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Cells, Volume 3, Issue 2 (June 2014) – 24 articles , Pages 180-661

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113 KiB  
Correction
Correction: Liberati, S., et al. Loss of TRPV2 Homeostatic Control of Cell Proliferation Drives Tumor Progression. Cells 2014, 3, 112–128
by Sonia Liberati, Maria Beatrice Morelli, Consuelo Amantini, Valerio Farfariello, Matteo Santoni, Alessandro Conti, Massimo Nabissi, Stefano Cascinu and Giorgio Santoni
Cells 2014, 3(2), 660-661; https://doi.org/10.3390/cells3020660 - 20 Jun 2014
Cited by 8 | Viewed by 5020
Abstract
The authors wish to make the following corrections to this paper [1]: [...] Full article
(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels)
143 KiB  
Editorial
Receptor Tyrosine Kinases — Expanding Horizons
by Sassan Hafizi
Cells 2014, 3(2), 657-659; https://doi.org/10.3390/cells3020657 - 20 Jun 2014
Cited by 37 | Viewed by 4715
Abstract
This Special Issue of Cells on receptor tyrosine kinases (RTKs) is a timely and unique assemblage of scholarly insights into topics that have relatively recently entered the spotlight in relation to this class of molecules. The review by Julien et al. [1] is [...] Read more.
This Special Issue of Cells on receptor tyrosine kinases (RTKs) is a timely and unique assemblage of scholarly insights into topics that have relatively recently entered the spotlight in relation to this class of molecules. The review by Julien et al. [1] is an overview of the knowledge on how gangliosides, constituting certain membrane microdomains, may interact with and regulate RTK activation and downstream signalling. Similarly, the review by Banning et al. [2] focuses on the influence of another type of membrane microdomain, namely that containing flotillins, on regulation of RTK signalling and its relevance to cancer. Both of these reviews provide novel insights into mechanisms of transmembrane receptor signalling that rely on the constitution of the microdomains the RTKs reside in, and how their modification may affect receptor clustering, activation and translocation. Thus, knowledge about such microdomains and their interactions with RTKs can provide new information on common regulation pathways starting at the membrane level, which could have implications for novel therapeutic angles in, e.g., cancer. [...] Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases)
638 KiB  
Review
The Challenge of Producing Ubiquitinated Proteins for Structural Studies
by Serena Faggiano and Annalisa Pastore
Cells 2014, 3(2), 639-656; https://doi.org/10.3390/cells3020639 - 12 Jun 2014
Cited by 16 | Viewed by 8272
Abstract
Protein ubiquitination is an important post-translational modification involved in several essential signalling pathways. It has different effects on the target protein substrate, i.e., it can trigger the degradation of the protein in the proteasome, change the interactions of the modified protein with [...] Read more.
Protein ubiquitination is an important post-translational modification involved in several essential signalling pathways. It has different effects on the target protein substrate, i.e., it can trigger the degradation of the protein in the proteasome, change the interactions of the modified protein with its partners, or affect its localization and activity. In order to understand the molecular mechanisms underlying the consequences of protein ubiquitination, scientists have to face the challenging task of producing ubiquitinated proteins for structural characterization with X-ray crystallography and/or nuclear magnetic resonance (NMR) spectroscopy. These techniques require milligrams of homogeneous samples of high purity. The strategies proposed so far for the production of ubiquitinated proteins can be divided into two groups, i.e., chemical (or non-enzymatic) and enzymatic methodologies. In this review, we summarize the still very sparse examples available in the literature that describe successful production of ubiquitinated proteins amenable for biochemical and structural studies, and discuss advantages and disadvantages of the techniques proposed. We also give a perspective of the direction in which the field might evolve. Full article
(This article belongs to the Special Issue Protein Ubiquitination)
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982 KiB  
Review
The Ufm1 Cascade
by Jens Daniel and Eva Liebau
Cells 2014, 3(2), 627-638; https://doi.org/10.3390/cells3020627 - 11 Jun 2014
Cited by 70 | Viewed by 9160
Abstract
The ubiquitin-fold modifier 1 (Ufm1) is a posttranslational modifier that belongs to the ubiquitin-like protein (UBL) family. Ufm1 is present in nearly all eukaryotic organisms, with the exception of fungi. It resembles ubiquitin in its ability to be ligated to other proteins, as [...] Read more.
The ubiquitin-fold modifier 1 (Ufm1) is a posttranslational modifier that belongs to the ubiquitin-like protein (UBL) family. Ufm1 is present in nearly all eukaryotic organisms, with the exception of fungi. It resembles ubiquitin in its ability to be ligated to other proteins, as well as in the mechanism of ligation. While the Ufm1 cascade has been implicated in endoplasmic reticulum functions and cell cycle control, its biological role still remains poorly understood. In this short review, we summarize the current state of Ufm1 research and its potential role in human diseases, like diabetes, ischemic heart disease and cancer. Full article
(This article belongs to the Special Issue Protein Ubiquitination)
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412 KiB  
Article
Unique Responses are Observed in Transient Receptor Potential Ankyrin 1 and Vanilloid 1 (TRPA1 and TRPV1) Co-Expressing Cells
by Laura R. Sadofsky, Koti T. Sreekrishna, Yakang Lin, Renee Schinaman, Kate Gorka, Yogita Mantri, John Christian Haught, Thomas G. Huggins, Robert J. Isfort, Charles C. Bascom and Alyn H. Morice
Cells 2014, 3(2), 616-626; https://doi.org/10.3390/cells3020616 - 11 Jun 2014
Cited by 28 | Viewed by 7735 | Correction
Abstract
Transient receptor potential (TRP) ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors are implicated in modulation of cough and nociception. In vivo, TRPA1 and TRPV1 are often co-expressed in neurons and TRPA1V1 hetero-tetramer formation is noted in cells co-transfected with the respective [...] Read more.
