scholarly journals Glycosylation of matrix metalloproteases and tissue inhibitors: present state, challenges and opportunities

2016 ◽  
Vol 473 (11) ◽  
pp. 1471-1482 ◽  
Author(s):  
Lise Boon ◽  
Estefania Ugarte-Berzal ◽  
Jennifer Vandooren ◽  
Ghislain Opdenakker
Keyword(s):  
Matrix Metalloproteinases ◽  
Present State ◽  
Cellular Localization ◽  
Current Knowledge ◽  
Matrix Metalloproteases ◽  
Inhibitor Binding ◽  
Attachment Sites ◽  
Functional Aspects ◽  
Functional Implications ◽  
Challenges And Opportunities

Current knowledge about the glycosylation of matrix metalloproteinases (MMPs) and the inhibitors of metalloproteinases (TIMPs) is reviewed. Whereas structural and functional aspects of the glycobiology of many MMPs is unknown, research on MMP-9 and MMP-14 glycosylation reveals important functional implications, such as altered inhibitor binding and cellular localization. This, together with the fact that MMPs contain conserved and many potential attachment sites for N-linked and O-linked oligosaccharides, proves the need for further studies on MMP glycobiology.

Modulation of Matrix Metalloproteinases by Plant-Derived Products

2020 ◽  
Vol 20 ◽  
Author(s):  
Nur Najmi Mohamad Anuar ◽  
Nurul Iman Natasya Zulkafali ◽  
Azizah Ugusman
Keyword(s):  
Clinical Trials ◽  
Natural Products ◽  
Matrix Metalloproteinases ◽  
Animal Studies ◽  
Current Knowledge ◽  
In Vitro Models ◽  
In Vivo Studies ◽  
Extracellular Matrix Components

: Matrix metalloproteinases (MMPs) are a group of zinc-dependent metallo-endopeptidase that are responsible towards the degradation, repair and remodelling of extracellular matrix components. MMPs play an important role in maintaining a normal physiological function and preventing diseases such as cancer and cardiovascular diseases. Natural products derived from plants have been used as traditional medicine for centuries. Its active compounds, such as catechin, resveratrol and quercetin, are suggested to play an important role as MMPs inhibitors, thereby opening new insights into their applications in many fields, such as pharmaceutical, cosmetic and food industries. This review summarises the current knowledge on plant-derived natural products with MMP-modulating activities. Most of the reviewed plant-derived products exhibit an inhibitory activity on MMPs. Amongst MMPs, MMP-2 and MMP-9 are the most studied. The expression of MMPs is inhibited through respective signalling pathways, such as MAPK, NF-κB and PI3 kinase pathways, which contribute to the reduction in cancer cell behaviours, such as proliferation and migration. Most studies have employed in vitro models, but a limited number of animal studies and clinical trials have been conducted. Even though plant-derived products show promising results in modulating MMPs, more in vivo studies and clinical trials are needed to support their therapeutic applications in the future.

scholarly journals Proprotein Convertase 5/6 Is Critical for Embryo Implantation in Women: Regulating Receptivity by Cleaving EBP50, Modulating Ezrin Binding, and Membrane-Cytoskeletal Interactions

Endocrinology ◽  
2011 ◽  
Vol 152 (12) ◽  
pp. 5041-5052 ◽  
Author(s):  
Sophea Heng ◽  
Ana Cervero ◽  
Carlos Simon ◽  
Andrew N. Stephens ◽  
Ying Li ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cellular Localization ◽  
Structural Changes ◽  
Current Knowledge ◽  
Embryo Implantation ◽  
Critical Role ◽  
Human Endometrium ◽  
Scaffolding Protein ◽  
Proprotein Convertase ◽  
Proteomic Approach

