scholarly journals The molecular, cellular and pathophysiological roles of iRhom pseudoproteases

Open Biology ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 190003 ◽  
Author(s):  
Iqbal Dulloo ◽  
Sonia Muliyil ◽  
Matthew Freeman
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Molecular Mechanisms ◽  
Cellular Mechanisms ◽  
Central Function ◽  
Full Extent ◽  
Intramembrane Proteases ◽  
Growing Body ◽  
Growth Factor Signalling ◽  
The Stability

iRhom proteins are catalytically inactive relatives of rhomboid intramembrane proteases. There is a rapidly growing body of evidence that these pseudoenzymes have a central function in regulating inflammatory and growth factor signalling and consequent roles in many diseases. iRhom pseudoproteases have evolved new domains from their proteolytic ancestors, which are integral to their modular regulation and functions. Although we cannot yet conclude the full extent of their molecular and cellular mechanisms, there is a clearly emerging theme that they regulate the stability and trafficking of other membrane proteins. In the best understood case, iRhoms act as regulatory cofactors of the ADAM17 protease, controlling its function of shedding cytokines and growth factors. It seems likely that as the involvement of iRhoms in human diseases is increasingly recognized, they will become the focus of pharmaceutical interest, and here we discuss what is known about their molecular mechanisms and relevance in known pathologies.

scholarly journals BASIC FIBROBLAST GROWTH FACTOR AND ADIPONECTIN IN ADOLESCENCE WITH JUVENILE IDIOPATHIC ARTHRITIS TREATED WITH METHOTREXATE

2020 ◽  
Vol 4 ◽  
pp. 70-76
Author(s):  
Liudmyla Parkhomenko ◽  
Larysa Strashok ◽  
Olga Pavlova
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Molecular Mechanisms ◽  
Fibroblast Growth ◽  
Cellular Mechanisms ◽  
Reactive Protein ◽  
Study Results ◽  
Methotrexate Dose

Methotrexate has been applied clinically for juvenile idiopathic arthritis (JIA) treatment for decades. It is recommended for use globally, according all modern guidelines. Despite the fact that fibrosis molecular mechanisms as well as methotrexate (MTX) elimination and fibrosis indexes were studied a lot there is still not enough information for adolescence. Adiponectin, fibroblast growth factor and fibrosis indexes in adolescents with JIA treated with methotrexate were studied in this work. The aim was to study dynamics of molecular-cellular mechanisms activation of fibrotic processes development in the liver in adolescents with juvenile idiopathic arthritis treated with methotrexate. Materials and methods: A total of 68 children with juvenile idiopathic arthritis, were enrolled in the study. 25 boys (36.8 %) and 43 girls (63.2 %) were examined. Children were divided into three groups in accordance with the methotrexate dose. The following data were analyzed: ESR (mm/hour), C-reactive protein (mg/l), Hemolytic activity (CU), circulating immune complexes, (g/l), ALT (U/l), AST (U/l), Adiponectin (mcg/ml), BFGF (pg/ml), APRI index, FIB-4 Score. Results: According to our results when patients start using MTX they have significantly positive effect. Therefore, when analyzing all parameters liver pathologies may occur before MTX use. When MTX used, its proinflammation and antifibrotic effects lead to normalization of all organs and systems, as well as joints and liver. Also, long-term MTX use can lead to adverse effects. Conclusions: So, it is important to control possible liver disorders in adolescence treated with MTX. According to our study results we find out that there are decreasing of liver damage parameters in patients which started using MTX.

Dual regulation of transcription factor Nrf2 by Keap1 and by the combined actions of β-TrCP and GSK-3

2015 ◽  
Vol 43 (4) ◽  
pp. 611-620 ◽  
Author(s):  
John D. Hayes ◽  
Sudhir Chowdhry ◽  
Albena T. Dinkova-Kostova ◽  
Calum Sutherland
Keyword(s):  
Transcription Factor ◽  
Growth Factors ◽  
Ubiquitin Ligase ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Proteasomal Degradation ◽  
Regulation Of Transcription ◽  
Related Factor ◽  
Nrf2 Target Gene ◽  
The Stability