Transient receptor potential (TRP) ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors are implicated in modulation of cough and nociception. In vivo, TRPA1 and TRPV1 are often co-expressed in neurons and TRPA1V1 hetero-tetramer formation is noted in cells co-transfected with the respective expression plasmids. In order to understand the impact of TRP receptor interaction on activity, we created stable cell lines expressing the TRPA1, TRPV1 and co-expressing the TRPA1 and TRPV1 (TRPA1V1) receptors. Among the 600 compounds screened against these receptors, we observed a number of compounds that activated the TRPA1, TRPV1 and TRPA1V1 receptors; compounds that activated TRPA1 and TRPA1V1; compounds that activated TRPV1 and TRPA1V1; compounds in which TRPA1V1 response was modulated by either TRPA1 or TRPV1; and compounds that activated only TRPV1 or TRPA1 or TRPA1V1; and one compound that activated TRPA1 and TRPV1, but not TRPA1V1. These results suggest that co-expression of TRPA1 and TRPV1 receptors imparts unique activation profiles different from that of cells expressing only TRPA1 or TRPV1. Full article
(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels)
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1382 KiB  
Review
The Cytolethal Distending Toxin Effects on Mammalian Cells: A DNA Damage Perspective
by Elisabeth Bezine, Julien Vignard and Gladys Mirey
Cells 2014, 3(2), 592-615; https://doi.org/10.3390/cells3020592 - 11 Jun 2014
Cited by 55 | Viewed by 11138
Abstract
The cytolethal distending toxin (CDT) is produced by many pathogenic Gram-negative bacteria and is considered as a virulence factor. In human cells, CDT exposure leads to a unique cytotoxicity associated with a characteristic cell distension and induces a cell cycle arrest dependent on [...] Read more.
The cytolethal distending toxin (CDT) is produced by many pathogenic Gram-negative bacteria and is considered as a virulence factor. In human cells, CDT exposure leads to a unique cytotoxicity associated with a characteristic cell distension and induces a cell cycle arrest dependent on the DNA damage response (DDR) triggered by DNA double-strand breaks (DSBs). CDT has thus been classified as a cyclomodulin and a genotoxin. Whereas unrepaired damage can lead to cell death, effective, but improper repair may be detrimental. Indeed, improper repair of DNA damage may allow cells to resume the cell cycle and induce genetic instability, a hallmark in cancer. In vivo, CDT has been shown to induce the development of dysplastic nodules and to lead to genetic instability, defining CDT as a potential carcinogen. It is therefore important to characterize the outcome of the CDT-induced DNA damage and the consequences for intoxicated cells and organisms. Here, we review the latest results regarding the host cell response to CDT intoxication and focus on DNA damage characteristics, cell cycle modulation and cell outcomes. Full article
(This article belongs to the Special Issue Cellular Interactions of the Cytolethal Distending Toxins)
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1568 KiB  
Review
Systems Analysis of Drug-Induced Receptor Tyrosine Kinase Reprogramming Following Targeted Mono- and Combination Anti-Cancer Therapy
by Alexey Goltsov, Yusuf Deeni, Hilal S. Khalil, Tero Soininen, Stylianos Kyriakidis, Huizhong Hu, Simon P. Langdon, David J. Harrison and James Bown
Cells 2014, 3(2), 563-591; https://doi.org/10.3390/cells3020563 - 10 Jun 2014
Cited by 27 | Viewed by 11485
Abstract
The receptor tyrosine kinases (RTKs) are key drivers of cancer progression and targets for drug therapy. A major challenge in anti-RTK treatment is the dependence of drug effectiveness on co-expression of multiple RTKs which defines resistance to single drug therapy. Reprogramming of the [...] Read more.
