scholarly journals PTEN negatively regulates the cell lineage progression from NG2+ glial progenitor to oligodendrocyte via mTOR-independent signaling

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Estibaliz González-Fernández ◽  
Hey-Kyeong Jeong ◽  
Masahiro Fukaya ◽  
Hyukmin Kim ◽  
Rabia R Khawaja ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Cell Lineage ◽  
Axonal Damage ◽  
Independent Manner ◽  
Cns Disorders ◽  
Cns Repair ◽  
Downstream Signaling ◽  
Signaling Mechanisms ◽  
Cellular Stresses ◽  
Glial Progenitor

Oligodendrocytes (OLs), the myelin-forming CNS glia, are highly vulnerable to cellular stresses, and a severe myelin loss underlies numerous CNS disorders. Expedited OL regeneration may prevent further axonal damage and facilitate functional CNS repair. Although adult OL progenitors (OPCs) are the primary players for OL regeneration, targetable OPC-specific intracellular signaling mechanisms for facilitated OL regeneration remain elusive. Here, we report that OPC-targeted PTEN inactivation in the mouse, in contrast to OL-specific manipulations, markedly promotes OL differentiation and regeneration in the mature CNS. Unexpectedly, an additional deletion of mTOR did not reverse the enhanced OL development from PTEN-deficient OPCs. Instead, ablation of GSK3β, another downstream signaling molecule that is negatively regulated by PTEN-Akt, enhanced OL development. Our results suggest that PTEN persistently suppresses OL development in an mTOR-independent manner, and at least in part, via controlling GSK3β activity. OPC-targeted PTEN-GSK3β inactivation may benefit facilitated OL regeneration and myelin repair.

The Pleiotropic Intricacies of Hedgehog Signaling: From Craniofacial Patterning to Carcinogenesis

FACE ◽  
2021 ◽  
pp. 273250162110243
Author(s):  
Mikhail Pakvasa ◽  
Andrew B. Tucker ◽  
Timothy Shen ◽  
Tong-Chuan He ◽  
Russell R. Reid
Keyword(s):  
Intracellular Signaling ◽  
Limb Development ◽  
Hedgehog Signaling ◽  
Target Genes ◽  
Craniofacial Development ◽  
Signaling Cascade ◽  
Signaling Mechanisms ◽  
Intracellular Signaling Cascade ◽  
And Function

Hedgehog signaling was discovered more than 40 years ago in experiments demonstrating that it is a fundamental mediator of limb development. Since that time, it has been shown to be important in development, homeostasis, and disease. The hedgehog pathway proceeds through a pathway highly conserved throughout animals beginning with the extracellular diffusion of hedgehog ligands, proceeding through an intracellular signaling cascade, and ending with the activation of specific target genes. A vast amount of research has been done elucidating hedgehog signaling mechanisms and regulation. This research has found a complex system of genetics and signaling that helps determine how organisms develop and function. This review provides an overview of what is known about hedgehog genetics and signaling, followed by an in-depth discussion of the role of hedgehog signaling in craniofacial development and carcinogenesis.

scholarly journals Immunoregulatory Property of C-Type Lectin-Like Receptors in Fibrosing Interstitial Lung Diseases

2020 ◽  
Vol 21 (10) ◽  
pp. 3665
Author(s):  
Wiwin Is Effendi ◽  
Tatsuya Nagano ◽  
Helmia Hasan ◽  
Resti Yudhawati
Keyword(s):  
Immune System ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Lung Diseases ◽  
Wound Repair ◽  
Tissue Injury ◽  
Interstitial Lung Diseases ◽  
Downstream Signaling ◽  
Cytokine Activation ◽  
Immune Impairment

