The Multifaceted Roles of USP15 in Signal Transduction

Ubiquitination and deubiquitination are protein post-translational modification processes that have been recognized as crucial mediators of many complex cellular networks, including maintaining ubiquitin homeostasis, controlling protein stability, and regulating several signaling pathways. Therefore, some of the enzymes involved in ubiquitination and deubiquitination, particularly E3 ligases and deubiquitinases, have attracted attention for drug discovery. Here, we review recent findings on USP15, one of the deubiquitinases, which regulates diverse signaling pathways by deubiquitinating vital target proteins. Even though several basic previous studies have uncovered the versatile roles of USP15 in different signaling networks, those have not yet been systematically and specifically reviewed, which can provide important information about possible disease markers and clinical applications. This review will provide a comprehensive overview of our current understanding of the regulatory mechanisms of USP15 on different signaling pathways for which dynamic reverse ubiquitination is a key regulator.

Download Full-text

Signaling-based neural networks for cellular computation

10.1101/2020.11.10.377077 ◽

2020 ◽

Author(s):

Christian Cuba Samaniego ◽

Andrew Moorman ◽

Giulia Giordano ◽

Elisa Franco

Keyword(s):

Neural Networks ◽

Decision Making ◽

Steady State ◽

Stability Analysis ◽

Signaling Pathways ◽

Signaling Networks ◽

Activation Functions ◽

Post Translational Modification ◽

Linear Classifiers ◽

Cellular Computation

AbstractCellular signaling pathways are responsible for decision making that sustains life. Most signaling pathways include post-translational modification cycles, that process multiple inputs and are tightly interconnected. Here we consider a model for phosphorylation/dephosphorylation cycles, and we show that under some assumptions they can operate as molecular neurons or perceptrons, that generate sigmoidal-like activation functions by processing sums of inputs with positive and negative weights. We carry out a steady-state and structural stability analysis for single molecular perceptrons as well as for feedforward interconnections, concluding that interconnected phosphorylation/dephosphorylation cycles may work as multi-layer biomolecular neural networks (BNNs) with the capacity to perform a variety of computations. As an application, we design signaling networks that behave as linear and non-linear classifiers.

Download Full-text

Review of Progress in Predicting Protein Methylation Sites

Current Organic Chemistry ◽

10.2174/1385272823666190723141347 ◽

2019 ◽

Vol 23 (15) ◽

pp. 1663-1670 ◽

Cited By ~ 1

Author(s):

Chunyan Ao ◽

Shunshan Jin ◽

Yuan Lin ◽

Quan Zou

Keyword(s):

Gene Expression ◽

Signal Transduction ◽

Transcriptional Activity ◽

Regulation Of Gene Expression ◽

Protein Methylation ◽

Biological Processes ◽

Post Translational Modification ◽

Regulatory Enzymes ◽

Lysine Residues ◽

Arginine Residues

Protein methylation is an important and reversible post-translational modification that regulates many biological processes in cells. It occurs mainly on lysine and arginine residues and involves many important biological processes, including transcriptional activity, signal transduction, and the regulation of gene expression. Protein methylation and its regulatory enzymes are related to a variety of human diseases, so improved identification of methylation sites is useful for designing drugs for a variety of related diseases. In this review, we systematically summarize and analyze the tools used for the prediction of protein methylation sites on arginine and lysine residues over the last decade.

Download Full-text

cROStalk for Life: Uncovering ROS Signaling in Plants and Animal Systems, from Gametogenesis to Early Embryonic Development

Genes ◽

10.3390/genes12040525 ◽

2021 ◽

Vol 12 (4) ◽

pp. 525

Author(s):

Valentina Lodde ◽

Piero Morandini ◽

Alex Costa ◽

Irene Murgia ◽

Ignacio Ezquer

Keyword(s):