The receptor tyrosine kinases (RTKs) are key drivers of cancer progression and targets for drug therapy. A major challenge in anti-RTK treatment is the dependence of drug effectiveness on co-expression of multiple RTKs which defines resistance to single drug therapy. Reprogramming of the RTK network leading to alteration in RTK co-expression in response to drug intervention is a dynamic mechanism of acquired resistance to single drug therapy in many cancers. One route to overcome this resistance is combination therapy. We describe the results of a joint in silico, in vitro, and in vivo investigations on the efficacy of trastuzumab, pertuzumab and their combination to target the HER2 receptors. Computational modelling revealed that these two drugs alone and in combination differentially suppressed RTK network activation depending on RTK co-expression. Analyses of mRNA expression in SKOV3 ovarian tumour xenograft showed up-regulation of HER3 following treatment. Considering this in a computational model revealed that HER3 up-regulation reprograms RTK kinetics from HER2 homodimerisation to HER3/HER2 heterodimerisation. The results showed synergy of the trastuzumab and pertuzumab combination treatment of the HER2 overexpressing tumour can be due to an independence of the combination effect on HER3/HER2 composition when it changes due to drug-induced RTK reprogramming. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases)
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451 KiB  
Review
Role of Ubiquitylation in Controlling Suppressor of Cytokine Signalling 3 (SOCS3) Function and Expression
by Jamie J. L. Williams, Kirsten M. A. Munro and Timothy M. Palmer
Cells 2014, 3(2), 546-562; https://doi.org/10.3390/cells3020546 - 30 May 2014
Cited by 31 | Viewed by 12529
Abstract
The realisation that unregulated activation of the Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathway is a key driver of a wide range of diseases has identified its components as targets for therapeutic intervention by small molecule inhibitors and biologicals. In this [...] Read more.
The realisation that unregulated activation of the Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathway is a key driver of a wide range of diseases has identified its components as targets for therapeutic intervention by small molecule inhibitors and biologicals. In this review, we discuss JAK-STAT signalling pathway inhibition by the inducible inhibitor “suppressor of cytokine signaling 3 (SOCS3), its role in diseases such as myeloproliferative disorders, and its function as part of a multi-subunit E3 ubiquitin ligase complex. In addition, we highlight potential applications of these insights into SOCS3-based therapeutic strategies for management of conditions such as vascular re-stenosis associated with acute vascular injury, where there is strong evidence that multiple processes involved in disease progression could be attenuated by localized potentiation of SOCS3 expression levels. Full article
(This article belongs to the Special Issue Protein Ubiquitination)
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657 KiB  
Review
TRPV1: A Potential Drug Target for Treating Various Diseases
by Rafael Brito, Sandeep Sheth, Debashree Mukherjea, Leonard P. Rybak and Vickram Ramkumar
Cells 2014, 3(2), 517-545; https://doi.org/10.3390/cells3020517 - 23 May 2014
Cited by 104 | Viewed by 12720
Abstract
Transient receptor potential vanilloid 1 (TRPV1) is an ion channel present on sensory neurons which is activated by heat, protons, capsaicin and a variety of endogenous lipids termed endovanilloids. As such, TRPV1 serves as a multimodal sensor of noxious stimuli which could trigger [...] Read more.
Transient receptor potential vanilloid 1 (TRPV1) is an ion channel present on sensory neurons which is activated by heat, protons, capsaicin and a variety of endogenous lipids termed endovanilloids. As such, TRPV1 serves as a multimodal sensor of noxious stimuli which could trigger counteractive measures to avoid pain and injury. Activation of TRPV1 has been linked to chronic inflammatory pain conditions and peripheral neuropathy, as observed in diabetes. Expression of TRPV1 is also observed in non-neuronal sites such as the epithelium of bladder and lungs and in hair cells of the cochlea. At these sites, activation of TRPV1 has been implicated in the pathophysiology of diseases such as cystitis, asthma and hearing loss. Therefore, drugs which could modulate TRPV1 channel activity could be useful for the treatment of conditions ranging from chronic pain to hearing loss. This review describes the roles of TRPV1 in the normal physiology and pathophysiology of selected organs of the body and highlights how drugs targeting this channel could be important clinically. Full article
(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels)
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1463 KiB  
Article
Aberrantly Over-Expressed TRPM8 Channels in Pancreatic Adenocarcinoma: Correlation with Tumor Size/Stage and Requirement for Cancer Cells Invasion
by Nelson S. Yee, Qin Li, Abid A. Kazi, Zhaohai Yang, Arthur Berg and Rosemary K. Yee
Cells 2014, 3(2), 500-516; https://doi.org/10.3390/cells3020500 - 23 May 2014
Cited by 22 | Viewed by 10637
Abstract
The transient receptor potential melastatin-subfamily member 8 (TRPM8) channels control Ca2+ homeostasis. Recent studies indicate that TRPM8 channels are aberrantly expressed and required for cellular proliferation in pancreatic adenocarcinoma. However, the functional significance of TRPM8 in pancreatic tissues is mostly unknown. The [...] Read more.