The innate immune system identifies exogenous threats or endogenous stress through germline-encoded receptors called pattern recognition receptors (PRRs) that initiate consecutive downstream signaling pathways to control immune responses. However, the contribution of the immune system and inflammation to fibrosing interstitial lung diseases (ILD) remains poorly understood. Immunoreceptor tyrosine-based motif-bearing C-type lectin-like receptors (CTLRs) may interact with various immune cells during tissue injury and wound repair processes. Dectin-1 is a CTLR with dominant mechanisms manifested through its intracellular signaling cascades, which regulate fibrosis-promoting properties through gene transcription and cytokine activation. Additionally, immune impairment in ILD facilitates microbiome colonization; hence, Dectin-1 is the master protector in host pulmonary defense against fungal invasion. Recent progress in determining the signaling pathways that control the balance of fibrosis has implicated immunoreceptor tyrosine-based motif-bearing CTLRs as being involved, either directly or indirectly, in the pathogenesis of fibrosing ILD.

scholarly journals On demand MyD88 oligomerization is controlled by IRAK4 during Myddosome signaling

2020 ◽  
Author(s):  
Rafael Deliz-Aguirre ◽  
Fakun Cao ◽  
Fenja H. U. Gerpott ◽  
Nichanok Auevechanichkul ◽  
Mariam Chupanova ◽  
...  
Keyword(s):  
Self Assembly ◽  
Intracellular Signaling ◽  
Innate Immune ◽  
Live Cells ◽  
Signaling Proteins ◽  
Protein Oligomerization ◽  
Downstream Signaling ◽  
Oligomeric Complex ◽  
Mechanistic Basis ◽  
Cell Signaling Pathways

AbstractA recurring feature of innate immune receptor signaling is the self-assembly of signaling proteins into oligomeric complexes. The Myddosome is an oligomeric complex that is required to transmit inflammatory signals from TLR/IL1Rs and consists of MyD88 and IRAK family kinases. However, the molecular basis for how Myddosome proteins self-assemble and regulate intracellular signaling remains poorly understood. Here, we developed a novel assay to analyze the spatiotemporal dynamics of IL1R and Myddosome signaling in live cells. We found that MyD88 oligomerization is inducible and initially reversible. Moreover, the formation of larger, stable oligomers consisting of more than 4 MyD88s triggers the sequential recruitment of IRAK4 and IRAK1. Notably, genetic knockout of IRAK4 enhanced MyD88 oligomerization, indicating that IRAK4 controls MyD88 oligomer size and growth. MyD88 oligomer size thus functions as a physical threshold to trigger downstream signaling. These results provide a mechanistic basis for how protein oligomerization might function in cell signaling pathways.

Abstract 140: Anti-inflammatory and Anti-atherogenic Role of Bmp Receptor II In Endothelial Cells

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Chanwoo Kim ◽  
Hannah Song ◽  
Sandeep Kumar ◽  
Douglas Nam ◽  
Hyuk Sang Kwon ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Intracellular Signaling ◽  
Independent Manner ◽  
Disturbed Flow ◽  
Bmp Receptors ◽  
Endothelial Inflammation ◽  
Anti Inflammatory

Atherosclerosis is a multifactorial disease that arises from a combination of endothelial dysfunction and inflammation, occurring preferentially in arterial regions exposed to disturbed flow. Bone morphogenic protein-4 (BMP4) produced by disturbed flow induces inflammation, endothelial dysfunction and hypertension, suggesting the importance of BMPs in vascular biology and disease. BMPs bind to two different types of BMP receptors (BMPRI and II) to instigate intracellular signaling. Increasing evidences suggest a correlative role of BMP4 and atherosclerosis, but the role of BMP receptors especially BMPRII in atherosclerosis is still unclear and whether knockdown of BMPRII is the cause or the consequence of atherosclerosis is still not known. It is therefore, imperative to investigate the mechanisms by which BMPRII expression is modulated and its ramifications in atherosclerosis. Initially, we expected that knockdown of BMPRII will result in loss of pro-atherogenic BMP4 signaling and will thereby prevent atherosclerosis. Contrarily, we found that loss of BMPRII expression causes endothelial inflammation and atherosclerosis. Using BMPRII siRNA and BMPRII +/- mice, we found that BMPRII knockdown induces endothelial inflammation in a BMP-independent manner via mechanisms involving reactive oxygen species (ROS), NFκB, and NADPH oxidases. Further, BMPRII +/- ApoE -/- mice develop accelerated atherosclerosis compared to BMPRII +/+ ApoE -/- mice, suggesting loss of BMPRII may induce atherosclerosis. Interestingly, we found that multiple pro-atherogenic stimuli such as hypercholesterolemia, disturbed flow, pro-hypertensive angiotensin II, and pro-inflammatory cytokine, TNFα, downregulate BMPRII expression in endothelium, while anti-atherogenic stimuli such as stable flow and statin treatment upregulate its expression, both in vivo and in vitro . Moreover, we found that BMPRII expression is significantly diminished in human coronary advanced atherosclerotic lesions. These results suggest that BMPRII is a critical, anti-inflammatory and anti-atherogenic protein that is commonly targeted by multiple pro- and anti-atherogenic factors. BMPRII could be used as a novel diagnostic and therapeutic target in atherosclerosis.

