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Vallet, Sylvain D., Martin N. Davis, Anna Barqué, Ali H. Thahab, Sylvie Ricard-Blum, and Alexandra Naba. "Computational and experimental characterization of the novel ECM glycoprotein SNED1 and prediction of its interactome." Biochemical Journal 478, no. 7 (2021): 1413–34. http://dx.doi.org/10.1042/bcj20200675.
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The extracellular matrix (ECM) is a complex meshwork of proteins and an essential component of multicellular life. We have recently reported the characterization of a novel ECM protein, SNED1, and showed that it promotes breast cancer metastasis and regulates craniofacial development. However, the mechanisms by which it does so remain unknown. ECM proteins exert their functions by binding to cell surface receptors and interacting with other ECM proteins, actions that we can predict using knowledge of protein's sequence, structure, and post-translational modifications. Here, we combined in-silico and in-vitro approaches to characterize the physico-chemical properties of SNED1 and infer its putative functions. To do so, we established a mammalian cell system to produce and purify SNED1 and its N-terminal fragment, which contains a NIDO domain, and demonstrated experimentally SNED1's potential to be glycosylated, phosphorylated, and incorporated into an insoluble ECM. We also determined the secondary and tertiary structures of SNED1 and its N-terminal fragment and obtained a model for its NIDO domain. Using computational predictions, we identified 114 proteins as putative SNED1 interactors, including the ECM protein fibronectin. Pathway analysis of the predicted SNED1 interactome further revealed that it may contribute to signaling through cell surface receptors, such as integrins, and participate in the regulation of ECM organization and developmental processes. Last, using fluorescence microscopy, we showed that SNED1 forms microfibrils within the ECM and partially colocalizes with fibronectin. Altogether, we provide a wealth of information on an understudied yet important ECM protein with the potential to decipher its pathophysiological functions.
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Liu, Binghui, Ling Leng, Xuer Sun, Yunfang Wang, Jie Ma, and Yunping Zhu. "ECMPride: prediction of human extracellular matrix proteins based on the ideal dataset using hybrid features with domain evidence." PeerJ 8 (April 29, 2020): e9066. http://dx.doi.org/10.7717/peerj.9066.
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Extracellular matrix (ECM) proteins play an essential role in various biological processes in multicellular organisms, and their abnormal regulation can lead to many diseases. For large-scale ECM protein identification, especially through proteomic-based techniques, a theoretical reference database of ECM proteins is required. In this study, based on the experimentally verified ECM datasets and by the integration of protein domain features and a machine learning model, we developed ECMPride, a flexible and scalable tool for predicting ECM proteins. ECMPride achieved excellent performance in predicting ECM proteins, with appropriate balanced accuracy and sensitivity, and the performance of ECMPride was shown to be superior to the previously developed tool. A new theoretical dataset of human ECM components was also established by applying ECMPride to all human entries in the SwissProt database, containing a significant number of putative ECM proteins as well as the abundant biological annotations. This dataset might serve as a valuable reference resource for ECM protein identification.
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Papadimitriou, E., V. G. Manolopoulos, G. T. Hayman, et al. "Thrombin modulates vectorial secretion of extracellular matrix proteins in cultured endothelial cells." American Journal of Physiology-Cell Physiology 272, no. 4 (1997): C1112—C1122. http://dx.doi.org/10.1152/ajpcell.1997.272.4.c1112.
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We have identified a novel cellular action of thrombin on cultured rat adrenal medullary endothelial cells (RAMEC). Five-minute incubation of RAMEC with physiological concentrations of thrombin (<1 U/ml) caused within 3 h an increase in the basolateral deposition of the extracellular matrix (ECM) proteins fibronectin, laminin, and collagens IV and I, concomitant with a corresponding decrease in the apical release of these proteins into the medium. This shift in vectorial secretion of ECM proteins, quantitated with enzyme-linked immunoassays, was time dependent. Maximal stimulation of ECM protein deposition was observed after incubation of cells with thrombin for 5-15 min. Prolonged exposure (>1 h) to thrombin resulted in loss of proteins from the ECM. Thrombin-stimulated ECM protein deposition exhibited a bell-shaped dose dependence, peaking for all proteins at 0.25 U/ml of thrombin, and was independent of de novo mRNA or protein synthesis. Maximal amounts of deposited proteins increased between 2.5-fold (fibronectin) and 4-fold (collagen I) over baseline values. Similar results were obtained with thrombin receptor agonist peptide (TRAP), proteolytically active gamma-thrombin, and, to a lesser extent, other serine proteases such as trypsin and plasmin. A scrambled TRAP, proteolytically inactive PPACK-thrombin, DIP-thrombin, and type IV collagenase were ineffective. Together, these results suggest that the thrombin effects are mediated by proteolytic activation of the thrombin receptor. Possible involvement of the phospholipase C-signaling pathway in thrombin-mediated ECM protein deposition was also investigated. Inhibition or downregulation of protein kinase C (PKC) and chelation of intracellular or extracellular Ca2+ did not suppress, but rather enhanced, basal and thrombin-stimulated ECM protein deposition. Quantitative differences in augmentation of basolateral deposition by these treatments suggest differential regulatory pathways for individual ECM proteins. Our data indicate that, in cultured RAMEC, short-term activation of the thrombin receptor causes an increase in amounts of deposited ECM protein by a cellular signaling pathway that is independent of PKC activation and/or elevation of intracellular Ca2+.
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Di Mola, Ida, Stefano Conti, Eugenio Cozzolino, et al. "Plant-Based Protein Hydrolysate Improves Salinity Tolerance in Hemp: Agronomical and Physiological Aspects." Agronomy 11, no. 2 (2021): 342. http://dx.doi.org/10.3390/agronomy11020342.
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Hemp (Cannabis sativa L.) is a multipurpose plant attracting increasing interest as a source for the production of natural fibers, paper, bio-building material and food. In this research we studied the agronomical performance of Cannabis sativa cv. Eletta Campana irrigated with saline water. Under those conditions, we tested the effect of protein hydrolysate (PH) biostimulant application in overcoming and/or balancing deleterious salinity effects. The results of the diverse treatments were also investigated at the physiological level, focusing on photosynthesis by means of a chlorophyll a fluorescence technique, which give an insight into the plant primary photochemical reactions. Four salinity levels of the irrigation solution (fresh water–EC0, and NaCl solutions at EC 2.0, 4.0 or 6.0 dS m−1, EC2, EC4 and EC6, respectively) were combined with 2 biostimulant treatments (untreated (control) or treated with a commercial legume-derived protein hydrolysate (LDPH)). The increasing salinity affected plant photochemistry resulting in lower plant growth and seed production, while the LDPH biostimulant showed a protective effect, which improved crop performance both in control and in salinity conditions. The LDPH treatment improved seeds yield (+38.6% on average of all treated plants respect to untreated plants), as well as residual biomass, relevant in fiber production.
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Liem, David A., Sanjana Murali, Dibakar Sigdel, et al. "Phrase mining of textual data to analyze extracellular matrix protein patterns across cardiovascular disease." American Journal of Physiology-Heart and Circulatory Physiology 315, no. 4 (2018): H910—H924. http://dx.doi.org/10.1152/ajpheart.00175.2018.