The transient receptor potential melastatin-subfamily member 8 (TRPM8) channels control Ca2+ homeostasis. Recent studies indicate that TRPM8 channels are aberrantly expressed and required for cellular proliferation in pancreatic adenocarcinoma. However, the functional significance of TRPM8 in pancreatic tissues is mostly unknown. The objectives of this study are to examine the expression of TRPM8 in various histopathological types of pancreatic tissues, determine its clinical significance in pancreatic adenocarcinoma, and investigate its functional role in cancer cells invasion. We present evidence that, in normal pancreatic tissues, anti-TRPM8 immunoreactivity is detected in the centroacinar cells and the islet endocrine cells. In pre-malignant pancreatic tissues and malignant neoplasms, TRPM8 is aberrantly expressed to variable extents. In the majority of pancreatic adenocarcinoma, TRPM8 is expressed at moderate or high levels, and anti-TRPM8 immunoreactivity positively correlates with the primary tumor size and stage. In the pancreatic adenocarcinoma cell lines that express relatively high levels of TRPM8, short hairpin RNA-mediated interference of TRPM8 expression impaired their ability of invasion. These data suggest that aberrantly expressed TRPM8 channels play contributory roles in pancreatic tumor growth and metastasis, and support exploration of TRPM8 as a biomarker and target of pancreatic adenocarcinoma. Full article
(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels)
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3418 KiB  
Review
Breaking the Gingival Epithelial Barrier: Role of the Aggregatibacter actinomycetemcomitans Cytolethal Distending Toxin in Oral Infectious Disease
by Joseph M. DiRienzo
Cells 2014, 3(2), 476-499; https://doi.org/10.3390/cells3020476 - 23 May 2014
Cited by 36 | Viewed by 9995
Abstract
The Gram-negative bacterium Aggregatibacter actinomycetemcomitans is part of the HACEK group that causes infective endocarditis, a constituent of the oral flora that promotes some forms of periodontal disease and a member of the family of species that secrete a cytolethal distending toxin (Cdt). [...] Read more.
The Gram-negative bacterium Aggregatibacter actinomycetemcomitans is part of the HACEK group that causes infective endocarditis, a constituent of the oral flora that promotes some forms of periodontal disease and a member of the family of species that secrete a cytolethal distending toxin (Cdt). The family of bacteria that express the cdt genes participate in diseases that involve the disruption of a mucosal or epithelial layer. In vitro studies have shown that human gingival epithelial cells (HGEC) are native targets of the Cdt that typically induces DNA damage that signals growth arrest at the G2/M interphase of the cell cycle. The gingival epithelium is an early line of defense in the oral cavity against microbial assault. When damaged, bacteria collectively gain entry into the underlying connective tissue where microbial products can affect processes and pathways in infiltrating inflammatory cells culminating in the destruction of the attachment apparatus of the tooth. One approach has been the use of an ex vivo gingival explant model to assess the effects of the Cdt on the morphology and integrity of the tissue. The goal of this review is to provide an overview of these studies and to critically examine the potential contribution of the Cdt to the breakdown of the protective gingival barrier. Full article
(This article belongs to the Special Issue Cellular Interactions of the Cytolethal Distending Toxins)
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387 KiB  
Review
Physiological Function and Characterization of TRPCs in Neurons
by Yuyang Sun, Pramod Sukumaran, Bidhan C. Bandyopadhyay and Brij B. Singh
Cells 2014, 3(2), 455-475; https://doi.org/10.3390/cells3020455 - 21 May 2014
Cited by 27 | Viewed by 9987
Abstract
Ca2+ entry is essential for regulating vital physiological functions in all neuronal cells. Although neurons are engaged in multiple modes of Ca2+ entry that regulates variety of neuronal functions, we will only discuss a subset of specialized Ca2+-permeable non-selective [...] Read more.
Ca2+ entry is essential for regulating vital physiological functions in all neuronal cells. Although neurons are engaged in multiple modes of Ca2+ entry that regulates variety of neuronal functions, we will only discuss a subset of specialized Ca2+-permeable non-selective Transient Receptor Potential Canonical (TRPC) channels and summarize their physiological and pathological role in these excitable cells. Depletion of endoplasmic reticulum (ER) Ca2+ stores, due to G-protein coupled receptor activation, has been shown to activate TRPC channels in both excitable and non-excitable cells. While all seven members of TRPC channels are predominately expressed in neuronal cells, the ion channel properties, mode of activation, and their physiological responses are quite distinct. Moreover, many of these TRPC channels have also been suggested to be associated with neuronal development, proliferation and differentiation. In addition, TRPCs also regulate neurosecretion, long-term potentiation and synaptic plasticity. Similarly, perturbations in Ca2+ entry via the TRPC channels have been also suggested in a spectrum of neuropathological conditions. Hence, understanding the precise involvement of TRPCs in neuronal function and in neurodegenerative conditions would presumably unveil avenues for plausible therapeutic interventions for these devastating neuronal diseases. Full article
(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels)
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475 KiB  
Review
HSV-1 ICP0: An E3 Ubiquitin Ligase That Counteracts Host Intrinsic and Innate Immunity
by Mirna Perusina Lanfranca, Heba H. Mostafa and David J. Davido
Cells 2014, 3(2), 438-454; https://doi.org/10.3390/cells3020438 - 20 May 2014
Cited by 68 | Viewed by 12756
Abstract
The herpes simplex virus type 1 (HSV-1) encoded E3 ubiquitin ligase, infected cell protein 0 (ICP0), is required for efficient lytic viral replication and regulates the switch between the lytic and latent states of HSV-1. As an E3 ubiquitin ligase, ICP0 directs the [...] Read more.