Okadaic acid, a phosphatase inhibitor, decreases macrophage motility

1991 ◽  
Vol 260 (2) ◽  
pp. L105-L112 ◽  
Author(s):  
A. K. Wilson ◽  
A. Takai ◽  
J. C. Ruegg ◽  
P. de Lanerolle
Keyword(s):  
Protein Phosphorylation ◽  
Okadaic Acid ◽  
Light Chain ◽  
Intracellular Signaling ◽  
Mammalian Cells ◽  
Morphological Changes ◽  
Phosphoprotein Phosphatase ◽  
Phosphatase Inhibitor ◽  
Signaling Mechanisms ◽  
Dose Dependent

Cellular locomotion results from a series of spatially and temporally integrated reactions. The coordinated regulation of these reactions requires sensitive intracellular signaling mechanisms. Because protein phosphorylation reactions represent important signaling mechanisms in mammalian cells, we investigated the effect of okadaic acid, a phosphoprotein phosphatase inhibitor, on protein phosphorylation and macrophage motility. Okadaic acid was applied to rat alveolar macrophages, and motility was quantitated by a directed chemotaxis assay. Okadaic acid inhibits macrophage motility in a dose-dependent fashion; the concentrations for 50 and 100% inhibition were 3 and 25 microM, respectively. Protein phosphorylation studies demonstrated a 2.5-fold increase in total protein phosphorylation in macrophages treated with 25 microM okadaic acid. These experiments also demonstrated a dose-dependent increase in the phosphorylation of the 20-kDa light chain of myosin. Moreover, 25 microM okadaic acid 1) maximally increased myosin light chain phosphorylation by 6.6-fold, 2) raised the level of myosin associated with the cytoskeleton from a basal level of 47.0 to 96.7% of the total myosin, and 3) induced profound morphological changes as visualized by scanning electron microscopy. These data correlate an increase in protein phosphorylation with a decrease in macrophage motility. Furthermore, they suggest that phosphoprotein phosphatase inhibition may prevent motility by uncoupling coordinated processes, such as cytoskeletal reorganization, that are essential for macrophage motility.

scholarly journals Phosphoproteomic quantitation and causal analysis reveal pathways in GPVI/ITAM-mediated platelet activation programs

Blood ◽  
2020 ◽  
Vol 136 (20) ◽  
pp. 2346-2358 ◽  
Author(s):  
Özgün Babur ◽  
Alexander R. Melrose ◽  
Jennifer M. Cunliffe ◽  
John Klimek ◽  
Jiaqing Pang ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Intracellular Signaling ◽  
Vascular Inflammation ◽  
Functional Screening ◽  
Tandem Mass ◽  
Rab Gtpases ◽  
Platelet Surface ◽  
Form And Function ◽  
Signaling Mechanisms ◽  
And Function