Nuclear factor-erythroid 2 p45 (NF-E2 p45)-related factor 2 (Nrf2) is a master regulator of redox homoeostasis that allows cells to adapt to oxidative stress and also promotes cell proliferation. In this review, we describe the molecular mechanisms by which oxidants/electrophilic agents and growth factors increase Nrf2 activity. In the former case, oxidants/electrophiles increase the stability of Nrf2 by antagonizing the ability of Kelch-like ECH-associated protein 1 (Keap1) to target the transcription factor for proteasomal degradation via the cullin-3 (Cul3)–RING ubiquitin ligase CRLKeap1. In the latter case, we speculate that growth factors increase the stability of Nrf2 by stimulating phosphoinositide 3-kinase (PI3K)−protein kinase B (PKB)/Akt signalling, which in turn results in inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) and in doing so prevents the formation of a DSGIS motif-containing phosphodegron in Nrf2 that is recognized by the β-transducin repeat-containing protein (β-TrCP) Cul1-based E3 ubiquitin ligase complex SCFβ-TrCP. We present data showing that in the absence of Keap1, the electrophile tert-butyl hydroquinone (tBHQ) can stimulate Nrf2 activity and induce the Nrf2-target gene NAD(P)H:quinone oxidoreductase-1 (NQO1), whilst simultaneously causing inhibitory phosphorylation of GSK-3β at Ser9. Together, these observations suggest that tBHQ can suppress the ability of SCFβ-TrCP to target Nrf2 for proteasomal degradation by increasing PI3K−PKB/Akt signalling. We also propose a scheme that explains how other protein kinases that inhibit GSK-3 could stimulate induction of Nrf2-target genes by preventing formation of the DSGIS motif-containing phosphodegron in Nrf2.

Cracking the mild, difficult and fiendish codes within and downstream of the EGFR to link diagnostics and therapeutics

2007 ◽  
Vol 35 (1) ◽  
pp. 1-6 ◽  
Author(s):  
M. Waterfield
Keyword(s):  
Signal Transduction ◽  
Growth Factors ◽  
Growth Factor ◽  
Signalling Pathways ◽  
Growth Factor Signalling ◽  
Transduction Mechanisms

Over the last 45 years, I have been working on growth factors, their receptors and signal transduction mechanisms. This period has seen a tremendous growth in knowledge and technology, and all of this, together with a focus interest in oncology, has steered me along a path designed to understand growth factor signalling so that we can see how drugs that target signalling pathways might be able to control cancer. The knowledge that we already have is likely to lead to cures for many common cancers within the next 25 years.

scholarly journals Endosomal receptor kinetics determine the stability of intracellular growth factor signalling complexes

2007 ◽  
Vol 402 (3) ◽  
pp. 537-549 ◽  
Author(s):  
A. Rami Tzafriri ◽  
Elazer R. Edelman
Keyword(s):  
Growth Factor ◽  
Cell Surface ◽  
Dissociation Constant ◽  
Specific Binding ◽  
Ph Dependence ◽  
Growth Factor Receptor ◽  
Factor Binding ◽  
Receptor Complexes ◽  
Growth Factor Signalling ◽  
The Stability

There is an emerging paradigm that growth factor signalling continues in the endosome and that cell response to a growth factor is defined by the integration of cell surface and endosomal events. As activated receptors in the endosome are exposed to a different set of binding partners, they probably elicit differential signals compared with when they are at the cell surface. As such, complete appreciation of growth factor signalling requires understanding of growth factor–receptor binding and trafficking kinetics both at the cell surface and in endosomes. Growth factor binding to surface receptors is well characterized, and endosomal binding is assumed to follow surface kinetics if one accounts for changes in pH. Yet, specific binding kinetics within the endosome has not been examined in detail. To parse the factors governing the binding state of endosomal receptors we analysed a whole-cell mathematical model of epidermal growth factor receptor trafficking and binding. We discovered that the stability of growth factor–receptor complexes within endosomes is governed by three primary independent factors: the endosomal dissociation constant, total endosomal volume and the number of endosomal receptors. These factors were combined into a single dimensionless parameter that determines the endosomal binding state of the growth factor–receptor complex and can distinguish different growth factors from each other and different cell states. Our findings indicate that growth factor binding within endosomal compartments cannot be appreciated solely on the basis of the pH-dependence of the dissociation constant and that the concentration of receptors in the endosomal compartment must also be considered.

scholarly journals The Role of Insulin-Like Growth Factors and Insulin-Like Growth Factor–Binding Proteins in the Nervous System

2019 ◽  
Vol 12 ◽  
pp. 117862641984217 ◽  
Author(s):  
Moira S Lewitt ◽  
Gary W Boyd
Keyword(s):  
Nervous System ◽  
Growth Factors ◽  
Growth Factor ◽  
Binding Proteins ◽  
Nervous System Development ◽  
Signalling Pathways ◽  
Igf Binding Proteins ◽  
Growth Factor Signalling ◽  
Igf Binding ◽  
Insulin Like Growth Factors