The herpes simplex virus type 1 (HSV-1) encoded E3 ubiquitin ligase, infected cell protein 0 (ICP0), is required for efficient lytic viral replication and regulates the switch between the lytic and latent states of HSV-1. As an E3 ubiquitin ligase, ICP0 directs the proteasomal degradation of several cellular targets, allowing the virus to counteract different cellular intrinsic and innate immune responses. In this review, we will focus on how ICP0’s E3 ubiquitin ligase activity inactivates the host intrinsic defenses, such as nuclear domain 10 (ND10), SUMO, and the DNA damage response to HSV-1 infection. In addition, we will examine ICP0’s capacity to impair the activation of interferon (innate) regulatory mediators that include IFI16 (IFN γ-inducible protein 16), MyD88 (myeloid differentiation factor 88), and Mal (MyD88 adaptor-like protein). We will also consider how ICP0 allows HSV-1 to evade activation of the NF-κB (nuclear factor kappa B) inflammatory signaling pathway. Finally, ICP0’s paradoxical relationship with USP7 (ubiquitin specific protease 7) and its roles in intrinsic and innate immune responses to HSV-1 infection will be discussed. Full article
(This article belongs to the Special Issue Protein Ubiquitination)
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258 KiB  
Review
Mcl-1 Ubiquitination: Unique Regulation of an Essential Survival Protein
by Barbara Mojsa, Iréna Lassot and Solange Desagher
Cells 2014, 3(2), 418-437; https://doi.org/10.3390/cells3020418 - 08 May 2014
Cited by 147 | Viewed by 14539
Abstract
Mcl-1 is an anti-apoptotic protein of the Bcl-2 family that is essential for the survival of multiple cell lineages and that is highly amplified in human cancer. Under physiological conditions, Mcl-1 expression is tightly regulated at multiple levels, involving transcriptional, post-transcriptional and post-translational [...] Read more.
Mcl-1 is an anti-apoptotic protein of the Bcl-2 family that is essential for the survival of multiple cell lineages and that is highly amplified in human cancer. Under physiological conditions, Mcl-1 expression is tightly regulated at multiple levels, involving transcriptional, post-transcriptional and post-translational processes. Ubiquitination of Mcl-1, that targets it for proteasomal degradation, allows for rapid elimination of the protein and triggering of cell death, in response to various cellular events. In the last decade, a number of studies have elucidated different pathways controlling Mcl-1 ubiquitination and degradation. Four different E3 ubiquitin-ligases (e.g., Mule, SCFβ-TrCP, SCFFbw7 and Trim17) and one deubiquitinase (e.g., USP9X), that respectively mediate and oppose Mcl-1 ubiquitination, have been formerly identified. The interaction between Mule and Mcl-1 can be modulated by other Bcl-2 family proteins, while recognition of Mcl-1 by the other E3 ubiquitin-ligases and deubiquitinase is influenced by phosphorylation of specific residues in Mcl-1. The protein kinases and E3 ubiquitin-ligases that are involved in the regulation of Mcl-1 stability vary depending on the cellular context, highlighting the complexity and pivotal role of Mcl-1 regulation. In this review, we attempt to recapitulate progress in understanding Mcl-1 regulation by the ubiquitin-proteasome system. Full article
(This article belongs to the Special Issue Protein Ubiquitination)
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631 KiB  
Review
The Ubiquitin-Conjugating System: Multiple Roles in Viral Replication and Infection
by Arianna Calistri, Denis Munegato, Ilaria Carli, Cristina Parolin and Giorgio Palù
Cells 2014, 3(2), 386-417; https://doi.org/10.3390/cells3020386 - 06 May 2014
Cited by 70 | Viewed by 11493
Abstract
Through the combined action of ubiquitinating and deubiquitinating enzymes, conjugation of ubiquitin to a target protein acts as a reversible post-translational modification functionally similar to phosphorylation. Indeed, ubiquitination is more and more recognized as a central process for the fine regulation of many [...] Read more.
Through the combined action of ubiquitinating and deubiquitinating enzymes, conjugation of ubiquitin to a target protein acts as a reversible post-translational modification functionally similar to phosphorylation. Indeed, ubiquitination is more and more recognized as a central process for the fine regulation of many cellular pathways. Due to their nature as obligate intracellular parasites, viruses rely on the most conserved host cell machineries for their own replication. Thus, it is not surprising that members from almost every viral family are challenged by ubiquitin mediated mechanisms in different steps of their life cycle and have evolved in order to by-pass or exploit the cellular ubiquitin conjugating system to maximize their chance to establish a successful infection. In this review we will present several examples of the complex interplay that links viruses and the ubiquitin conjugation machinery, with a special focus on the mechanisms evolved by the human immunodeficiency virus to escape from cellular restriction factors and to exit from infected cells. Full article
(This article belongs to the Special Issue Protein Ubiquitination)
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Article
Endosome-to-Plasma Membrane Recycling of VEGFR2 Receptor Tyrosine Kinase Regulates Endothelial Function and Blood Vessel Formation
by Helen M. Jopling, Adam F. Odell, Caroline Pellet-Many, Antony M. Latham, Paul Frankel, Asipu Sivaprasadarao, John H. Walker, Ian C. Zachary and Sreenivasan Ponnambalam
Cells 2014, 3(2), 363-385; https://doi.org/10.3390/cells3020363 - 29 Apr 2014
Cited by 51 | Viewed by 11718
Abstract
Rab GTPases are implicated in endosome-to-plasma membrane recycling, but how such membrane traffic regulators control vascular endothelial growth factor receptor 2 (VEGFR2/KDR) dynamics and function are not well understood. Here, we evaluated two different recycling Rab GTPases, Rab4a and Rab11a, in regulating endothelial [...] Read more.