Establishment of endometrial receptivity is vital for successful embryo implantation; its failure causes infertility. Epithelial receptivity acquisition involves dramatic structural changes in the plasma membrane and cytoskeleton. Proprotein convertase 5/6 (PC6), a serine protease of the proprotein convertase (PC) family, is up-regulated in the human endometrium specifically at the time of epithelial receptivity and stromal cell decidualization. PC6 is the only PC member tightly regulated in this manner. The current study addressed the importance and mechanisms of PC6 action in regulating receptivity in women. PC6 was dysregulated in the endometrial epithelium during the window of implantation in infertile women of three demographically different cohorts. Its critical role in receptivity was evidenced by a significant reduction in mouse blastocyst attachment of endometrial epithelial cells after PC6 knockdown by small interfering RNA. Using a proteomic approach, we discovered that PC6 cleaved the key scaffolding protein, ezrin-radixin-moesin binding phosphoprotein 50 (EBP50), thereby profoundly affecting its interaction with binding protein ezrin (a key protein bridging actin filaments and plasma membrane), EBP50/ezrin cellular localization, and cytoskeleton-membrane connections. We further validated this novel PC6 regulation of receptivity in human endometrium in vivo in fertile vs. infertile patients. These results strongly indicate that PC6 plays a key role in regulating fundamental cellular remodeling processes, such as plasma membrane transformation and membrane-cytoskeletal interface reorganization. PC6 cleavage of a crucial scaffolding protein EBP50, thereby profoundly regulating membrane-cytoskeletal reorganization, greatly extends the current knowledge of PC biology and provides substantial new mechanistic insight into the fields of reproduction, basic cellular biology, and PC biochemistry.

scholarly journals Challenges and Opportunities in NUT Carcinoma Research

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 235
Author(s):  
Bin Gu ◽  
Maxwell C. Hakun
Keyword(s):  
Cell Biology ◽  
Current Knowledge ◽  
Short Review ◽  
Specific Protein ◽  
Cell Of Origin ◽  
Chromosome Translocations ◽  
Very Young Children ◽  
Aggressive Cancer ◽  
Challenges And Opportunities ◽  
Nut Carcinoma

NUT carcinoma (NC) is a type of aggressive cancer driven by chromosome translocations. Fusion genes between a DNA-binding protein, such as bromodomain and extraterminal domain (BET) proteins, and the testis-specific protein NUTM1 generated by these translocations drive the formation of NC. NC can develop in very young children without significant accumulation of somatic mutations, presenting a relatively clean model to study the genetic etiology of oncogenesis. However, after 20 years of research, a few challenging questions still remain for understanding the mechanism and developing therapeutics for NC. In this short review, we first briefly summarize the current knowledge regarding the molecular mechanism and targeted therapy development of NC. We then raise three challenging questions: (1) What is the cell of origin of NC? (2) How does the germline analogous epigenetic reprogramming process driven by the BET-NUTM1 fusion proteins cause NC? and (3) How will BET-NUTM1 targeted therapies be developed? We propose that with the unprecedented technological advancements in genome editing, animal models, stem cell biology, organoids, and chemical biology, we have unique opportunities to address these challenges.

Ca2+-dependent interaction of S100A2 with muscle and nonmuscle tropomyosins

1997 ◽  
Vol 110 (5) ◽  
pp. 611-621 ◽  
Author(s):  
M. Gimona ◽  
Z. Lando ◽  
Y. Dolginov ◽  
J. Vandekerckhove ◽  
R. Kobayashi ◽  
...  
Keyword(s):  
Cellular Localization ◽  
Epithelial Cell Line ◽  
Chemical Crosslinking ◽  
Related Function ◽  
Differentiated Cells ◽  
Cell Extracts ◽  
Sds Page ◽  
Functional Implications ◽  
Dependent Interaction