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Extracellular matrix (ECM) proteins have been shown to play important roles regulating multiple biological processes in an array of organ systems, including the cardiovascular system. Using a novel bioinformatics text-mining tool, we studied six categories of cardiovascular disease (CVD), namely, ischemic heart disease, cardiomyopathies, cerebrovascular accident, congenital heart disease, arrhythmias, and valve disease, anticipating novel ECM protein-disease and protein-protein relationships hidden within vast quantities of textual data. We conducted a phrase-mining analysis, delineating the relationships of 709 ECM proteins with the 6 groups of CVDs reported in 1,099,254 abstracts. The technology pipeline known as Context-Aware Semantic Online Analytical Processing was applied to semantically rank the association of proteins to each CVD and all six CVDs, performing analyses to quantify each protein-disease relationship. We performed principal component analysis and hierarchical clustering of the data, where each protein was visualized as a six-dimensional vector. We found that ECM proteins display variable degrees of association with the six CVDs; certain CVDs share groups of associated proteins, whereas others have divergent protein associations. We identified 82 ECM proteins sharing associations with all 6 CVDs. Our bioinformatics analysis ascribed distinct ECM pathways (via Reactome) from this subset of proteins, namely, insulin-like growth factor regulation and interleukin-4 and interleukin-13 signaling, suggesting their contribution to the pathogenesis of all six CVDs. Finally, we performed hierarchical clustering analysis and identified protein clusters predominantly associated with a targeted CVD; analyses of these proteins revealed unexpected insights underlying the key ECM-related molecular pathogenesis of each CVD, including virus assembly and release in arrhythmias. NEW & NOTEWORTHY The present study is the first application of a text-mining algorithm to characterize the relationships of 709 extracellular matrix-related proteins with 6 categories of cardiovascular disease described in 1,099,254 abstracts. Our analysis informed unexpected extracellular matrix functions, pathways, and molecular relationships implicated in the six cardiovascular diseases.
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Hoke, David E., Suhelen Egan, Paul A. Cullen, and Ben Adler. "LipL32 Is an Extracellular Matrix-Interacting Protein of Leptospira spp. and Pseudoalteromonas tunicata." Infection and Immunity 76, no. 5 (2008): 2063–69. http://dx.doi.org/10.1128/iai.01643-07.
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ABSTRACT LipL32 is the major outer membrane protein in pathogenic Leptospira. It is highly conserved throughout pathogenic species and is expressed in vivo during human infection. While these data suggest a role in pathogenesis, a function for LipL32 has not been defined. Outer membrane proteins of gram-negative bacteria are the first line of molecular interaction with the host, and many have been shown to bind host extracellular matrix (ECM). A search for leptospiral ECM-interacting proteins identified the major outer membrane protein, LipL32. To verify this finding, recombinant LipL32 was expressed in Escherichia coli and was found to bind Matrigel ECM and individual components of ECM, including laminin, collagen I, and collagen V. Likewise, an orthologous protein found in the genome of Pseudoalteromonas tunicata strain D2 was expressed and found to be functionally similar and immunologically cross-reactive. Lastly, binding activity was mapped to the C-terminal 72 amino acids. These studies show that LipL32 and an orthologous protein in P. tunicata are immunologically cross-reactive and function as ECM-interacting proteins via a conserved C-terminal region.
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Chan, Gek Cher, Diana G. Eng, Jeffrey H. Miner, et al. "Differential expression of parietal epithelial cell and podocyte extracellular matrix proteins in focal segmental glomerulosclerosis and diabetic nephropathy." American Journal of Physiology-Renal Physiology 317, no. 6 (2019): F1680—F1694. http://dx.doi.org/10.1152/ajprenal.00266.2019.
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In healthy glomeruli, parietal epithelial cell (PEC)-derived extracellular matrix (ECM) proteins include laminin-β1, perlecan, and collagen type IV-α2 and podocyte-specific ECM proteins include laminin-β2, agrin, and collagen type IV-α4. This study aimed to define individual ECM protein isoform expression by PECs in both experimental and human focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy (DN) and to determine if changes were CD44 dependent. In experimental FSGS induced with a cytotoxic podocyte antibody and in the BTBR ob/ob mouse model of DN, PEC-derived protein staining was significantly increased in PECs. Dual staining also showed de novo expression of the podocyte-specific ECM proteins laminin-β2 and agrin in PECs. Similar findings were observed in biopsies from patients with FSGS and DN. Increases in individual ECM proteins colocalized with CD44 in PECs in disease. To determine the role of CD44, FSGS was induced in CD44−/− and CD44+/+ mice. PEC staining for perlecan, collagen type IV-α2, laminin-β2, and agrin were significantly lower in diseased CD44−/− mice compared with diseased CD44+/+ mice. These results show that in experimental and human FSGS and DN, PECs typically in an activated state, produce both PEC-derived and podocyte-specific ECM protein isoforms, and that the majority of these changes were dependent on CD44.
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Lipp, Sarah N., Kathryn R. Jacobson, David S. Hains, Andrew L. Schwarderer, and Sarah Calve. "3D Mapping Reveals a Complex and Transient Interstitial Matrix During Murine Kidney Development." Journal of the American Society of Nephrology 32, no. 7 (2021): 1649–65. http://dx.doi.org/10.1681/asn.2020081204.
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BackgroundThe extracellular matrix (ECM) is a network of proteins and glycosaminoglycans that provides structural and biochemical cues to cells. In the kidney, the ECM is critical for nephrogenesis; however, the dynamics of ECM composition and how it relates to 3D structure during development is unknown.MethodsUsing embryonic day 14.5 (E14.5), E18.5, postnatal day 3 (P3), and adult kidneys, we fractionated proteins based on differential solubilities, performed liquid chromatography–tandem mass spectrometry, and identified changes in ECM protein content (matrisome). Decellularized kidneys were stained for ECM proteins and imaged in 3D using confocal microscopy.ResultsWe observed an increase in interstitial ECM that connects the stromal mesenchyme to the basement membrane (TNXB, COL6A1, COL6A2, COL6A3) between the embryo and adult, and a transient elevation of interstitial matrix proteins (COL5A2, COL12A1, COL26A1, ELN, EMID1, FBN1, LTBP4, THSD4) at perinatal time points. Basement membrane proteins critical for metanephric induction (FRAS1, FREM2) were highest in abundance in the embryo, whereas proteins necessary for integrity of the glomerular basement membrane (COL4A3, COL4A4, COL4A5, LAMB2) were more abundant in the adult. 3D visualization revealed a complex interstitial matrix that dramatically changed over development, including the perinatal formation of fibrillar structures that appear to support the medullary rays.ConclusionBy correlating 3D ECM spatiotemporal organization with global protein abundance, we revealed novel changes in the interstitial matrix during kidney development. This new information regarding the ECM in developing kidneys offers the potential to inform the design of regenerative scaffolds that can guide nephrogenesis in vitro.
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Ghanemi, Abdelaziz, Mayumi Yoshioka, and Jonny St-Amand. "Secreted Protein Acidic and Rich in Cysteine: Metabolic and Homeostatic Properties beyond the Extracellular Matrix Structure." Applied Sciences 10, no. 7 (2020): 2388. http://dx.doi.org/10.3390/app10072388.
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An extracellular matrix (ECM) is a network of numerous macromolecules that represents the cellular structural support involved in key biofunctions such as signal transduction and cellular adhesion. In addition, ECM-associated proteins interact with ECM and with other endogenous structures and molecules to control cellular growth, structural modifications, cellular migration, etc. Among the ECM-associated proteins, secreted protein acidic and rich in cysteine (SPARC) is a protein that is known to be expressed when tissues change. Herein, we put a spotlight on selected, metabolic and homeostatic properties beyond the known properties of ECM and SPARC. Importantly, the synchronization of the metabolic and structural implications of SPARC and the ECM would indicate an adaptation of the metabolism to meet the needs of the changes that the tissues undergo. Highlighting such properties would have important applications in diverse fields that include therapeutics, metabolics, and pathogenesis.