Signal Transduction ◽

Signaling Pathways ◽

Analytical Techniques ◽

Antioxidant Systems ◽

Developmental Studies ◽

Science Field ◽

Ros Signaling ◽

Reproductive Processes

This review explores the role of reactive oxygen species (ROS)/Ca2+ in communication within reproductive structures in plants and animals. Many concepts have been described during the last years regarding how biosynthesis, generation products, antioxidant systems, and signal transduction involve ROS signaling, as well as its possible link with developmental processes and response to biotic and abiotic stresses. In this review, we first addressed classic key concepts in ROS and Ca2+ signaling in plants, both at the subcellular, cellular, and organ level. In the plant science field, during the last decades, new techniques have facilitated the in vivo monitoring of ROS signaling cascades. We will describe these powerful techniques in plants and compare them to those existing in animals. Development of new analytical techniques will facilitate the understanding of ROS signaling and their signal transduction pathways in plants and mammals. Many among those signaling pathways already have been studied in animals; therefore, a specific effort should be made to integrate this knowledge into plant biology. We here discuss examples of how changes in the ROS and Ca2+ signaling pathways can affect differentiation processes in plants, focusing specifically on reproductive processes where the ROS and Ca2+ signaling pathways influence the gametophyte functioning, sexual reproduction, and embryo formation in plants and animals. The study field regarding the role of ROS and Ca2+ in signal transduction is evolving continuously, which is why we reviewed the recent literature and propose here the potential targets affecting ROS in reproductive processes. We discuss the opportunities to integrate comparative developmental studies and experimental approaches into studies on the role of ROS/ Ca2+ in both plant and animal developmental biology studies, to further elucidate these crucial signaling pathways.

Download Full-text

Targeting the Ubiquitin Signaling Cascade in Tumor Microenvironment for Cancer Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms22020791 ◽

2021 ◽

Vol 22 (2) ◽

pp. 791

Author(s):

Qi Liu ◽

Bayonle Aminu ◽

Olivia Roscow ◽

Wei Zhang

Keyword(s):

Tumor Microenvironment ◽

Cancer Therapy ◽

Therapeutic Agents ◽

Biological Processes ◽

Post Translational Modification ◽

E3 Ligases ◽

Tumor Microenvironments ◽

Cellular Immune ◽

Ubiquitin Conjugating Enzymes ◽

Cellular Components

Tumor microenvironments are composed of a myriad of elements, both cellular (immune cells, cancer-associated fibroblasts, mesenchymal stem cells, etc.) and non-cellular (extracellular matrix, cytokines, growth factors, etc.), which collectively provide a permissive environment enabling tumor progression. In this review, we focused on the regulation of tumor microenvironment through ubiquitination. Ubiquitination is a reversible protein post-translational modification that regulates various key biological processes, whereby ubiquitin is attached to substrates through a catalytic cascade coordinated by multiple enzymes, including E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes and E3 ubiquitin ligases. In contrast, ubiquitin can be removed by deubiquitinases in the process of deubiquitination. Here, we discuss the roles of E3 ligases and deubiquitinases as modulators of both cellular and non-cellular components in tumor microenvironment, providing potential therapeutic targets for cancer therapy. Finally, we introduced several emerging technologies that can be utilized to develop effective therapeutic agents for targeting tumor microenvironment.

Download Full-text

Comparison of SYK Signaling Networks Reveals the Potential Molecular Determinants of Its Tumor-Promoting and Suppressing Functions

Biomolecules ◽

10.3390/biom11020308 ◽

2021 ◽

Vol 11 (2) ◽

pp. 308

Author(s):

Marion Buffard ◽

Aurélien Naldi ◽

Gilles Freiss ◽

Marcel Deckert ◽

Ovidiu Radulescu ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Suppressor ◽

Signaling Pathways ◽

Burkitt Lymphoma ◽

Molecular Mechanisms ◽

Signal Propagation ◽

Tumor Formation ◽

Tissue Type ◽

Signaling Networks ◽

Proteomic Profiling

Spleen tyrosine kinase (SYK) can behave as an oncogene or a tumor suppressor, depending on the cell and tissue type. As pharmacological SYK inhibitors are currently evaluated in clinical trials, it is important to gain more information on the molecular mechanisms underpinning these opposite roles. To this aim, we reconstructed and compared its signaling networks using phosphoproteomic data from breast cancer and Burkitt lymphoma cell lines where SYK behaves as a tumor suppressor and promoter. Bioinformatic analyses allowed for unveiling the main differences in signaling pathways, network topology and signal propagation from SYK to its potential effectors. In breast cancer cells, the SYK target-enriched signaling pathways included intercellular adhesion and Hippo signaling components that are often linked to tumor suppression. In Burkitt lymphoma cells, the SYK target-enriched signaling pathways included molecules that could play a role in SYK pro-oncogenic function in B-cell lymphomas. Several protein interactions were profoundly rewired in the breast cancer network compared with the Burkitt lymphoma network. These data demonstrate that proteomic profiling combined with mathematical network modeling allows untangling complex pathway interplays and revealing difficult to discern interactions among the SYK pathways that positively and negatively affect tumor formation and progression.