Rab GTPases are implicated in endosome-to-plasma membrane recycling, but how such membrane traffic regulators control vascular endothelial growth factor receptor 2 (VEGFR2/KDR) dynamics and function are not well understood. Here, we evaluated two different recycling Rab GTPases, Rab4a and Rab11a, in regulating endothelial VEGFR2 trafficking and signalling with implications for endothelial cell migration, proliferation and angiogenesis. In primary endothelial cells, VEGFR2 displays co-localisation with Rab4a, but not Rab11a GTPase, on early endosomes. Expression of a guanosine diphosphate (GDP)-bound Rab4a S22N mutant caused increased VEGFR2 accumulation in endosomes. TfR and VEGFR2 exhibited differences in endosome-to-plasma membrane recycling in the presence of chloroquine. Depletion of Rab4a, but not Rab11a, levels stimulated VEGF-A-dependent intracellular signalling. However, depletion of either Rab4a or Rab11a levels inhibited VEGF-A-stimulated endothelial cell migration. Interestingly, depletion of Rab4a levels stimulated VEGF-A-regulated endothelial cell proliferation. Rab4a and Rab11a were also both required for endothelial tubulogenesis. Evaluation of a transgenic zebrafish model showed that both Rab4 and Rab11a are functionally required for blood vessel formation and animal viability. Rab-dependent endosome-to-plasma membrane recycling of VEGFR2 is important for intracellular signalling, cell migration and proliferation during angiogenesis. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases)
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2462 KiB  
Review
TRP Channels Involved in Spontaneous L-Glutamate Release Enhancement in the Adult Rat Spinal Substantia Gelatinosa
by Eiichi Kumamoto, Tsugumi Fujita and Chang-Yu Jiang
Cells 2014, 3(2), 331-362; https://doi.org/10.3390/cells3020331 - 29 Apr 2014
Cited by 24 | Viewed by 19031
Abstract
The spinal substantia gelatinosa (SG) plays a pivotal role in modulating nociceptive transmission through dorsal root ganglion (DRG) neurons from the periphery. TRP channels such as TRPV1 and TRPA1 channels expressed in the SG are involved in the regulation of the nociceptive transmission. [...] Read more.
The spinal substantia gelatinosa (SG) plays a pivotal role in modulating nociceptive transmission through dorsal root ganglion (DRG) neurons from the periphery. TRP channels such as TRPV1 and TRPA1 channels expressed in the SG are involved in the regulation of the nociceptive transmission. On the other hand, the TRP channels located in the peripheral terminals of the DRG neurons are activated by nociceptive stimuli given to the periphery and also by plant-derived chemicals, which generates a membrane depolarization. The chemicals also activate the TRP channels in the SG. In this review, we introduce how synaptic transmissions in the SG neurons are affected by various plant-derived chemicals and suggest that the peripheral and central TRP channels may differ in property from each other. Full article
(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels)
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297 KiB  
Review
Mechanisms of Activation of Receptor Tyrosine Kinases: Monomers or Dimers
by Ichiro N. Maruyama
Cells 2014, 3(2), 304-330; https://doi.org/10.3390/cells3020304 - 22 Apr 2014
Cited by 137 | Viewed by 19214
Abstract
Receptor tyrosine kinases (RTKs) play essential roles in cellular processes, including metabolism, cell-cycle control, survival, proliferation, motility and differentiation. RTKs are all synthesized as single-pass transmembrane proteins and bind polypeptide ligands, mainly growth factors. It has long been thought that all RTKs, except [...] Read more.
Receptor tyrosine kinases (RTKs) play essential roles in cellular processes, including metabolism, cell-cycle control, survival, proliferation, motility and differentiation. RTKs are all synthesized as single-pass transmembrane proteins and bind polypeptide ligands, mainly growth factors. It has long been thought that all RTKs, except for the insulin receptor (IR) family, are activated by ligand-induced dimerization of the receptors. An increasing number of diverse studies, however, indicate that RTKs, previously thought to exist as monomers, are present as pre-formed, yet inactive, dimers prior to ligand binding. The non-covalently associated dimeric structures are reminiscent of those of the IR family, which has a disulfide-linked dimeric structure. Furthermore, recent progress in structural studies has provided insight into the underpinnings of conformational changes during the activation of RTKs. In this review, I discuss two mutually exclusive models for the mechanisms of activation of the epidermal growth factor receptor, the neurotrophin receptor and IR families, based on these new insights. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases)
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658 KiB  
Review
The Role of Canonical Transient Receptor Potential Channels in Seizure and Excitotoxicity
by Fang Zheng and Kevin D. Phelan
Cells 2014, 3(2), 288-303; https://doi.org/10.3390/cells3020288 - 09 Apr 2014
Cited by 30 | Viewed by 8422
Abstract
Canonical transient receptor potential (TRPC) channels are a family of polymodal cation channels with some degree of Ca2+ permeability. Although initially thought to be channels mediating store-operated Ca2+ influx, TRPC channels can be activated by stimulation of Gq-coupled G-protein coupled receptors, [...] Read more.