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Curtis, Patrick D., James Atwood, Ron Orlando, and Lawrence J. Shimkets. "Proteins Associated with the Myxococcus xanthus Extracellular Matrix." Journal of Bacteriology 189, no. 21 (2007): 7634–42. http://dx.doi.org/10.1128/jb.01007-07.
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ABSTRACT Fruiting body formation of Myxococcus xanthus, like biofilm formation of many other organisms, involves the production of an extracellular matrix (ECM). While the polysaccharide component has been studied, the protein component has been largely unexplored. Proteins associated with the ECM were solubilized from purified ECM by boiling with sodium dodecyl sulfate and were identified by liquid chromatography-tandem mass spectrometry of tryptic fragments. The ECM is enriched in proteins of novel function; putative functions were assigned for only 5 of the 21 proteins. Thirteen putative ECM proteins had lipoprotein secretion signals. The genes for many ECM proteins were disrupted in the wild-type (WT), fibA, and pilA backgrounds. Disruption of the MXAN4860 gene had no effect in the WT or fibA background but in the pilA background resulted in a 24-h delay in aggregation and sporulation compared to its parent. The results of this study show that the M. xanthus ECM proteome is diverse and novel.
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Yamamoto, H., Y. Shibata, and T. Miyazaki. "Anode Glow Discharge Plasma Treatment of Titanium Plates Facilitates Adsorption of Extracellular Matrix Proteins to the Plates." Journal of Dental Research 84, no. 7 (2005): 668–71. http://dx.doi.org/10.1177/154405910508400717.
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Glow discharge plasma (GDP) supplied to an anode (GDP+) promotes calcium phosphate adsorption onto titanium better than that supplied to a cathode (GDP-). However, the adsorption of extracellular matrix (ECM) proteins is crucial for cell adhesion to titanium. Since GDP+ induced both inorganic adsorption and cell adhesion, we hypothesized that the inorganic adsorption in a culture medium might affect the adsorption of the ECM proteins. In this study, ECM proteins adsorbed on titanium with and without GDP were examined by x-ray photoelectron spectroscopy. After 1 hr of incubation, increasing sodium adsorption on GDP+ specimens induced adsorption of ECM proteins as shown by NH+ and COO− signals without calcium adsorption. In contrast, since no specific adsorption of sodium on GDP-specimens was detected, GDP-did not contribute to the adsorption of ECM proteins. Thus, promotion of sodium adsorption of GDP+ was effective, at least in the initial ECM protein adsorption on a titanium surface.
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Jamaluddin, M. Fairuz B., Yi-An Ko, Manish Kumar, et al. "Proteomic Profiling of Human Uterine Fibroids Reveals Upregulation of the Extracellular Matrix Protein Periostin." Endocrinology 159, no. 2 (2017): 1106–18. http://dx.doi.org/10.1210/en.2017-03018.
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Abstract The central characteristic of uterine fibroids is excessive deposition of extracellular matrix (ECM), which contributes to fibroid growth and bulk-type symptoms. Despite this, very little is known about patterns of ECM protein expression in fibroids and whether these are influenced by the most common genetic anomalies, which relate to MED12. We performed extensive genetic and proteomic analyses of clinically annotated fibroids and adjacent normal myometrium to identify the composition and expression patterns of ECM proteins in MED12 mutation–positive and mutation–negative uterine fibroids. Genetic sequencing of tissue samples revealed MED12 alterations in 39 of 65 fibroids (60%) from 14 patients. Using isobaric tagged–based quantitative mass spectrometry on three selected patients (n = 9 fibroids), we observed a common set of upregulated (&gt;1.5-fold) and downregulated (&lt;0.66-fold) proteins in small, medium, and large fibroid samples of annotated MED12 status. These two sets of upregulated and downregulated proteins were the same in all patients, regardless of variations in fibroid size and MED12 status. We then focused on one of the significant upregulated ECM proteins and confirmed the differential expression of periostin using western blotting and immunohistochemical analysis. Our study defined the proteome of uterine fibroids and identified that increased ECM protein expression, in particular periostin, is a hallmark of uterine fibroids regardless of MED12 mutation status. This study sets the foundation for further investigations to analyze the mechanisms regulating ECM overexpression and the functional role of upregulated ECM proteins in leiomyogenesis.
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Pokhilko, Alexandra, Gaia Brezzo, Lahiru Handunnetthi, et al. "Global proteomic analysis of extracellular matrix in mouse and human brain highlights relevance to cerebrovascular disease." Journal of Cerebral Blood Flow & Metabolism 41, no. 9 (2021): 2423–38. http://dx.doi.org/10.1177/0271678x211004307.
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The extracellular matrix (ECM) is a key interface between the cerebrovasculature and adjacent brain tissues. Deregulation of the ECM contributes to a broad range of neurological disorders. However, despite this importance, our understanding of the ECM composition remains very limited mainly due to difficulties in its isolation. To address this, we developed an approach to extract the cerebrovascular ECM from mouse and human post-mortem normal brain tissues. We then used mass spectrometry with off-line high-pH reversed-phase fractionation to increase the protein detection. This identified more than 1000 proteins in the ECM-enriched fraction, with > 66% of the proteins being common between the species. We report 147 core ECM proteins of the human brain vascular matrisome, including collagens, laminins, fibronectin and nidogens. We next used network analysis to identify the connection between the brain ECM proteins and cerebrovascular diseases. We found that genes related to cerebrovascular diseases, such as COL4A1, COL4A2, VCAN and APOE were significantly enriched in the cerebrovascular ECM network. This provides unique mechanistic insight into cerebrovascular disease and potential drug targets. Overall, we provide a powerful resource to study the functions of brain ECM and highlight a specific role for brain vascular ECM in cerebral vascular disease.
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Evans, J., T. Kaitu'u Lino, S. Fernando, and L. Salamonsen. "173. ENDOMETRIAL REPAIR - ENTER THE MATRIX." Reproduction, Fertility and Development 21, no. 9 (2009): 91. http://dx.doi.org/10.1071/srb09abs173.
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Menstruation and endometrial repair are two opposing functions which occur simultaneously within the menstruating uterus. Whilst the factors that control menstruation are increasingly understood1 the endometrial milieu which governs repair remains elusive. The extracellular-matrix (ECM) plays a dynamic role within the repairing endometrium, with roles suggested for fibronectin and certain integrins2. We have utilised two models of endometrial repair, a mouse menstruation model3, and an endometrial luminal epithelial cell-line (ECC-1)4 with the aim of defining the adhesion and ECM molecules important for endometrial repair. Uterine horns (repairing and non-repairing control from each of 4 mice) were subjected to laser-capture microdissection of the repairing luminal epithelium (LE) and immediate sub-luminal stroma. RNA was extracted and processed for pathway-focused array. ECC-1 cells were grown to over-confluence, wounded and allowed to repair. RNA was extracted on each day during repair and used for oligo-microarray analysis. Menstruating/repairing human endometrium was investigated for expression of ECM molecules by immunohistochemistry.A host of ECM molecules (ADAMTS's, MMP's, cadherins, integrins and matrix proteins) were shown to be altered in the repairing murine endometrium. In agreement with published data2, fibronectin and integrins α5 and β1 were elevated at the time of repair. However, in our models, fibronectin was regulated mainly in the stromal compartment, demonstrated by its absence in the ECC-1 model and concentrated stromal immunolocalization in human endometrium. Both integrins displayed regulated expression in the ECC-1 model and localised to repairing LE of human endometrium. Other noteworthy ECM molecules regulated solely within the murine model include integrins (αM, αL, β2) and selectins expressed on lymphocytes, which may reflect the importance of these cells in endometrial repair5. In conclusion, these data suggest the ECM contributes to the dynamic changes observed during endometrial repair and these models may enable further insight into the roles of each cellular compartment.