Abstract Platelets engage cues of pending vascular injury through coordinated adhesion, secretion, and aggregation responses. These rapid, progressive changes in platelet form and function are orchestrated downstream of specific receptors on the platelet surface and through intracellular signaling mechanisms that remain systematically undefined. This study brings together cell physiological and phosphoproteomics methods to profile signaling mechanisms downstream of the immunotyrosine activation motif (ITAM) platelet collagen receptor GPVI. Peptide tandem mass tag (TMT) labeling, sample multiplexing, synchronous precursor selection (SPS), and triple stage tandem mass spectrometry (MS3) detected >3000 significant (false discovery rate < 0.05) phosphorylation events on >1300 proteins over conditions initiating and progressing GPVI-mediated platelet activation. With literature-guided causal inference tools, >300 site-specific signaling relations were mapped from phosphoproteomics data among key and emerging GPVI effectors (ie, FcRγ, Syk, PLCγ2, PKCδ, DAPP1). Through signaling validation studies and functional screening, other less-characterized targets were also considered within the context of GPVI/ITAM pathways, including Ras/MAPK axis proteins (ie, KSR1, SOS1, STAT1, Hsp27). Highly regulated GPVI/ITAM targets out of context of curated knowledge were also illuminated, including a system of >40 Rab GTPases and associated regulatory proteins, where GPVI-mediated Rab7 S72 phosphorylation and endolysosomal maturation were blocked by TAK1 inhibition. In addition to serving as a model for generating and testing hypotheses from omics datasets, this study puts forth a means to identify hemostatic effectors, biomarkers, and therapeutic targets relevant to thrombosis, vascular inflammation, and other platelet-associated disease states.

scholarly journals THE ROLE OF SYNAPSIN I IN INTRACELLULAR SIGNALING MECHANISMS UNDERLIES EXERCISE-INDUCED IMPROVEMENT IN SOCIAL MEMORY: A SYSTEMATIC REVIEW

2017 ◽  
Vol 10 (9) ◽  
pp. 88
Author(s):  
Ria Margiana ◽  
Akmal Primadian Suprapto
Keyword(s):  
Cell Signaling ◽  
Intracellular Signaling ◽  
Laboratory Experiments ◽  
Biological Function ◽  
Social Memory ◽  
Synapsin I ◽  
Signaling Mechanism ◽  
Signaling Mechanisms ◽  
Exercise Induced

  Objective: Intracellular signaling mechanism is an important biological function, as scholars continue to seek new ways of improving social memory. Researchers have conducted several studies on the role of synapsin I in intracellular signaling mechanism. This study assessed the empirical evidence that shows the role of synapsin I in intracellular signaling mechanism with the aim of achieving exercise-induced improvement in social memory.Methods: Nine previously conducted researches were reviewed in this paper. The included studies were controlled laboratory experiments involving mice as the subjects.Results: Although the studies included were done in different timelines, the researchers agreed in unison that synapsin I plays a crucial role in cell signaling. The outcome of the practical studies was vital in understanding function and physiology of human cells, which is fundamental in science and human anatomy.Conclusion: In particular, the findings shows how exercise can improve social memory by triggering the intracellular signaling mechanism. The limited number of studies addressing the topic of intracellular cell signaling suggests that more study is needed to provide more evidence on the issue.

Factors controlling ovarian apoptosis

2000 ◽  
Vol 78 (12) ◽  
pp. 1003-1012 ◽  
Author(s):  
C V Andreu-Vieyra ◽  
H R Habibi
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Intestinal Epithelium ◽  
Intracellular Signaling ◽  
Adult Tissue ◽  
Hematopoietic System ◽  
Apoptotic Process ◽  
Signaling Mechanisms ◽  
Biochemical Features

Apoptosis is a form of programmed cell death that is essential for the development of the embryo and adult tissue plasticity. In adults, it is observed mainly in those tissues undergoing active differentiation such as the hematopoietic system, testis, ovary, and intestinal epithelium. Apoptosis can be triggered by many factors, such as hormones, cytokines, and drugs, depending on the type of the cell. While the intracellular signaling mechanisms may vary in different cells, they all display similar morphological and biochemical features at the later stages of the apoptotic process. This review focuses on the factors controlling ovarian apoptosis, emphasizing observations made on GnRH-induced apoptotic process in goldfish follicles.Key words: apoptosis, ovary, GnRH.

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