Zero-length chemical crosslinking with 1-ethyl-3-[3-(dimethyl amino)propyl]carbodiimide (EDC) indicated an association of the Ca2+-binding protein S100A2 with tropomyosin (TM) in vitro. The mobility of the crosslinked product on SDS-PAGE gels indicated the formation of a 1:1 complex between S100A2 and TM and the interaction was Ca2+ dependent. Monoclonal antibodies were raised against S100A2 and used to determine its cellular localization in the porcine epithelial cell line LLC PK1. It was found that the localization of S100A2 depended on the differentiation state of the cells, being absent from actin stress fibers in sparsely seeded cultures, but present in the actin-containing microvilli characteristic of differentiated cells. Immunoprecipitations of [35S]methionine-labeled extracts using S100A2 as well as TM-specific antibodies failed to co-precipitate TM and S100A2, indicating a transient association between these two molecules in solution. Affinity chromatography of cell extracts on immobilized recombinant TMs, however, confirmed the Ca2+-dependent interaction between S100A2 and both muscle TMs as well as with high and low molecular mass nonmuscle TMs, suggesting that the binding site resides in one of the conserved regions of TM. Our data demonstrate the possible interaction of S100A2 with TM that is not bound to the microfilaments and indicate a differentiation-related function for S100A2 in LLC PK1 cells. The possible functional implications of this interaction are discussed.

scholarly journals Matrix Metalloproteinases: A Review

1993 ◽  
Vol 4 (2) ◽  
pp. 197-250 ◽  
Author(s):  
H. Birkedal-Hansen ◽  
W.G.I. Moore ◽  
M.K. Bodden ◽  
L.J. Windsor ◽  
B. Birkedal-Hansen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Matrix Metalloproteinases ◽  
Current Knowledge ◽  
Periodontal Diseases ◽  
Present Review ◽  
Transcriptional Level ◽  
Substrate Specificities ◽  
Pathological Conditions ◽  
Final Segment ◽  
Extracellular Level

Matrix metalloproteinases (MMPs) are a family of nine or more highly homologous Zn++endopeptidases that collectively cleave most if not all of the constituents of the extracellular matrix. The present review discusses in detail the primary structures and the overlapping yet distinct substrate specificities of MMPs as well as the mode of activation of the unique MMP precursors. The regulation of MMP activity at the transcriptional level and at the extracellular level (precursor activation, inhibition of activated, mature enzymes) is also discussed. A final segment of the review details the current knowledge of the involvement of MMP in specific developmental or pathological conditions, including human periodontal diseases.

Protein Glycation: An Old Villain is Shedding Secrets

2019 ◽  
Vol 22 (6) ◽  
pp. 362-369
Author(s):  
Gerald H. Lushington ◽  
Anthony C. Barnes
Keyword(s):  
Drug Targets ◽  
Current Knowledge ◽  
Treatment Options ◽  
Protein Glycation ◽  
Target Area ◽  
Disease Etiology ◽  
Glycated Proteins ◽  
Parkinson’S Diseases ◽  
Challenges And Opportunities ◽  
Novel Drug

: The glycation of proteins is non-physiological post-translational incorporation of carbohydrates onto the free amines or guanidines of proteins and some lipids. Although the existence of glycated proteins has been known for forty years, a full understanding of their pathogenic nature has been slow in accruing. In recent years, however, glycation has gained widespread acceptance as a contributing factor in numerous metabolic, autoimmune, and neurological disorders, tying together several confounding aspects of disease etiology. From diabetes, arthritis, and lupus, to multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer’s, and Parkinson’s diseases, an emerging glycation/inflammation paradigm now offers significant new insight into a physiologically important toxicological phenomenon. It exposes novel drug targets and treatment options, and may even lay foundations for long-awaited breakthroughs. : This ‘current frontier’ article briefly profiles current knowledge regarding the underlying causes of glycation, the structural biology implications of such modifications, and their pathological consequences. Although several emerging therapeutic strategies for addressing glycation pathologies are introduced, the primary purpose of this mini-review is to raise awareness of the challenges and opportunities inherent in this emerging new medicinal target area.

scholarly journals FMS-like Tyrosine Kinase 3/FLT3: From Basic Science to Clinical Implications