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Taha, Isra N., and Alexandra Naba. "Exploring the extracellular matrix in health and disease using proteomics." Essays in Biochemistry 63, no. 3 (2019): 417–32. http://dx.doi.org/10.1042/ebc20190001.
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Abstract The extracellular matrix (ECM) is a complex assembly of hundreds of proteins that constitutes the scaffold of multicellular organisms. In addition to providing architectural and mechanical support to the surrounding cells, it conveys biochemical signals that regulate cellular processes including proliferation and survival, fate determination, and cell migration. Defects in ECM protein assembly, decreased ECM protein production or, on the contrary, excessive ECM accumulation, have been linked to many pathologies including cardiovascular and skeletal diseases, cancers, and fibrosis. The ECM thus represents a potential reservoir of prognostic biomarkers and therapeutic targets. However, our understanding of the global protein composition of the ECM and how it changes during pathological processes has remained limited until recently. In this mini-review, we provide an overview of the latest methodological advances in sample preparation and mass spectrometry-based proteomics that have permitted the profiling of the ECM of now dozens of normal and diseased tissues, including tumors and fibrotic lesions.
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Wu, Chuanyue, and Shoukat Dedhar. "Integrin-linked kinase (ILK) and its interactors." Journal of Cell Biology 155, no. 4 (2001): 505–10. http://dx.doi.org/10.1083/jcb.200108077.
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How intracellular cytoskeletal and signaling proteins connect and communicate with the extracellular matrix (ECM) is a fundamental question in cell biology. Recent biochemical, cell biological, and genetic studies have revealed important roles of cytoplasmic integrin-linked kinase (ILK) and its interactive proteins in these processes. Cell adhesion to ECM is an important process that controls cell shape change, migration, proliferation, survival, and differentiation. Upon adhesion to ECM, integrins and a selective group of cytoskeletal and signaling proteins are recruited to cell matrix contact sites where they link the actin cytoskeleton to the ECM and mediate signal transduction between the intracellular and extracellular compartments. In this review, we discuss the molecular activities and cellular functions of ILK, a protein that is emerging as a key component of the cell–ECM adhesion structures.
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van Dijk, Christian G. M., Laura Louzao-Martinez, Elise van Mulligen, et al. "Extracellular Matrix Analysis of Human Renal Arteries in Both Quiescent and Active Vascular State." International Journal of Molecular Sciences 21, no. 11 (2020): 3905. http://dx.doi.org/10.3390/ijms21113905.
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In vascular tissue engineering strategies, the addition of vascular-specific extracellular matrix (ECM) components may better mimic the in vivo microenvironment and potentially enhance cell–matrix interactions and subsequent tissue growth. For this purpose, the exact composition of the human vascular ECM first needs to be fully characterized. Most research has focused on characterizing ECM components in mature vascular tissue; however, the developing fetal ECM matches the active environment required in vascular tissue engineering more closely. Consequently, we characterized the ECM protein composition of active (fetal) and quiescent (mature) renal arteries using a proteome analysis of decellularized tissue. The obtained human fetal renal artery ECM proteome dataset contains higher levels of 15 ECM proteins versus the mature renal artery ECM proteome, whereas 16 ECM proteins showed higher levels in the mature tissue compared to fetal. Elastic ECM proteins EMILIN1 and FBN1 are significantly enriched in fetal renal arteries and are mainly produced by cells of mesenchymal origin. We functionally tested the role of EMILIN1 and FBN1 by anchoring the ECM secreted by vascular smooth muscle cells (SMCs) to glass coverslips. This ECM layer was depleted from either EMILIN1 or FBN1 by using siRNA targeting of the SMCs. Cultured endothelial cells (ECs) on this modified ECM layer showed alterations on the transcriptome level of multiple pathways, especially the Rho GTPase controlled pathways. However, no significant alterations in adhesion, migration or proliferation were observed when ECs were cultured on EMILIN1- or FNB1-deficient ECM. To conclude, the proteome analysis identified unique ECM proteins involved in the embryonic development of renal arteries. Alterations in transcriptome levels of ECs cultured on EMILIN1- or FBN1-deficient ECM showed that these candidate proteins could affect the endothelial (regenerative) response.
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Tan, Hong, Lorain Junor, Robert L. Price, Russell A. Norris, Jay D. Potts, and Richard L. Goodwin. "Expression and Deposition of Fibrous Extracellular Matrix Proteins in Cardiac Valves during Chick Development." Microscopy and Microanalysis 17, no. 1 (2010): 91–100. http://dx.doi.org/10.1017/s1431927610094365.
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AbstractExtracellular matrix (ECM) plays essential signaling and structural roles required for the proper function of cardiac valves. Cardiac valves initially form as jelly-like cushions, which must adapt to withstand the increased circulation hemodynamics associated with fetal development and birth. This increased biomechanical stability of the developing valves is largely imparted by ECM proteins, which form a highly organized fibrous meshwork. Since heart valve defects contribute to most congenital heart diseases, understanding valve development will provide insight into the pathogenesis of various congenital valve anomalies. Thus, the goal of this study is to describe the spatiotemporal deposition of fibrous ECM proteins during cardiac valve development. Chick embryonic and fetal atrioventricular and semilunar valves were examined by light, confocal, and transmission electron microscopy (TEM). Our data demonstrate that fibrous ECM proteins are deposited when the leaflets are adopting an elongated and compacted phenotype. A general pattern of increased fibrotic ECM deposition was detected in valve tissues. Also, each ECM protein examined displayed a unique pattern of organization, suggesting that regulation of fibrous protein deposition is complex and likely involves both genetic and mechanical factors. In addition, the TEM study revealed the presence of membrane protrusions from valvular endocardium, indicating a potential mechanism for mechanical force transduction.
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Rannels, D. E., S. E. Dunsmore, and R. N. Grove. "Extracellular matrix synthesis and turnover by type II pulmonary epithelial cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 262, no. 5 (1992): L582—L589. http://dx.doi.org/10.1152/ajplung.1992.262.5.l582.
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Both type I and type II pulmonary epithelial cells contact the extracellular matrix (ECM). Type II cell-ECM interactions are bidirectional; they involve matrix-mediated modulation of type II cell differentiation, as well as cellular synthesis and deposition of ECM components. The present experiments examine the kinetics of accumulation of newly synthesized proteins in cell and matrix fractions from primary cultures of type II pneumocytes. Cycloheximide-sensitive incorporation of [3H]leucine into total protein of both the cell and ECM fractions was linear for 24–30 h, when steady-state labeling was reached and maintained to at least day 8. Over this interval, the cells enlarged but did not divide. Newly synthesized proteins recovered in the matrix fraction averaged 1–2% of those in the cells. Relative rates of radiolabeling of matrix proteins peaked at culture day 2 and increased in the absence of serum. In short-pulse studies, initial rates of protein synthesis were equal on culture days 1 and 3; this suggested that the steady-state labeling kinetics above reflected protein turnover. This was supported by rapid loss of radioactivity from the ECM after fresh type II cells were seeded on a prelabeled, cell-free matrix surface. Fresh or conditioned Dulbecco's modified Eagle's medium containing 10% fetal calf serum had little effect on matrix stability. These results demonstrate regulated deposition and turnover of a complex ECM by type II cells and provide a basis for further investigations of factors that control these processes.
