scholarly journals Targeting Hedgehog Signalling through the Ubiquitylation Process: The Multiple Roles of the HECT-E3 Ligase Itch

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 98 ◽  
Author(s):  
Paola Infante ◽  
Ludovica Lospinoso Severini ◽  
Flavia Bernardi ◽  
Francesca Bufalieri ◽  
Lucia Di Marcotullio
Keyword(s):  
E3 Ligase ◽  
Multiple Roles ◽  
Post Translational Modification ◽  
Therapeutic Approaches ◽  
Cellular Functions ◽  
Hedgehog Signalling ◽  
Promising Target ◽  
Important Pathway ◽  
Multiple Levels

Hedgehog signalling (Hh) is a developmental conserved pathway strongly involved in cancers when deregulated. This important pathway is orchestrated by numerous regulators, transduces through distinct routes and is finely tuned at multiple levels. In this regard, ubiquitylation processes stand as essential for controlling Hh pathway output. Although this post-translational modification governs proteins turnover, it is also implicated in non-proteolytic events, thereby regulating the most important cellular functions. The HECT E3 ligase Itch, well known to control immune response, is emerging to have a pivotal role in tumorigenesis. By illustrating Itch specificities on Hh signalling key components, here we review the role of this HECT E3 ubiquitin ligase in suppressing Hh-dependent tumours and explore its potential as promising target for innovative therapeutic approaches.

scholarly journals Zooming out: actor engagement beyond the dyadic

2018 ◽  
Vol 29 (3) ◽  
pp. 333-351 ◽  
Author(s):  
Matthew J. Alexander ◽  
Elina Jaakkola ◽  
Linda D. Hollebeek
Keyword(s):  
Structuration Theory ◽  
Multiple Roles ◽  
Content Type ◽  
Meta Level ◽  
Analytical Perspective ◽  
Conceptual Paper ◽  
Multiple Levels ◽  
Service Ecosystem ◽  
Organizational Mechanisms

Purpose The purpose of this paper is to broaden extant understanding of actor engagement behavior beyond its currently dominant dyadic (micro-level) focus, by examining it from multiple levels of aggregation within a service ecosystem framework. Design/methodology/approach This conceptual paper draws on service-dominant logic and structuration theory as theoretical lenses to inform engagement research. Findings By means of a stepwise exercise of “zooming out,” the paper introduces a multi-perspective (micro-, meso-, macro- and meta-level) view of actor engagement that develops understanding of multiple engagement contexts, and suggests that balancing multiple roles may result in actor disengagement behavior. The role of reference groups and role conflict associated with balancing multiple roles is critical to understanding why engaged actor proclivities may wax and wane between contexts. Research limitations/implications The paper offers a set of five propositions that can be utilized by engagement scholars undertaking further research in this area. Practical implications Firms need to understand the values and norms embedded in diverse engagement contexts which can affect actor groups’ needs and motivations. Firms should develop appropriate organizational mechanisms to facilitate (rather than impede or obstruct) the desired behaviors of engaged actors. Originality/value The broader context within which engaged actors operate, and its effects on engagement, has been largely overlooked to date. By broadening the analytical perspective on engagement beyond the dyadic this paper reveals previously unaddressed aspects of this phenomenon, such as the role of disengagement behavior, and the effects of multiple engagement contexts on actors’ future behaviors.