Download Full-text

Advances in the Development Ubiquitin-Specific Peptidase (USP) Inhibitors

International Journal of Molecular Sciences ◽

10.3390/ijms22094546 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4546

Author(s):

Shiyao Chen ◽

Yunqi Liu ◽

Huchen Zhou

Keyword(s):

Signaling Pathways ◽

Transforming Growth Factor ◽

Regulatory System ◽

Transforming Growth Factor Β ◽

Molecular Signaling ◽

Post Translational Modification ◽

The Past ◽

Damage Repair ◽

Wide Range ◽

Cancer And Inflammation

Ubiquitylation and deubiquitylation are reversible protein post-translational modification (PTM) processes involving the regulation of protein degradation under physiological conditions. Loss of balance in this regulatory system can lead to a wide range of diseases, such as cancer and inflammation. As the main members of the deubiquitinases (DUBs) family, ubiquitin-specific peptidases (USPs) are closely related to biological processes through a variety of molecular signaling pathways, including DNA damage repair, p53 and transforming growth factor-β (TGF-β) pathways. Over the past decade, increasing attention has been drawn to USPs as potential targets for the development of therapeutics across diverse therapeutic areas. In this review, we summarize the crucial roles of USPs in different signaling pathways and focus on advances in the development of USP inhibitors, as well as the methods of screening and identifying USP inhibitors.

Download Full-text

MicroRNA-Assisted Hormone Cell Signaling in Colorectal Cancer Resistance

Cells ◽

10.3390/cells10010039 ◽

2020 ◽

Vol 10 (1) ◽

pp. 39

Author(s):

Crescenzo Massaro ◽

Elham Safadeh ◽

Giulia Sgueglia ◽

Hendrik G. Stunnenberg ◽

Lucia Altucci ◽

...

Keyword(s):

Colorectal Cancer ◽

Drug Resistance ◽

Signaling Pathways ◽

Cancer Progression ◽

Therapy Resistance ◽

Disease Recurrence ◽

Hormone Signaling ◽

Cancer Resistance ◽

Comprehensive Overview ◽

Substantial Progress

Despite substantial progress in cancer therapy, colorectal cancer (CRC) is still the third leading cause of cancer death worldwide, mainly due to the acquisition of resistance and disease recurrence in patients. Growing evidence indicates that deregulation of hormone signaling pathways and their cross-talk with other signaling cascades inside CRC cells may have an impact on therapy resistance. MicroRNAs (miRNAs) are small conserved non-coding RNAs thatfunction as negative regulators in many gene expression processes. Key studies have identified miRNA alterations in cancer progression and drug resistance. In this review, we provide a comprehensive overview and assessment of miRNAs role in hormone signaling pathways in CRC drug resistance and their potential as future targets for overcoming resistance to treatment.

Download Full-text

Modulation of Bovine Endometrial Cell Receptors and Signaling Pathways as a Nanotherapeutic Exploration against Dairy Cow Postpartum Endometritis

Animals ◽

10.3390/ani11061516 ◽

2021 ◽

Vol 11 (6) ◽

pp. 1516

Author(s):

Ayodele Olaolu Oladejo ◽

Yajuan Li ◽

Xiaohu Wu ◽

Bereket Habte Imam ◽

Jie Yang ◽

...

Keyword(s):

Signal Transduction ◽

Signaling Pathways ◽

Inflammatory Cytokines ◽

Signal Transduction Pathway ◽

Endometrial Cell ◽

Cell Receptors ◽

Endometrial Cells ◽

Microbial Invasion ◽

Pass Through ◽

Pro Inflammatory Cytokines

In order to control and prevent bovine endometritis, there is a need to understand the molecular pathogenesis of the infectious disease. Bovine endometrium is usually invaded by a massive mobilization of microorganisms, especially bacteria, during postpartum dairy cows. Several reports have implicated the Gram-negative bacteria in the pathogenesis of bovine endometritis, with information dearth on the potentials of Gram-positive bacteria and their endotoxins. The invasive bacteria and their ligands pass through cellular receptors such as TLRs, NLRs, and biomolecular proteins of cells activate the specific receptors, which spontaneously stimulates cellular signaling pathways like MAPK, NF-kB and sequentially triggers upregulation of pro-inflammatory cytokines. The cascade of inflammatory induction involves a dual signaling pathway; the transcription factor NF-κB is released from its inhibitory molecule and can bind to various inflammatory genes promoter. The MAPK pathways are concomitantly activated, leading to specific phosphorylation of the NF-κB. The provision of detailed information on the molecular pathomechanism of bovine endometritis with the interaction between host endometrial cells and invasive bacteria in this review would widen the gap of exploring the potential of receptors and signal transduction pathways in nanotechnology-based drug delivery system. The nanotherapeutic discovery of endometrial cell receptors, signal transduction pathway, and cell biomolecules inhibitors could be developed for strategic inhibition of infectious signals at the various cell receptors and signal transduction levels, interfering on transcription factors activation and pro-inflammatory cytokines and genes expression, which may significantly protect endometrium against postpartum microbial invasion.