2019 ◽  
Vol 99 (3) ◽  
pp. 1433-1466 ◽  
Author(s):  
Julhash U. Kazi ◽  
Lars Rönnstrand
Keyword(s):  
Signal Transduction ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Current Knowledge ◽  
Biological Effects ◽  
Acquired Resistance ◽  
Cell Proliferation And Differentiation ◽  
Functional Aspects ◽  
Proliferation And Differentiation ◽  
Targeted Inhibition

FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is expressed almost exclusively in the hematopoietic compartment. Its ligand, FLT3 ligand (FL), induces dimerization and activation of its intrinsic tyrosine kinase activity. Activation of FLT3 leads to its autophosphorylation and initiation of several signal transduction cascades. Signaling is initiated by the recruitment of signal transduction molecules to activated FLT3 through binding to specific phosphorylated tyrosine residues in the intracellular region of FLT3. Activation of FLT3 mediates cell survival, cell proliferation, and differentiation of hematopoietic progenitor cells. It acts in synergy with several other cytokines to promote its biological effects. Deregulated FLT3 activity has been implicated in several diseases, most prominently in acute myeloid leukemia where around one-third of patients carry an activating mutant of FLT3 which drives the disease and is correlated with poor prognosis. Overactivity of FLT3 has also been implicated in autoimmune diseases, such as rheumatoid arthritis. The observation that gain-of-function mutations of FLT3 can promote leukemogenesis has stimulated the development of inhibitors that target this receptor. Many of these are in clinical trials, and some have been approved for clinical use. However, problems with acquired resistance to these inhibitors are common and, furthermore, only a fraction of patients respond to these selective treatments. This review provides a summary of our current knowledge regarding structural and functional aspects of FLT3 signaling, both under normal and pathological conditions, and discusses challenges for the future regarding the use of targeted inhibition of these pathways for the treatment of patients.

scholarly journals Mesenchymal Stem Cells and Cancer: Clinical Challenges and Opportunities

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Weiping Lin ◽  
Linfeng Huang ◽  
Ying Li ◽  
Bin Fang ◽  
Gang Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Anticancer Agents ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Cell Types ◽  
Inhibit Tumor Growth ◽  
Challenges And Opportunities ◽  
Promising Source ◽  
Target Cancer

Stem cell-based therapies exhibit profound therapeutic potential for treating various human diseases, including cancer. Among the cell types that can be used for this purpose, mesenchymal stem cells (MSCs) are considered as promising source of stem cells in personalized cell-based therapies. The inherent tumor-tropic property of MSCs can be used to target cancer cells. Although the impacts of MSCs on tumor progression remain elusive, they have been genetically modified or engineered as targeted anticancer agents which could inhibit tumor growth by blocking different processes of tumor. In addition, there are close interactions between MSCs and cancer stem cells (CSCs). MSCs can regulate the growth of CSCs through paracrine mechanisms. This review aims to focus on the current knowledge about MSCs-based tumor therapies, the opportunities and challenges, as well as the prospective of its further clinical implications.

scholarly journals The Role of Microglia and Matrix Metalloproteinases Involvement in Neuroinflammation and Gliomas

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Helen Könnecke ◽  
Ingo Bechmann
Keyword(s):  
Multiple Sclerosis ◽  
Matrix Metalloproteinases ◽  
Current Knowledge ◽  
Malignant Gliomas ◽  
Therapeutic Strategies ◽  
Glioma Invasion ◽  
Glia Limitans ◽  
And Migration

Matrix metalloproteinases (MMPs) are involved in the pathogenesis of neuroinflammatory diseases (such as multiple sclerosis) as well as in the expansion of malignant gliomas because they facilitate penetration of anatomical barriers (such as the glia limitans) and migration within the neuropil. This review elucidates pathomechanisms and summarizes the current knowledge of the involvement of MMPs in neuroinflammation and glioma, invasion highlighting microglia as major sources of MMPs. The induction of expression, suppression, and multiple pathways of function of MMPs in these scenarios will also be discussed. Understanding the induction and action of MMPs might provide valuable information and reveal attractive targets for future therapeutic strategies.

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