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Park, Jisook, Hyun-Seung Lee, Eun-Bi Go, et al. "Proteomic Analysis of the Meniscus Cartilage in Osteoarthritis." International Journal of Molecular Sciences 22, no. 15 (2021): 8181. http://dx.doi.org/10.3390/ijms22158181.
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The distribution of differential extracellular matrix (ECM) in the lateral and medial menisci can contribute to knee instability, and changes in the meniscus tissue can lead to joint disease. Thus, deep proteomic identification of the lateral and medial meniscus cartilage is expected to provide important information for treatment and diagnosis of various knee joint diseases. We investigated the proteomic profiles of 12 lateral/medial meniscus pairs obtained from excess tissue of osteoarthritis patients who underwent knee arthroscopy surgery using mass spectrometry-based techniques and measured 75 ECM protein levels in the lesions using a multiple reaction monitoring (MRM) assay we developed. A total of 906 meniscus proteins with a 1% false discovery rate (FDR) was identified through a tandem mass tag (TMT) analysis showing that the lateral and medial menisci had similar protein expression profiles. A total of 131 ECM-related proteins was included in meniscus tissues such as collagen, fibronectin, and laminin. Our data showed that 14 ECM protein levels were differentially expressed in lateral and medial lesions (p < 0.05). We present the proteomic characterization of meniscal tissue with mass spectrometry-based comparative proteomic analysis and developed an MRM-based assay of ECM proteins correlated with tissue regeneration. The mass spectrometry dataset has been deposited to the MassIVE repository with the dataset identifier MSV000087753.
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Khan, Zia A., and Subrata Chakrabarti. "Cellular Signaling and Potential New Treatment Targets in Diabetic Retinopathy." Experimental Diabetes Research 2007 (2007): 1–12. http://dx.doi.org/10.1155/2007/31867.
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Dysfunction and death of microvascular cells and imbalance between the production and the degradation of extracellular matrix (ECM) proteins are a characteristic feature of diabetic retinopathy (DR). Glucose-induced biochemical alterations in the vascular endothelial cells may activate a cascade of signaling pathways leading to increased production of ECM proteins and cellular dysfunction/death. Chronic diabetes leads to the activation of a number of signaling proteins including protein kinase C, protein kinase B, and mitogen-activated protein kinases. These signaling cascades are activated in response to hyperglycemia-induced oxidative stress, polyol pathway, and advanced glycation end product formation among others. The aberrant signaling pathways ultimately lead to activation of transcription factors such as nuclear factor-κB and activating protein-1. The activity of these transcription factors is also regulated by epigenetic mechanisms through transcriptional coactivator p300. These complex signaling pathways may be involved in glucose-induced alterations of endothelial cell phenotype leading to the production of increased ECM proteins and vasoactive effector molecules causing functional and structural changes in the microvasculature. Understanding of such mechanistic pathways will help to develop future adjuvant therapies for diabetic retinopathy.
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Chaher, Nadia, Reza Hajhosseiny, Alkystis Phinikaridou, and René M. Botnar. "Imaging the Extracellular Matrix in Prevalent Cardiovascular Diseases." Applied Sciences 10, no. 11 (2020): 4001. http://dx.doi.org/10.3390/app10114001.
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The extracellular matrix (ECM) is a highly complex macromolecular network present in all tissues and organs. The ECM is continuously remodelling under an orchestrated process facilitated by many matrix-degrading and matrix-synthesising enzymes in both health and disease. Disturbance of this balance can be the result of or can lead to various diseases. In cardiovascular diseases (CVDs), changes to the ECM are evident in conditions including: atherosclerosis, myocardial infarction (MI), venous thromboembolism (VTE) and abdominal aortic aneurysm (AAA). ECM proteins and ECM regulating enzymes are differently expressed in various CVDs. Most importantly, the altered deposition, macromolecule arrangement and activity of the ECM makes it an attractive marker of disease onset, pathogenesis and progression. Many medical imaging modalities allow disease assessment by exploiting native image contrast, by using non-targeted or by using protein or cell specific (targeted) imaging probes. However, the ability to directly visualise and quantify changes in specific ECM proteins enhances our understanding of the biological role of these proteins, enables monitoring of disease progression and response to treatment and may improve patient diagnosis and allocation of personalised therapies. This review focuses on the biochemistry of the major extracellular matrix proteins and advancements in the development of ECM-targeted probes for molecular imaging of CVD, particularly for applications of molecular magnetic resonance imaging (MRI) and position emission tomography (PET) imaging.
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Ba, X., Y. Meng, Y. Huang, et al. "In Vitro Biomineralization Induced by Self-Assembled Extracellular Matrix Proteins." Key Engineering Materials 361-363 (November 2007): 427–30. http://dx.doi.org/10.4028/www.scientific.net/kem.361-363.427.
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Extracellular matrix (ECM) proteins play an essential role during biomineralization in bone and engineered tissues. In a previous study [1], we showed that calcite preferentially nucleated on pure elastin fibers. However, the actual cellular ECM fibers are composed of a combination of proteins, primarily collagen, fibronectin and some elastin. Here we follow the calcium carbonate- and calcium phosphate- mineralization process in vitro when these ECM proteins are combined and determine the differences between these proteins in the biomineralization process. The surface morphology and mechanical properties of the protein fibers during the early stages were probed by atomic force microscopy (AFM) and shear modulation force microscopy (SMFM). The nucleation of the mineral crystals on the protein matrices was investigated by scanning electron microscopy (SEM). Preliminary data showed that the moduli of all protein fibers increased at the early stages, with collagen having the largest increase in supersaturated calcium bicarbonate solution. In metastable calcium phosphate solutions the modulus of the mixed elastin-fibronectin fibres increased to a greater extent than the moduli of the fibers composed of the single proteins. Longer exposure in the mineral solutions led to the formation of crystals templated along the self-assembled fiber structures.
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Dalton, Caleb J., and Christopher A. Lemmon. "Fibronectin: Molecular Structure, Fibrillar Structure and Mechanochemical Signaling." Cells 10, no. 9 (2021): 2443. http://dx.doi.org/10.3390/cells10092443.
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The extracellular matrix (ECM) plays a key role as both structural scaffold and regulator of cell signal transduction in tissues. In times of ECM assembly and turnover, cells upregulate assembly of the ECM protein, fibronectin (FN). FN is assembled by cells into viscoelastic fibrils that can bind upward of 40 distinct growth factors and cytokines. These fibrils play a key role in assembling a provisional ECM during embryonic development and wound healing. Fibril assembly is also often upregulated during disease states, including cancer and fibrotic diseases. FN fibrils have unique mechanical properties, which allow them to alter mechanotransduction signals sensed and relayed by cells. Binding of soluble growth factors to FN fibrils alters signal transduction from these proteins, while binding of other ECM proteins, including collagens, elastins, and proteoglycans, to FN fibrils facilitates the maturation and tissue specificity of the ECM. In this review, we will discuss the assembly of FN fibrils from individual FN molecules; the composition, structure, and mechanics of FN fibrils; the interaction of FN fibrils with other ECM proteins and growth factors; the role of FN in transmitting mechanobiology signaling events; and approaches for studying the mechanics of FN fibrils.