ADP-ribosylation and intracellular traffic: an emerging role for PARP enzymes

2019 ◽  
Vol 47 (1) ◽  
pp. 357-370 ◽  
Author(s):  
Giovanna Grimaldi ◽  
Daniela Corda
Keyword(s):  
Intracellular Transport ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Intracellular Traffic ◽  
Adp Ribosylation ◽  
Cell Responses ◽  
Physiological Processes ◽  
Dependent Cell ◽  
Ribose Moiety

AbstractADP-ribosylation is an ancient and reversible post-translational modification (PTM) of proteins, in which the ADP-ribose moiety is transferred from NAD+ to target proteins by members of poly-ADP-ribosyl polymerase (PARP) family. The 17 members of this family have been involved in a variety of cellular functions, where their regulatory roles are exerted through the modification of specific substrates, whose identification is crucial to fully define the contribution of this PTM. Evidence of the role of the PARPs is now available both in the context of physiological processes and of cell responses to stress or starvation. An emerging role of the PARPs is their control of intracellular transport, as it is the case for tankyrases/PARP5 and PARP12. Here, we discuss the evidence pointing at this novel aspect of PARPs-dependent cell regulation.

scholarly journals Therapeutic Potential of Targeting the SUMO Pathway in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4402
Author(s):  
Antti Kukkula ◽  
Veera K. Ojala ◽  
Lourdes M. Mendez ◽  
Lea Sistonen ◽  
Klaus Elenius ◽  
...  
Keyword(s):  
Tumor Suppressors ◽  
Protein Function ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Dependent Manner ◽  
Post Translational Modification ◽  
Recent Developments ◽  
Sumo Pathway ◽  
Multiple Levels

SUMOylation is a dynamic and reversible post-translational modification, characterized more than 20 years ago, that regulates protein function at multiple levels. Key oncoproteins and tumor suppressors are SUMO substrates. In addition to alterations in SUMO pathway activity due to conditions typically present in cancer, such as hypoxia, the SUMO machinery components are deregulated at the genomic level in cancer. The delicate balance between SUMOylation and deSUMOylation is regulated by SENP enzymes possessing SUMO-deconjugation activity. Dysregulation of SUMO machinery components can disrupt the balance of SUMOylation, contributing to the tumorigenesis and drug resistance of various cancers in a context-dependent manner. Many molecular mechanisms relevant to the pathogenesis of specific cancers involve SUMO, highlighting the potential relevance of SUMO machinery components as therapeutic targets. Recent advances in the development of inhibitors targeting SUMOylation and deSUMOylation permit evaluation of the therapeutic potential of targeting the SUMO pathway in cancer. Finally, the first drug inhibiting SUMO pathway, TAK-981, is currently also being evaluated in clinical trials in cancer patients. Intriguingly, the inhibition of SUMOylation may also have the potential to activate the anti-tumor immune response. Here, we comprehensively and systematically review the recent developments in understanding the role of SUMOylation in cancer and specifically focus on elaborating the scientific rationale of targeting the SUMO pathway in different cancers.

scholarly journals The Role of gp130 Cytokines in Tuberculosis

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2695
Author(s):  
Kristina Ritter ◽  
Jasmin Rousseau ◽  
Christoph Hölscher
Keyword(s):  
Inflammatory Diseases ◽  
Therapeutic Approaches ◽  
Duration Of Treatment ◽  
Common Receptor ◽  
Promising Target ◽  
Increased Risk ◽  
The Common ◽  
Combine Administration ◽  
Cytokine Networks

Protective immune responses to Mycobacterium tuberculosis (Mtb) infection substantially depend on a delicate balance within cytokine networks. Thus, immunosuppressive therapy by cytokine blockers, as successfully used in the management of various chronic inflammatory diseases, is often connected with an increased risk for tuberculosis (TB) reactivation. Hence, identification of alternative therapeutics which allow the treatment of inflammatory diseases without compromising anti-mycobacterial immunity remains an important issue. On the other hand, in the context of novel therapeutic approaches for the management of TB, host-directed adjunct therapies, which combine administration of antibiotics with immunomodulatory drugs, play an increasingly important role, particularly to reduce the duration of treatment. In both respects, cytokines/cytokine receptors related to the common receptor subunit gp130 may serve as promising target candidates. Within the gp130 cytokine family, interleukin (IL)-6, IL-11 and IL-27 are most explored in the context of TB. This review summarizes the differential roles of these cytokines in protection and immunopathology during Mtb infection and discusses potential therapeutic implementations with respect to the aforementioned approaches.