The insulin-like growth factors (IGF-I and IGF-II) and their receptors are widely expressed in nervous tissue from early embryonic life. They also cross the blood brain barriers by active transport, and their regulation as endocrine factors therefore differs from other tissues. In brain, IGFs have paracrine and autocrine actions that are modulated by IGF-binding proteins and interact with other growth factor signalling pathways. The IGF system has roles in nervous system development and maintenance. There is substantial evidence for a specific role for this system in some neurodegenerative diseases, and neuroprotective actions make this system an attractive target for new therapeutic approaches. In developing new therapies, interaction with IGF-binding proteins and other growth factor signalling pathways should be considered. This evidence is reviewed, gaps in knowledge are highlighted, and recommendations are made for future research.

scholarly journals Tiny dancers

2002 ◽  
Vol 158 (1) ◽  
pp. 17-21 ◽  
Author(s):  
Susan S. Smyth ◽  
Cam Patterson
Keyword(s):  
Extracellular Matrix ◽  
Growth Factors ◽  
Growth Factor ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Surface Receptors

A vital step in growth factor–driven angiogenesis is the coordinated engagement of endothelial integrins with the extracellular matrix. The molecular mechanisms that partner growth factors and integrins are being elucidated, revealing an intricate interaction of surface receptors and their signaling pathways.

scholarly journals Cardiac fibrosis

2020 ◽  
Author(s):  
Nikolaos G Frangogiannis
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Matrix Proteins ◽  
Matrix Assembly ◽  
Myocardial Diseases ◽  
Signalling Cascades

Abstract Myocardial fibrosis, the expansion of the cardiac interstitium through deposition of extracellular matrix proteins, is a common pathophysiologic companion of many different myocardial conditions. Fibrosis may reflect activation of reparative or maladaptive processes. Activated fibroblasts and myofibroblasts are the central cellular effectors in cardiac fibrosis, serving as the main source of matrix proteins. Immune cells, vascular cells and cardiomyocytes may also acquire a fibrogenic phenotype under conditions of stress, activating fibroblast populations. Fibrogenic growth factors (such as transforming growth factor-β and platelet-derived growth factors), cytokines [including tumour necrosis factor-α, interleukin (IL)-1, IL-6, IL-10, and IL-4], and neurohumoral pathways trigger fibrogenic signalling cascades through binding to surface receptors, and activation of downstream signalling cascades. In addition, matricellular macromolecules are deposited in the remodelling myocardium and regulate matrix assembly, while modulating signal transduction cascades and protease or growth factor activity. Cardiac fibroblasts can also sense mechanical stress through mechanosensitive receptors, ion channels and integrins, activating intracellular fibrogenic cascades that contribute to fibrosis in response to pressure overload. Although subpopulations of fibroblast-like cells may exert important protective actions in both reparative and interstitial/perivascular fibrosis, ultimately fibrotic changes perturb systolic and diastolic function, and may play an important role in the pathogenesis of arrhythmias. This review article discusses the molecular mechanisms involved in the pathogenesis of cardiac fibrosis in various myocardial diseases, including myocardial infarction, heart failure with reduced or preserved ejection fraction, genetic cardiomyopathies, and diabetic heart disease. Development of fibrosis-targeting therapies for patients with myocardial diseases will require not only understanding of the functional pluralism of cardiac fibroblasts and dissection of the molecular basis for fibrotic remodelling, but also appreciation of the pathophysiologic heterogeneity of fibrosis-associated myocardial disease.

scholarly journals Platelet-Released Growth Factors Induce Genes Involved in Extracellular Matrix Formation in Human Fibroblasts

2021 ◽  
Vol 22 (19) ◽  
pp. 10536
Author(s):  
Andreas Bayer ◽  
Bernard Wijaya ◽  
Franziska Rademacher ◽  
Lena Möbus ◽  
Mark Preuß ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Growth Factors ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Lysyl Oxidase ◽  
Human Fibroblasts ◽  
Dermal Fibroblasts ◽  
Type I ◽  
Cellular Mechanisms