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Wang, Minghui, Lingling Yue, Xiaowen Cui, et al. "Prediction of Extracellular Matrix Proteins by Fusing Multiple Feature Information, Elastic Net, and Random Forest Algorithm." Mathematics 8, no. 2 (2020): 169. http://dx.doi.org/10.3390/math8020169.
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Extracellular matrix (ECM) proteins play an important role in a series of biological processes of cells. The study of ECM proteins is helpful to further comprehend their biological functions. We propose ECMP-RF (extracellular matrix proteins prediction by random forest) to predict ECM proteins. Firstly, the features of the protein sequence are extracted by combining encoding based on grouped weight, pseudo amino-acid composition, pseudo position-specific scoring matrix, a local descriptor, and an autocorrelation descriptor. Secondly, the synthetic minority oversampling technique (SMOTE) algorithm is employed to process the class imbalance data, and the elastic net (EN) is used to reduce the dimension of the feature vectors. Finally, the random forest (RF) classifier is used to predict the ECM proteins. Leave-one-out cross-validation shows that the balanced accuracy of the training and testing datasets is 97.3% and 97.9%, respectively. Compared with other state-of-the-art methods, ECMP-RF is significantly better than other predictors.
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Dekkers, Bart G. J., Dedmer Schaafsma, S. Adriaan Nelemans, Johan Zaagsma, and Herman Meurs. "Extracellular matrix proteins differentially regulate airway smooth muscle phenotype and function." American Journal of Physiology-Lung Cellular and Molecular Physiology 292, no. 6 (2007): L1405—L1413. http://dx.doi.org/10.1152/ajplung.00331.2006.
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Changes in the ECM and increased airway smooth muscle (ASM) mass are major contributors to airway remodeling in asthma and chronic obstructive pulmonary disease. It has recently been demonstrated that ECM proteins may differentially affect proliferation and expression of phenotypic markers of cultured ASM cells. In the present study, we investigated the functional relevance of ECM proteins in the modulation of ASM contractility using bovine tracheal smooth muscle (BTSM) preparations. The results demonstrate that culturing of BSTM strips for 4 days in the presence of fibronectin or collagen I depressed maximal contraction (Emax) both for methacholine and KCl, which was associated with decreased contractile protein expression. By contrast, both fibronectin and collagen I increased proliferation of cultured BTSM cells. Similar effects were observed for PDGF. Moreover, PDGF augmented fibronectin- and collagen I-induced proliferation in an additive fashion, without an additional effect on contractility or contractile protein expression. The fibronectin-induced depression of contractility was blocked by the integrin antagonist Arg-Gly-Asp-Ser (RGDS) but not by its negative control Gly-Arg-Ala-Asp-Ser-Pro (GRADSP). Laminin, by itself, did not affect contractility or proliferation but reduced the effects of PDGF on these parameters. Strong relationships were found between the ECM-induced changes in Emax in BTSM strips and their proliferative responses in BSTM cells and for Emax and contractile protein expression. Our results indicate that ECM proteins differentially regulate both phenotype and function of intact ASM.
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Franco-Serrano, Luis, David Sánchez-Redondo, Araceli Nájar-García, et al. "Pathogen Moonlighting Proteins: From Ancestral Key Metabolic Enzymes to Virulence Factors." Microorganisms 9, no. 6 (2021): 1300. http://dx.doi.org/10.3390/microorganisms9061300.
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Moonlighting and multitasking proteins refer to proteins with two or more functions performed by a single polypeptide chain. An amazing example of the Gain of Function (GoF) phenomenon of these proteins is that 25% of the moonlighting functions of our Multitasking Proteins Database (MultitaskProtDB-II) are related to pathogen virulence activity. Moreover, they usually have a canonical function belonging to highly conserved ancestral key functions, and their moonlighting functions are often involved in inducing extracellular matrix (ECM) protein remodeling. There are three main questions in the context of moonlighting proteins in pathogen virulence: (A) Why are a high percentage of pathogen moonlighting proteins involved in virulence? (B) Why do most of the canonical functions of these moonlighting proteins belong to primary metabolism? Moreover, why are they common in many pathogen species? (C) How are these different protein sequences and structures able to bind the same set of host ECM protein targets, mainly plasminogen (PLG), and colonize host tissues? By means of an extensive bioinformatics analysis, we suggest answers and approaches to these questions. There are three main ideas derived from the work: first, moonlighting proteins are not good candidates for vaccines. Second, several motifs that might be important in the adhesion to the ECM were identified. Third, an overrepresentation of GO codes related with virulence in moonlighting proteins were seen.
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Senthebane, Dimakatso, Tina Jonker, Arielle Rowe, et al. "The Role of Tumor Microenvironment in Chemoresistance: 3D Extracellular Matrices as Accomplices." International Journal of Molecular Sciences 19, no. 10 (2018): 2861. http://dx.doi.org/10.3390/ijms19102861.
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Background: The functional interplay between tumor cells and their adjacent stroma has been suggested to play crucial roles in the initiation and progression of tumors and the effectiveness of chemotherapy. The extracellular matrix (ECM), a complex network of extracellular proteins, provides both physical and chemicals cues necessary for cell proliferation, survival, and migration. Understanding how ECM composition and biomechanical properties affect cancer progression and response to chemotherapeutic drugs is vital to the development of targeted treatments. Methods: 3D cell-derived-ECMs and esophageal cancer cell lines were used as a model to investigate the effect of ECM proteins on esophageal cancer cell lines response to chemotherapeutics. Immunohistochemical and qRT-PCR evaluation of ECM proteins and integrin gene expression was done on clinical esophageal squamous cell carcinoma biopsies. Esophageal cancer cell lines (WHCO1, WHCO5, WHCO6, KYSE180, KYSE 450 and KYSE 520) were cultured on decellularised ECMs (fibroblasts-derived ECM; cancer cell-derived ECM; combinatorial-ECM) and treated with 0.1% Dimethyl sulfoxide (DMSO), 4.2 µM cisplatin, 3.5 µM 5-fluorouracil and 2.5 µM epirubicin for 24 h. Cell proliferation, cell cycle progression, colony formation, apoptosis, migration and activation of signaling pathways were used as our study endpoints. Results: The expression of collagens, fibronectin and laminins was significantly increased in esophageal squamous cell carcinomas (ESCC) tumor samples compared to the corresponding normal tissue. Decellularised ECMs abrogated the effect of drugs on cancer cell cycling, proliferation and reduced drug induced apoptosis by 20–60% that of those plated on plastic. The mitogen-activated protein kinase-extracellular signal-regulated kinase (MEK-ERK) and phosphoinositide 3-kinase-protein kinase B (PI3K/Akt) signaling pathways were upregulated in the presence of the ECMs. Furthermore, our data show that concomitant addition of chemotherapeutic drugs and the use of collagen- and fibronectin-deficient ECMs through siRNA inhibition synergistically increased cancer cell sensitivity to drugs by 30–50%, and reduced colony formation and cancer cell migration. Conclusion: Our study shows that ECM proteins play a key role in the response of cancer cells to chemotherapy and suggest that targeting ECM proteins can be an effective therapeutic strategy against chemoresistant tumors.