scholarly journals Shedding light on the role of keratinocyte-derived extracellular vesicles on skin-homing cells

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Golara Nasiri ◽  
Negar Azarpira ◽  
Aliakbar Alizadeh ◽  
Sanaz Goshtasbi ◽  
Lobat Tayebi
Keyword(s):  
Extracellular Vesicles ◽  
Lipid Membranes ◽  
Inflammatory Cells ◽  
Therapeutic Approaches ◽  
Cellular Functions ◽  
Skin Cells ◽  
Physiological Properties ◽  
Cutaneous Immunity ◽  
Skin Homing

Abstract Extracellular vesicles (EVs) are secretory lipid membranes with the ability to regulate cellular functions by exchanging biological components between different cells. Resident skin cells such as keratinocytes, fibroblasts, melanocytes, and inflammatory cells can secrete different types of EVs depending on their biological state. These vesicles can influence the physiological properties and pathological processes of skin, such as pigmentation, cutaneous immunity, and wound healing. Since keratinocytes constitute the majority of skin cells, secreted EVs from these cells may alter the pathophysiological behavior of other skin cells. This paper reviews the contents of keratinocyte-derived EVs and their impact on fibroblasts, melanocytes, and immune cells to provide an insight for better understanding of the pathophysiological mechanisms of skin disorders and their use in related therapeutic approaches.

Postsynaptic nanodomains generated by local palmitoylation cycles

2015 ◽  
Vol 43 (2) ◽  
pp. 199-204 ◽  
Author(s):  
Masaki Fukata ◽  
Atsushi Sekiya ◽  
Tatsuro Murakami ◽  
Norihiko Yokoi ◽  
Yuko Fukata
Keyword(s):  
Plasma Membrane ◽  
Protein Targeting ◽  
Scaffolding Protein ◽  
Dependent Manner ◽  
Membrane Domains ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Protein Palmitoylation ◽  
Specific Proteins

Precise regulation of protein assembly at specialized membrane domains is essential for diverse cellular functions including synaptic transmission. However, it is incompletely understood how protein clustering at the plasma membrane is initiated, maintained and controlled. Protein palmitoylation, a common post-translational modification, regulates protein targeting to the plasma membrane. Such modified proteins are enriched in these specialized membrane domains. In this review, we focus on palmitoylation of PSD-95, which is a major postsynaptic scaffolding protein and makes discrete postsynaptic nanodomains in a palmitoylation-dependent manner and discuss a determinant role of local palmitoylation cycles in creating highly localized hotspots at the membrane where specific proteins concentrate to organize functional domains.

scholarly journals Recent advances in combretastatin based derivatives and prodrugs as antimitotic agents

MedChemComm ◽  
2017 ◽  
Vol 8 (8) ◽  
pp. 1592-1603 ◽  
Author(s):  
Zaki S. Seddigi ◽  
M. Shaheer Malik ◽  
A Prasanth Saraswati ◽  
Saleh A. Ahmed ◽  
Ahmed O. Babalghith ◽  
...  
Keyword(s):  
Drug Development ◽  
Anticancer Drug ◽  
Crucial Role ◽  
Cellular Functions ◽  
Recent Advances ◽  
Promising Target ◽  
Anticancer Drug Development

The dynamic and crucial role of tubulin in different cellular functions rendered it a promising target in anticancer drug development.

scholarly journals Dengue virus non structural protein 1 disrupts the TGF-β/Smad signaling by utilizing E3 ligase Smurf2

2020 ◽  
Author(s):  
Anismrita Lahon ◽  
Ravi Arya ◽  
Vivek Kumar ◽  
Akhil Banerjea
Keyword(s):  
Dengue Virus ◽  
Virus Replication ◽  
Nuclear Translocation ◽  
E3 Ligase ◽  
Inhibitory Effect ◽  
Structural Protein ◽  
Cellular Functions ◽  
Smad Signaling