Platelet concentrate products are increasingly used in many medical disciplines due to their regenerative properties. As they contain a variety of chemokines, cytokines, and growth factors, they are used to support the healing of chronic or complicated wounds. To date, underlying cellular mechanisms have been insufficiently investigated. Therefore, we analyzed the influence of Platelet-Released Growth Factors (PRGF) on human dermal fibroblasts. Whole transcriptome sequencing and gene ontology (GO) enrichment analysis of PRGF-treated fibroblasts revealed an induction of several genes involved in the formation of the extracellular matrix (ECM). Real-time PCR analyses of PRGF-treated fibroblasts and skin explants confirmed the induction of ECM-related genes, in particular transforming growth factor beta-induced protein (TGFBI), fibronectin 1 (FN1), matrix metalloproteinase-9 (MMP-9), transglutaminase 2 (TGM2), fermitin family member 1 (FERMT1), collagen type I alpha 1 (COL1A1), a disintegrin and metalloproteinase 19 (ADAM19), serpin family E member 1 (SERPINE1) and lysyl oxidase-like 3 (LOXL3). The induction of these genes was time-dependent and in part influenced by the epidermal growth factor receptor (EGFR). Moreover, PRGF induced migration and proliferation of the fibroblasts. Taken together, the observed effects of PRGF on human fibroblasts may contribute to the underlying mechanisms that support the beneficial wound-healing effects of thrombocyte concentrate products.

scholarly journals Nutrients and growth factors in mTORC1 activation

2013 ◽  
Vol 41 (4) ◽  
pp. 902-905 ◽  
Author(s):  
Alejo Efeyan ◽  
David M. Sabatini
Keyword(s):  
Human Physiology ◽  
Growth Factors ◽  
Growth Factor ◽  
Mouse Model ◽  
Mouse Models ◽  
Mechanistic Target Of Rapamycin ◽  
Rag Gtpases ◽  
Growth Factor Signalling ◽  
Mtorc1 Activation

Growth factors and nutrients regulate the mTORC1 [mammalian (or mechanistic) target of rapamycin complex 1] by different mechanisms. The players that link growth factors and mTORC1 activation have been known for several years and mouse models have validated its relevance for human physiology and disease. In contrast with the picture for growth factor signalling, the means by which nutrient availability leads to mTORC1 activation have remained elusive until recently, with the discovery of the Rag GTPases upstream of mTORC1. The Rag GTPases recruit mTORC1 to the outer lysosomal surface, where growth factor signalling and nutrient signalling converge on mTORC1 activation. A mouse model of constitutive RagA activity has revealed qualitative differences between growth-factor- and nutrient-dependent regulation of mTORC1. Regulation of mTORC1 activity by the Rag GTPases in vivo is key for enduring early neonatal starvation, showing its importance for mammalian physiology.

scholarly journals Molecular genetic mechanisms of ovarian organization and development

2018 ◽  
Vol 17 (2) ◽  
pp. 133-142
Author(s):  
V. G. Zenkina ◽  
O. A. Solodkova
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Bone Morphogenetic Proteins ◽  
Germ Cells ◽  
Molecular Mechanisms ◽  
Molecular Genetic ◽  
Genetic Mechanisms ◽  
Development And Differentiation ◽  
The Moment ◽  
Sex Cells

A review of the literature devoted to the analysis of conditions and development of the female reproductive gland. From the moment of the formation of urogenital scallops to the formation of a full gonad, at the different stages of ontogeny, a huge number of genes, factors and proteins are expressed, since in them the primary sex cells and in their surroundings render folliculogenesis and determine the reproductive health of a woman. Aberrant production of these factors can be the cause of ovarian dysfunction and disorders. Different points of view on the emergence of the problem of migration and colonization of germ cells in female gonads, as well as directions for further fundamental and practical research. The development and differentiation of the follicle is a succession of events that are tightly regulated by endocrine factors, intraocular regulators and intercellular interactions. The initial migration of germ cells and their multiplication within the urogenital scallop require regulation using integrated signals such as growth factors, transcription and differentiation, secreted oocytes, transforming growth factors, growth factor and differentiation-9, bone morphogenetic proteins, stem cell factor, basic growth factor of fibroblasts, tumor factor of Williams transcription, gene steroidogenesis, antimulylerovy hormone, meiosis-regulating genes and many others, as well as a contact these interactions of germ cells with extracellular matrix proteins and cellular substrates attract the developing gonads. Recent studies indicate the possibility of obtaining human gametes from the culture of stem cells, a distinct molecular genetic mechanism of the origin, migration and colonization of the sex cells. Consequently, the understanding that all the subtleties and molecular mechanisms at each stage of the bookmarking and development of the ovaries, germ cells and their environment, the death of gametes, can help in finding regulators and preventing pathological follicular depletion.

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