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Cameron, Caroline E. "Identification of a Treponema pallidum Laminin-Binding Protein." Infection and Immunity 71, no. 5 (2003): 2525–33. http://dx.doi.org/10.1128/iai.71.5.2525-2533.2003.
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ABSTRACT Host extracellular matrix (ECM) components represent ideal microbial adhesion targets that many pathogens use for colonization of tissues and initiation of infection. This study investigated the interaction of the spirochete Treponema pallidum with the ECM component laminin. To identify candidate laminin-binding adhesins, the T. pallidum genome was analyzed to predict open reading frames that encode putative outer membrane proteins, as these proteins interact directly with host ECM components. Subsequent recombinant expression of these proteins and analysis of their laminin-binding potential identified one protein, Tp0751, that demonstrated specific attachment to laminin. Tp0751 attached to laminin in a dose-dependent, saturable manner but did not attach to the ECM component collagen type I or IV or to the negative control proteins fetuin or bovine serum albumin. Sodium metaperiodate treatment of laminin reduced the Tp0751-laminin interaction in a concentration-dependent manner, suggesting that oligosaccharides play a role in this interaction. In addition, Tp0751-specific antibodies were detected in serum samples collected from both experimental and natural syphilis infections, indicating that Tp0751 is expressed in vivo during the course of infection. Collectively, these experiments identified Tp0751 as a laminin-binding protein that is expressed during infection and may be involved in attachment of T. pallidum to host tissues.
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Boshuizen, J. A., J. W. A. Rossen, C. K. Sitaram та ін. "Rotavirus Enterotoxin NSP4 Binds to the Extracellular Matrix Proteins Laminin-β3 and Fibronectin". Journal of Virology 78, № 18 (2004): 10045–53. http://dx.doi.org/10.1128/jvi.78.18.10045-10053.2004.
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ABSTRACT Rotavirus is the most important cause of viral gastroenteritis and dehydrating diarrhea in young children. Rotavirus nonstructural protein 4 (NSP4) is an enterotoxin that was identified as an important agent in symptomatic rotavirus infection. To identify cellular proteins that interact with NSP4, a two-hybrid technique with Saccharomyces cerevisiae was used. NSP4 cDNA, derived from the human rotavirus strain Wa, was cloned into the yeast shuttle vector pGBKT7. An intestinal cDNA library derived from Caco-2 cells cloned into the yeast shuttle vector pGAD10 was screened for proteins that interact with NSP4. Protein interactions were confirmed in vivo by coimmunoprecipitation and immunohistochemical colocalization. After two-hybrid library screening, we repeatedly isolated cDNAs encoding the extracellular matrix (ECM) protein laminin-β3 (amino acids [aa] 274 to 878) and a cDNA encoding the ECM protein fibronectin (aa 1755 to 1884). Using deletion mutants of NSP4, we mapped the region of interaction with the ECM proteins between aa 87 and 145. Deletion analysis of laminin-β3 indicated that the region comprising aa 726 to 875 of laminin-β3 interacts with NSP4. Interaction of NSP4 with either laminin-β3 or fibronectin was confirmed by coimmunoprecipitation. NSP4 was present in infected enterocytes and in the basement membrane (BM) of infected neonatal mice and colocalized with laminin-β3, indicating a physiological interaction. In conclusion, two-hybrid screening with NSP4 yielded two potential target proteins, laminin-β3 and fibronectin, interacting with the enterotoxin NSP4. The release of NSP4 from the basal side of infected epithelial cells and the subsequent binding to ECM proteins localized at the BM may signify a new mechanism by which rotavirus disease is established.
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Clarke, Simon R., Llinos G. Harris, R. Geoff Richards, and Simon J. Foster. "Analysis of Ebh, a 1.1-Megadalton Cell Wall-Associated Fibronectin-Binding Protein of Staphylococcus aureus." Infection and Immunity 70, no. 12 (2002): 6680–87. http://dx.doi.org/10.1128/iai.70.12.6680-6687.2002.
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ABSTRACT In order for Staphylococcus aureus to adhere to host extracellular matrix (ECM) substrates, it elicits a wide range of surface proteins. We have characterized a novel ∼1.1-MDa protein in S. aureus, termed Ebh (for ECM-binding protein homologue), which has homology to other ECM-binding proteins. Ebh consists of several domains, including a large central region with 44 imperfect repeats of 126 amino acids. Expression analysis revealed ebh to be growth phase regulated and repressed by agr. A fragment of the central repeat region of Ebh was cloned, overexpressed, and used in ligand-binding studies to determine Ebh function. The recombinant protein was found to specifically bind human fibronectin. Ebh is produced during human infection since serum samples taken from patients with confirmed S. aureus infections were found to contain anti-Ebh antibodies. Localization studies revealed Ebh to be cell envelope associated and is proposed to form a specialized surface structure involved in cellular adhesion.
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Guo, Yihe, Cara Martinez-Williams, Clare E. Yellowley, Henry J. Donahue, and D. Eugene Rannels. "Connexin expression by alveolar epithelial cells is regulated by extracellular matrix." American Journal of Physiology-Lung Cellular and Molecular Physiology 280, no. 2 (2001): L191—L202. http://dx.doi.org/10.1152/ajplung.2001.280.2.l191.
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Extracellular matrix (ECM) proteins promote attachment, spreading, and differentiation of cultured alveolar type II epithelial cells. The present studies address the hypothesis that the ECM also regulates expression and function of gap junction proteins, connexins, in this cell population. Expression of cellular fibronectin and connexin (Cx) 43 increase in parallel during early type II cell culture as Cx26 expression declines. Gap junction intercellular communication is established over the same interval. Cells plated on a preformed, type II cell-derived, fibronectin-rich ECM demonstrate accelerated formation of gap junction plaques and elevated gap junction intercellular communication. These effects are blocked by antibodies against fibronectin, which cause redistribution of Cx43 protein from the plasma membrane to the cytoplasm. Conversely, cells cultured on a laminin-rich ECM, Matrigel, express low levels of Cx43 but high levels of Cx26, reflecting both transcriptional and translational regulation. Cx26 and Cx43 thus demonstrate reciprocal regulation by ECM constituents.
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Pasquali, Guilherme Aguiar Mateus, Raphael Fortes de Oliveira, Paula Andressa Bedim Aiello, Gustavo Do Valle Polycarpo, Rafael Crivellari, and Valquíria Cação da Cruz-Polycarpo. "Performance and economic viability of broiler chicken fed diets with multienzyme complexes." Acta Scientiarum. Animal Sciences 39, no. 1 (2017): 91. http://dx.doi.org/10.4025/actascianimsci.v39i1.32765.
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This study evaluated the effect of multienzyme complexes (EC1 and EC2) in low nutritional density diets on performance and economic viability of broilers. A total of 840 day-old chicks were assigned to 7 treatments, distributed in a completely randomized design: (1) PC: positive control, basal diet formulated to meet nutritional requirements; (2) NC1: negative control, reduced energy and nutrient density diet without enzymes; (3) NC1+EC1; (4) NC2: negative control, diet formulated with 7% over-estimated crude protein and amino acids of soybean meal without enzymes; (5) NC2+EC2; (6) NC3: negative control, reduced energy and nutrient density diet and over-estimation of crude protein and amino acids of soybean meal; (7) NC3+EC1+EC2. Feeding NC1 or NC3 impaired feed conversion ratio at 7, 21 and 42 days, and NC2 at 21 days. Inclusion of EC2 in NC2 diet improved feed conversion ratio and kept it similar to basal diets from 1 to 21 days. Association of EC1 with EC2 in NC3 diet did not improve performance. In summary, inclusion of EC2 in diets with reduced nutrient density keep feed conversion ratio similar to basal diets from 1 to 21 days but does not improve performance of broiler chicken from 1 to 42 days post-hatch.
