M2 muscarinic receptor.

    abstract::Since the cloning and expression of many of the G protein-coupled receptors during the 1980s, there has been a massive increase in our understanding of many aspects of their function. The use of molecular biology to engineer and express mutant receptors has made it possible to determine key amino acids involved in rec...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/s0165-6147(98)01231-0

    authors: Haddad el-B,Rousell J

    更新日期:1998-08-01 00:00:00

  • New advances in NMDA receptor pharmacology.

    abstract::N-Methyl-D-aspartate (NMDA) receptors are tetrameric ion channels containing two of four possible GluN2 subunits. These receptors have been implicated for decades in neurological diseases such as stroke, traumatic brain injury, dementia and schizophrenia. The GluN2 subunits substantially contribute to functional diver...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2011.08.003

    authors: Ogden KK,Traynelis SF

    更新日期:2011-12-01 00:00:00

  • Exploring the potential of adjunct therapy in tuberculosis.

    abstract::A critical unmet need for treatment of drug-resistant tuberculosis (TB) is to find novel therapies that are efficacious, safe, and shorten the duration of treatment. Drug discovery approaches for TB primarily target essential genes of the pathogen Mycobacterium tuberculosis (Mtb) but novel strategies such as host-dire...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2015.05.005

    authors: Rayasam GV,Balganesh TS

    更新日期:2015-08-01 00:00:00

  • Reactivation of p53: from peptides to small molecules.

    abstract::Approximately 27 million people are living with a tumour in which the tumour suppressing activity of p53 has been inactivated. In half of these tumours, p53 itself is not mutated but the pathway is partially abrogated. Mechanisms include the overexpression of negative regulators of p53, such as MDM2 and MDM4, and dele...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2010.11.004

    authors: Brown CJ,Cheok CF,Verma CS,Lane DP

    更新日期:2011-01-01 00:00:00

  • Comparing nuclear receptors in worms, flies and humans.

    abstract::Complete nucleotide sequences are now available for different species of the animal kingdom: Caenorhabditis elegans - a nematode, Drosophila - an insect, and humans - a mammal. Such information makes it possible to compare the set of nuclear receptors found in these organisms, and to discuss the possible reasons for t...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/s0165-6147(00)01859-9

    authors: Enmark E,Gustafsson JA

    更新日期:2001-12-01 00:00:00

  • Functional, molecular and pharmacological advances in 5-HT7 receptor research.

    abstract::The 5-HT7 receptor was among a group of 5-HT receptors that were discovered using targeted cloning strategies 12 years ago. This receptor is a seven-transmembrane-domain G-protein-coupled receptor that is positively linked to adenylyl cyclase. The distributions of 5-HT7 receptor mRNA, immunolabeling and radioligand bi...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2004.07.002

    authors: Hedlund PB,Sutcliffe JG

    更新日期:2004-09-01 00:00:00

  • Non-genomic loss of PTEN function in cancer: not in my genes.

    abstract::Loss of function of the phosphatase and tensin homolog (PTEN) tumour suppressor contributes to the development of many cancers. However, in contrast to classical models of tumour suppression, partial loss of PTEN function appears to be frequently observed in the clinic. In addition, studies of both humans and mice wit...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2010.12.005

    authors: Leslie NR,Foti M

    更新日期:2011-03-01 00:00:00

  • Unveiling the role of network and systems biology in drug discovery.

    abstract::Network and systems biology offer a novel way of approaching drug discovery by developing models that consider the global physiological environment of protein targets, and the effects of modifying them, without losing the key molecular details. Here we review some recent advances in network and systems biology applied...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2009.11.006

    authors: Pujol A,Mosca R,Farrés J,Aloy P

    更新日期:2010-03-01 00:00:00

  • Location, location, location...site-specific GPCR phosphorylation offers a mechanism for cell-type-specific signalling.

    abstract::It is now established that most of the approximately 800 G-protein-coupled receptors (GPCRs) are regulated by phosphorylation in a process that results in the recruitment of arrestins, leading to receptor desensitization and the activation of arrestin-dependent processes. This generalized view of GPCR regulation, howe...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2008.05.006

    authors: Tobin AB,Butcher AJ,Kong KC

    更新日期:2008-08-01 00:00:00

  • Research applications and implications of adenosine in diseased airways.

    abstract::Adenosine, when given by inhalation, initiates the narrowing of airways in subjects with asthma or chronic obstructive pulmonary disease (COPD). The underlying mechanism of this narrowing appears to involve the stimulation of specific mast cell surface adenosine receptors with the subsequent release of mediators and c...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/S0165-6147(03)00193-7

    authors: Spicuzza L,Bonfiglio C,Polosa R

    更新日期:2003-08-01 00:00:00

  • Do computer simulations of laboratory practicals meet learning needs?