Canonical transient receptor potential (TRPC) channels are a family of polymodal cation channels with some degree of Ca2+ permeability. Although initially thought to be channels mediating store-operated Ca2+ influx, TRPC channels can be activated by stimulation of Gq-coupled G-protein coupled receptors, or by an increase in intracellular free Ca2+ concentration. Thus, activation of TRPC channels could be a common downstream event of many signaling pathways that contribute to seizure and excitotoxicity, such as N-methyl-D-aspartate (NMDA) receptor-mediated Ca2+ influx, or metabotropic glutamate receptor activation. Recent studies with genetic ablation of various TRPC family members have demonstrated that TRPC channels, in particular heteromeric TRPC1/4 channels and homomeric TRPC5 channels, play a critical role in both pilocarpine-induced acute seizures and neuronal cell death. However, exact underlying mechanisms remain to be fully elucidated, and selective TRPC modulators and antibodies with better specificity are urgently needed for future research. Full article
(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels)
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1325 KiB  
Review
Post-Translational Modifications of TRP Channels
by Olaf Voolstra and Armin Huber
Cells 2014, 3(2), 258-287; https://doi.org/10.3390/cells3020258 - 08 Apr 2014
Cited by 41 | Viewed by 9472
Abstract
Transient receptor potential (TRP) channels constitute an ancient family of cation channels that have been found in many eukaryotic organisms from yeast to human. TRP channels exert a multitude of physiological functions ranging from Ca2+ homeostasis in the kidney to pain reception [...] Read more.
Transient receptor potential (TRP) channels constitute an ancient family of cation channels that have been found in many eukaryotic organisms from yeast to human. TRP channels exert a multitude of physiological functions ranging from Ca2+ homeostasis in the kidney to pain reception and vision. These channels are activated by a wide range of stimuli and undergo covalent post-translational modifications that affect and modulate their subcellular targeting, their biophysical properties, or channel gating. These modifications include N-linked glycosylation, protein phosphorylation, and covalent attachment of chemicals that reversibly bind to specific cysteine residues. The latter modification represents an unusual activation mechanism of ligand-gated ion channels that is in contrast to the lock-and-key paradigm of receptor activation by its agonists. In this review, we summarize the post-translational modifications identified on TRP channels and, when available, explain their physiological role. Full article
(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels)
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582 KiB  
Article
PKC-dependent Phosphorylation of the H1 Histamine Receptor Modulates TRPC6 Activity
by Xingjuan Chen, Christian Egly, Ashley M. Riley, Wennan Li, Paul Tewson, Thomas E. Hughes, Anne Marie Quinn and Alexander G. Obukhov
Cells 2014, 3(2), 247-257; https://doi.org/10.3390/cells3020247 - 04 Apr 2014
Cited by 15 | Viewed by 15260
Abstract
Transient receptor potential canonical 6 (TRPC6) is a cation selective, DAG-regulated, Ca2+-permeable channel activated by the agonists of Gq-protein-coupled heptahelical receptors. Dysfunctions of TRPC6 are implicated in the pathogenesis of various cardiovascular and kidney conditions such as vasospasm and [...] Read more.
Transient receptor potential canonical 6 (TRPC6) is a cation selective, DAG-regulated, Ca2+-permeable channel activated by the agonists of Gq-protein-coupled heptahelical receptors. Dysfunctions of TRPC6 are implicated in the pathogenesis of various cardiovascular and kidney conditions such as vasospasm and glomerulosclerosis. When stimulated by agonists of the histamine H1 receptor (H1R), TRPC6 activity decays to the baseline despite the continuous presence of the agonist. In this study, we examined whether H1R desensitization contributes to regulating the decay rate of TRPC6 activity upon receptor stimulation. We employed the HEK expression system and a biosensor allowing us to simultaneously detect the changes in intracellular diacylglycerol (DAG) and Ca2+ concentrations. We found that the histamine-induced DAG response was biphasic, in which a transient peak was followed by maintained elevated plateau, suggesting that desensitization of H1R takes place in the presence of histamine. The application of PKC inhibitor Gö6983 slowed the decay rate of intracellular DAG concentration. Activation of the mouse H1R mutant lacking a putative PKC phosphorylation site, Ser399, responsible for the receptor desensitization, resulted in a prolonged intracellular DAG increase and greater Mn2+ influx through the TRPC6 channel. Thus, our data support the hypothesis that PKC-dependent H1R phosphorylation leads to a reduced production of intracellular DAG that contributes to TRPC6 activity regulation. Full article
(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels)
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194 KiB  
Review
Inflammatory and Bone Remodeling Responses to the Cytolethal Distending Toxins
by Georgios N. Belibasakis and Nagihan Bostanci
Cells 2014, 3(2), 236-246; https://doi.org/10.3390/cells3020236 - 04 Apr 2014
Cited by 12 | Viewed by 5471
Abstract
The cytolethal distending toxins (CDTs) are a family of exotoxins produced by a wide range of Gram-negative bacteria. They are known for causing genotoxic stress to the cell, resulting in growth arrest and eventually apoptotic cell death. Nevertheless, there is evidence that CDTs [...] Read more.