Download Full-text

Heparan Sulfate Proteoglycan Sulfation Regulates Uterine Differentiation and Signaling During Embryo Implantation

Endocrinology ◽

10.1210/en.2018-00105 ◽

2018 ◽

Vol 159 (6) ◽

pp. 2459-2472 ◽

Cited By ~ 2

Author(s):

Yan Yin ◽

Adam Wang ◽

Li Feng ◽

Yu Wang ◽

Hong Zhang ◽

...

Keyword(s):

Signal Transduction ◽

Heparan Sulfate ◽

Signaling Pathways ◽

Reproductive Tract ◽

Ovarian Function ◽

Embryo Implantation ◽

Uterine Epithelium ◽

Female Reproductive Tract ◽

Uterine Receptivity ◽

Mouse Uterus

Abstract To prepare for embryo implantation, the uterus must undergo a series of reciprocal interactions between the uterine epithelium and the underlying stroma, which are orchestrated by ovarian hormones. During this process, multiple signaling pathways are activated to direct cell proliferation and differentiation, which render the uterus receptive to the implanting blastocysts. One important modulator of these signaling pathways is the cell surface and extracellular matrix macromolecules, heparan sulfate proteoglycans (HSPGs). HSPGs play crucial roles in signal transduction by regulating morphogen transport and ligand binding. In this study, we examine the role of HSPG sulfation in regulating uterine receptivity by conditionally deleting the N-deacetylase/N-sulfotransferase (NDST) 1 gene (Ndst1) in the mouse uterus using the Pgr-Cre driver, on an Ndst2- and Ndst3-null genetic background. Although development of the female reproductive tract and subsequent ovarian function appear normal in Ndst triple-knockout females, they are infertile due to implantation defects. Embryo attachment appears to occur but the uterine epithelium at the site of implantation persists rather than disintegrates in the mutant. Uterine epithelial cells continued to proliferate past day 4 of pregnancy, accompanied by elevated Fgf2 and Fgf9 expression, whereas uterine stroma failed to undergo decidualization, as evidenced by lack of Bmp2 induction. Despite normal Indian hedgehog expression, transcripts of Ptch1 and Gli1, both components as well as targets of the hedgehog (Hh) pathway, were detected only in the subepithelial stroma, indicating altered Hh signaling in the mutant uterus. Taken together, these data implicate an essential role for HSPGs in modulating signal transduction during mouse implantation.

Download Full-text

Mechanical signal transduction in skeletal muscle growth and adaptation

Journal of Applied Physiology ◽

10.1152/japplphysiol.01178.2004 ◽

2005 ◽

Vol 98 (5) ◽

pp. 1900-1908 ◽

Cited By ~ 103

Author(s):

James G. Tidball

Keyword(s):

Skeletal Muscle ◽

Signal Transduction ◽

Mechanical Activation ◽

Signaling Pathways ◽

Mechanical Stimulation ◽

Muscle Growth ◽

Mammalian Target Of Rapamycin ◽

Target Of Rapamycin ◽

Mechanical Signal ◽

Igf I

The adaptability of skeletal muscle to changes in the mechanical environment has been well characterized at the tissue and system levels, but the mechanisms through which mechanical signals are transduced to chemical signals that influence muscle growth and metabolism remain largely unidentified. However, several findings have suggested that mechanical signal transduction in muscle may occur through signaling pathways that are shared with insulin-like growth factor (IGF)-I. The involvement of IGF-I-mediated signaling for mechanical signal transduction in muscle was originally suggested by the observations that muscle releases IGF-I on mechanical stimulation, that IGF-I is a potent agent for promoting muscle growth and affecting phenotype, and that IGF-I can function as an autocrine hormone in muscle. Accumulating evidence shows that at least two signaling pathways downstream of IGF-I binding can influence muscle growth and adaptation. Signaling via the calcineurin/nuclear factor of activated T-cell pathway has been shown to have a powerful influence on promoting the slow/type I phenotype in muscle but can also increase muscle mass. Neural stimulation of muscle can activate this pathway, although whether neural activation of the pathway can occur independent of mechanical activation or independent of IGF-I-mediated signaling remains to be explored. Signaling via the Akt/mammalian target of rapamycin pathway can also increase muscle growth, and recent findings show that activation of this pathway can occur as a response to mechanical stimulation applied directly to muscle cells, independent of signals derived from other cells. In addition, mechanical activation of mammalian target of rapamycin, Akt, and other downstream signals is apparently independent of autocrine factors, which suggests that activation of the mechanical pathway occurs independent of muscle-mediated IGF-I release.

Download Full-text