    abstract::There is a variety of pressures on pharmacology teachers to replace real laboratory practicals with simulations but do they help students achieve the required learning objectives? In this article, the marks obtained by students in a variety of assessments using 'wet' or simulated practicals are analysed. Poorer perfor...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/s0165-6147(00)01605-9

    authors: Hughes IE

    更新日期:2001-02-01 00:00:00

  • Regulation of free calmodulin levels by neuromodulin: neuron growth and regeneration.

    abstract::Neuromodulin is a neurospecific calmodulin binding protein that is implicated in neurite extension, axonal elongation and long-term potentiation. Yuechueng Liu and Daniel Storm propose that neuromodulin binds and concentrates calmodulin on growth cone membranes and that stimulation of protein kinase C releases high lo...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/0165-6147(90)90195-e

    authors: Liu YC,Storm DR

    更新日期:1990-03-01 00:00:00

  • Off-target effects associated with long dsRNAs in Drosophila RNAi screens.

    abstract::Evidence of off-target effects (OTEs) associated with small interfering (si)RNAs (19-29bp) in mammalian cells has existed for several years. Two recent articles demonstrate that short sequences within long double-stranded (ds)RNAs frequently cause undesirable OTEs in cultured Drosophila cells. These results reveal the...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章

    doi:10.1016/j.tips.2007.02.009

    authors: Moffat J,Reiling JH,Sabatini DM

    更新日期:2007-04-01 00:00:00

  • Methylphenidate and cocaine: the same effects on gene regulation?

    abstract::Methylphenidate (Ritalin), a psychostimulant used in the treatment of Attention-Deficit Hyperactivity Disorder, has pharmacological effects similar to cocaine and amphetamine. Clinical use of methylphenidate, as well as diversion and abuse, have significantly increased during the past 10-15 years, heightening concerns...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2007.10.004

    authors: Yano M,Steiner H

    更新日期:2007-11-01 00:00:00

  • Targeting the Type Three Secretion System in Pseudomonas aeruginosa.

    abstract::The injectisome type three secretion system (T3SS) is a major virulence factor in Pseudomonas aeruginosa. This bacterium is responsible for severe infections in immunosuppressed or cystic fibrosis patients and has become resistant to many antibiotics. Inhibitors of T3SS may therefore constitute an innovative therapeut...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2016.05.011

    authors: Anantharajah A,Mingeot-Leclercq MP,Van Bambeke F

    更新日期:2016-09-01 00:00:00

  • Neoceptors: reengineering GPCRs to recognize tailored ligands.

    abstract::Efforts to model and reengineer the putative binding sites of G-protein-coupled receptors (GPCRs) have led to an approach that combines small-molecule 'classical' medicinal chemistry and gene therapy. In this approach, complementary structural changes (e.g. based on novel ionic or H-bonds) are made in the receptor and...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2007.01.006

    authors: Jacobson KA,Gao ZG,Liang BT

    更新日期:2007-03-01 00:00:00

  • The hypothalamic H1 receptor: a novel therapeutic target for disrupting diurnal feeding rhythm and obesity.

    abstract::Histamine-containing neurons and histamine H1 receptors are distributed within the brain and peripheral tissues. The results of physiological and pharmacological studies have revealed that brain histamine and H1 receptors are involved in the regulation of feeding and obesity in rodents. The adipocytokine leptin regula...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2006.03.008

    authors: Masaki T,Yoshimatsu H

    更新日期:2006-05-01 00:00:00

  • The sigma-1 receptor chaperone as an inter-organelle signaling modulator.

    abstract::Inter-organelle signaling plays important roles in many physiological functions. Endoplasmic reticulum (ER)-mitochondrion signaling affects intramitochondrial calcium (Ca(2+)) homeostasis and cellular bioenergetics. ER-nucleus signaling attenuates ER stress. ER-plasma membrane signaling regulates cytosolic Ca(2+) home...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章

    doi:10.1016/j.tips.2010.08.007

    authors: Su TP,Hayashi T,Maurice T,Buch S,Ruoho AE

    更新日期:2010-12-01 00:00:00

  • Peptides for cell-selective drug delivery.

    abstract::The ability to target specific cell types to achieve optimal distribution of therapeutic entities into diseased tissues, while limiting possible adverse off-target effects, has long been a goal of many research groups and pharmaceutical organizations. This review focuses on peptidic tissue-specific biomarkers that all...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2012.02.002

    authors: Svensen N,Walton JG,Bradley M

    更新日期:2012-04-01 00:00:00