The cytolethal distending toxins (CDTs) are a family of exotoxins produced by a wide range of Gram-negative bacteria. They are known for causing genotoxic stress to the cell, resulting in growth arrest and eventually apoptotic cell death. Nevertheless, there is evidence that CDTs can also perturb the innate immune responses, by regulating inflammatory cytokine production and molecular mediators of bone remodeling in various cell types. These cellular and molecular events may in turn have an effect in enhancing local inflammation in diseases where CDT-producing bacteria are involved, such as Aggregatibacter actinomycetemcomitans, Haemophilus ducreyi, Campylobacter jejuni and Helicobacter hepaticus. One special example is the induction of pathological bone destruction in periodontitis. The opportunistic oral pathogen Aggregatibatcer actinoycemetemcomitans, which is involved in the aggressive form of the disease, can regulate the molecular mechanisms of bone remodeling in a manner that favors bone resorption, with the potential involvement of its CDT. The present review provides an overview of all known to-date inflammatory or bone remodeling responses of CDTs produced by various bacterial species, and discusses their potential contribution to the pathogenesis of the associated diseases. Full article
(This article belongs to the Special Issue Cellular Interactions of the Cytolethal Distending Toxins)
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Review
Role of Receptor Tyrosine Kinases and Their Ligands in Glioblastoma
by Estefanía Carrasco-García, Miguel Saceda and Isabel Martínez-Lacaci
Cells 2014, 3(2), 199-235; https://doi.org/10.3390/cells3020199 - 04 Apr 2014
Cited by 65 | Viewed by 11998
Abstract
Glioblastoma multiforme is the most frequent, aggressive and fatal type of brain tumor. Glioblastomas are characterized by their infiltrating nature, high proliferation rate and resistance to chemotherapy and radiation. Recently, oncologic therapy experienced a rapid evolution towards “targeted therapy,” which is the employment [...] Read more.
Glioblastoma multiforme is the most frequent, aggressive and fatal type of brain tumor. Glioblastomas are characterized by their infiltrating nature, high proliferation rate and resistance to chemotherapy and radiation. Recently, oncologic therapy experienced a rapid evolution towards “targeted therapy,” which is the employment of drugs directed against particular targets that play essential roles in proliferation, survival and invasiveness of cancer cells. A number of molecules involved in signal transduction pathways are used as molecular targets for the treatment of various tumors. In fact, inhibitors of these molecules have already entered the clinic or are undergoing clinical trials. Cellular receptors are clear examples of such targets and in the case of glioblastoma multiforme, some of these receptors and their ligands have become relevant. In this review, the importance of glioblastoma multiforme in signaling pathways initiated by extracellular tyrosine kinase receptors such as EGFR, PDGFR and IGF-1R will be discussed. We will describe their ligands, family members, structure, activation mechanism, downstream molecules, as well as the interaction among these pathways. Lastly, we will provide an up-to-date review of the current targeted therapies in cancer, in particular glioblastoma that employ inhibitors of these pathways and their benefits. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases)
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2690 KiB  
Article
Yeast Irc22 Is a Novel Dsk2-Interacting Protein that Is Involved in Salt Tolerance
by Takashi Ishii, Minoru Funakoshi, Hideki Kobayashi and Takeshi Sekiguchi
Cells 2014, 3(2), 180-198; https://doi.org/10.3390/cells3020180 - 27 Mar 2014
Cited by 6 | Viewed by 7661
Abstract
The yeast ubiquitin-like and ubiquitin-associated protein Dsk2 is one of the ubiquitin receptors that function in the ubiquitin-proteasome pathway. We screened the Dsk2-interacting proteins in Saccharomyces cerevisiae by a two-hybrid assay and identified a novel Dsk2-interacting protein, Irc22, the gene locus of which [...] Read more.
The yeast ubiquitin-like and ubiquitin-associated protein Dsk2 is one of the ubiquitin receptors that function in the ubiquitin-proteasome pathway. We screened the Dsk2-interacting proteins in Saccharomyces cerevisiae by a two-hybrid assay and identified a novel Dsk2-interacting protein, Irc22, the gene locus of which has previously been described as YEL001C, but the function of which is unknown. IRC22/YEL001C encodes 225 amino acid residues with a calculated molecular weight of 25 kDa. The Irc22 protein was detected in yeast cells. IRC22 was a nonessential gene for yeast growth, and its homologs were found among ascomycetous yeasts. Irc22 interacted with Dsk2 in yeast cells, but not with Rad23 and Ddi1. Ubiquitin-dependent degradation was impaired mildly by over-expression or disruption of IRC22. Compared with the wild-type strain, dsk2D exhibited salt sensitivity while irc22D exhibited salt tolerance at high temperatures. The salt-tolerant phenotype that was observed in irc22D disappeared in the dsk2Dirc22D double disruptant, indicating that DSK2 is positively and IRC22 is negatively involved in salt stress tolerance. IRC22 disruption did not affect any responses to DNA damage and oxidative stress when comparing the irc22D and wild-type strains. Collectively, these results suggest that Dsk2 and Irc22 are involved in salt stress tolerance in yeast. Full article
(This article belongs to the Special Issue Protein Ubiquitination)
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