Abstract TGF-β signaling is tightly regulated to ensure cellular functions. Role of DENV on the TGF-β/Smad signaling has not been well established. Therefore, we aimed to study the association between DENV replication and TGF-β/Smad signaling. We observed impaired expression of Smad2/3/4 during DENV replication along with significant reduction in the expression of phosphorylated Smad3. Overexpression of Smad6/7 showed inhibitory effect on DENV replication. We observed DENV-NS1 not only physically interacts with Smad2/3/4 but also impaired their expression by utilizing Smurf2 E3 ligase. Co-immunoprecipitation of NS1 and Smurf2 suggests that NS1 may acts as a co-factor to escalate the lysosomal mediated degradation of Smads. Additionally we observed, NS1 is capable of blocking the nuclear translocation of Smad3 and thus further ensuring inhibition of Smad signaling. Therefore, our results confirm that DENV-NS1 interacts with Smads and reduces their expression that may favor in virus replication.

scholarly journals Ubiquitin-Specific Proteases: Players in Cancer Cellular Processes

2021 ◽  
Vol 14 (9) ◽  
pp. 848
Author(s):  
Lucas Cruz ◽  
Paula Soares ◽  
Marcelo Correia
Keyword(s):  
Protein Function ◽  
Deubiquitinating Enzymes ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Cellular Targets ◽  
Cellular Processes ◽  
Protein Ubiquitination ◽  
Damage Repair ◽  
Ubiquitin Molecule

Ubiquitination represents a post-translational modification (PTM) essential for the maintenance of cellular homeostasis. Ubiquitination is involved in the regulation of protein function, localization and turnover through the attachment of a ubiquitin molecule(s) to a target protein. Ubiquitination can be reversed through the action of deubiquitinating enzymes (DUBs). The DUB enzymes have the ability to remove the mono- or poly-ubiquitination signals and are involved in the maturation, recycling, editing and rearrangement of ubiquitin(s). Ubiquitin-specific proteases (USPs) are the biggest family of DUBs, responsible for numerous cellular functions through interactions with different cellular targets. Over the past few years, several studies have focused on the role of USPs in carcinogenesis, which has led to an increasing development of therapies based on USP inhibitors. In this review, we intend to describe different cellular functions, such as the cell cycle, DNA damage repair, chromatin remodeling and several signaling pathways, in which USPs are involved in the development or progression of cancer. In addition, we describe existing therapies that target the inhibition of USPs.

scholarly journals The Role of the Host Ubiquitin System in Promoting Replication of Emergent Viruses

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 369
Author(s):  
Karl M. Valerdi ◽  
Adam Hage ◽  
Sarah van van Tol ◽  
Ricardo Rajsbaum ◽  
Maria I. Giraldo
Keyword(s):  
Virus Replication ◽  
Defense Mechanism ◽  
Replication Cycle ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Emerging Viruses ◽  
Highly Pathogenic ◽  
Ubiquitin System ◽  
Pathogenic Viruses

Ubiquitination of proteins is a post-translational modification process with many different cellular functions, including protein stability, immune signaling, antiviral functions and virus replication. While ubiquitination of viral proteins can be used by the host as a defense mechanism by destroying the incoming pathogen, viruses have adapted to take advantage of this cellular process. The ubiquitin system can be hijacked by viruses to enhance various steps of the replication cycle and increase pathogenesis. Emerging viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), flaviviruses like Zika and dengue, as well as highly pathogenic viruses like Ebola and Nipah, have the ability to directly use the ubiquitination process to enhance their viral-replication cycle, and evade immune responses. Some of these mechanisms are conserved among different virus families, especially early during virus entry, providing an opportunity to develop broad-spectrum antivirals. Here, we discuss the mechanisms used by emergent viruses to exploit the host ubiquitin system, with the main focus on the role of ubiquitin in enhancing virus replication.

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