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Lin, Yi Hsing, Zee-Yong Park, Dayin Lin, et al. "Regulation of cell migration and survival by focal adhesion targeting of Lasp-1." Journal of Cell Biology 165, no. 3 (2004): 421–32. http://dx.doi.org/10.1083/jcb.200311045.
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Large-scale proteomic and functional analysis of isolated pseudopodia revealed the Lim, actin, and SH3 domain protein (Lasp-1) as a novel protein necessary for cell migration, but not adhesion to, the extracellular matrix (ECM). Lasp-1 is a ubiquitously expressed actin-binding protein with a unique domain configuration containing SH3 and LIM domains, and is overexpressed in 8–12% of human breast cancers. We find that stimulation of nonmotile and quiescent cells with growth factors or ECM proteins facilitates Lasp-1 relocalization from the cell periphery to the leading edge of the pseudopodium, where it associates with nascent focal complexes and areas of actin polymerization. Interestingly, although Lasp-1 dynamics in migratory cells occur independently of c-Abl kinase activity and tyrosine phosphorylation, c-Abl activation by apoptotic agents specifically promotes phosphorylation of Lasp-1 at tyrosine 171, which is associated with the loss of Lasp-1 localization to focal adhesions and induction of cell death. Thus, Lasp-1 is a dynamic focal adhesion protein necessary for cell migration and survival in response to growth factors and ECM proteins.
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Shi, Feng, Jennifer Harman, Keigi Fujiwara, and Jane Sottile. "Collagen I matrix turnover is regulated by fibronectin polymerization." American Journal of Physiology-Cell Physiology 298, no. 5 (2010): C1265—C1275. http://dx.doi.org/10.1152/ajpcell.00341.2009.
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Extracellular matrix (ECM) remodeling occurs during normal homeostasis and also plays an important role during development, tissue repair, and in various disease processes. ECM remodeling involves changes in the synthesis, deposition, and degradation of ECM molecules. ECM molecules can be degraded extracellularly, as well as intracellularly following endocytosis. Our data show that the ECM protein fibronectin is an important regulator of ECM remodeling. We previously showed that agents that inhibit the polymerization of fibronectin into ECM fibrils promote the loss of preexisting fibronectin matrix and accelerate fibronectin endocytosis and degradation. In this paper we show that inhibition of fibronectin polymerization leads to the loss of collagen I matrix fibrils and a corresponding increase in the levels of endocytosed collagen I. In contrast, manipulations that stabilize fibronectin matrix fibrils, such as caveolin-1 depletion, stabilize collagen I matrix fibrils and cause a decrease in ECM collagen I endocytosis. Our data also show that endocytosis of ECM collagen I is regulated by both β1 integrins and Endo180/urokinase plasminogen activator associated protein (uPARAP). Unexpectedly, Endo180/uPARAP was also shown to promote the endocytosis of fibronectin from the ECM. These data demonstrate that fibronectin polymerization regulates the remodeling of ECM collagen I, in part, by regulating collagen I endocytosis. Furthermore, these data show that processes that regulate ECM deposition coordinately regulate the removal of proteins from the ECM. These data highlight the complexity of ECM remodeling. This multifaceted regulatory process may be important to ensure tight regulation of ECM fibronectin and collagen I levels.
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Lorentz, Axel, Detlef Schuppan, Andreas Gebert, Michael P. Manns, and Stephan C. Bischoff. "Regulatory effects of stem cell factor and interleukin-4 on adhesion of human mast cells to extracellular matrix proteins." Blood 99, no. 3 (2002): 966–72. http://dx.doi.org/10.1182/blood.v99.3.966.
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Abstract Mast cells are inflammatory and immunoregulatory cells resident in tissues. They develop from bone marrow-derived progenitor cells that enter the tissue through the blood circulation. The specific localization and migration of mast cells in tissues is dependent on their interaction with extracellular matrix (ECM) proteins. Adhesion of human mast cells isolated from intestinal mucosa and cultured in the presence of stem cell factor (SCF) to ECM proteins is analyzed. It was observed that SCF is a unique cytokine enhancing mast cell adhesion to all tested ECM proteins (fibronectin, laminin, collagen I, III, IV, VI, XIV) up to 5-fold, particularly to fibronectin (54% ± 12% of mast cells) and to denatured collagens (40% ± 12% on cyanogen bromide-cleaved peptides of collagen I). Most noteworthy, preculture of mast cells with interleukin-4 (IL-4), in addition to SCF, reduced their potency to adhere to ECM proteins to one third compared to mast cells cultured with SCF alone. Mast cell adhesion was preferentially mediated by β1 integrins, and most cells expressed the ECM-binding integrins α2β1, α3β1, α4β1, α5β1, and αVβ3. SCF-induced mast cell adhesion was totally blocked by wortmannin and apigenin, indicating an involvement of phosphatidylinositol 3-kinase and mitogen-activated protein kinase, and it was related to an up-regulation of the HUTS-21 β1 epitope, which is associated with an activated conformation of β1. In conclusion, these data indicate that SCF induces the adhesion of cultured mast cells to ECM proteins, whereas IL-4 may promote detachment from the ECM.
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Izzi, Valerio, Martin N. Davis, and Alexandra Naba. "Pan-Cancer Analysis of the Genomic Alterations and Mutations of the Matrisome." Cancers 12, no. 8 (2020): 2046. http://dx.doi.org/10.3390/cancers12082046.
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The extracellular matrix (ECM) is a master regulator of all cellular functions and a major component of the tumor microenvironment. We previously defined the “matrisome” as the ensemble of genes encoding ECM proteins and proteins modulating ECM structure or function. While compositional and biomechanical changes in the ECM regulate cancer progression, no study has investigated the genomic alterations of matrisome genes in cancers and their consequences. Here, mining The Cancer Genome Atlas (TCGA) data, we found that copy number alterations and mutations are frequent in matrisome genes, even more so than in the rest of the genome. We also found that these alterations are predicted to significantly impact gene expression and protein function. Moreover, we identified matrisome genes whose mutational burden is an independent predictor of survival. We propose that studying genomic alterations of matrisome genes will further our understanding of the roles of this compartment in cancer progression and will lead to the development of innovative therapeutic strategies targeting the ECM.
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Ishikawa, Yoshihiro, Shinya Ito, Kazuhiro Nagata, Lynn Y. Sakai, and Hans Peter Bächinger. "Intracellular mechanisms of molecular recognition and sorting for transport of large extracellular matrix molecules." Proceedings of the National Academy of Sciences 113, no. 41 (2016): E6036—E6044. http://dx.doi.org/10.1073/pnas.1609571113.
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Extracellular matrix (ECM) proteins are biosynthesized in the rough endoplasmic reticulum (rER) and transported via the Golgi apparatus to the extracellular space. The coat protein complex II (COPII) transport vesicles are approximately 60–90 nm in diameter. However, several ECM molecules are much larger, up to several hundreds of nanometers. Therefore, special COPII vesicles are required to coat and transport these molecules. Transmembrane Protein Transport and Golgi Organization 1 (TANGO1) facilitates loading of collagens into special vesicles. The Src homology 3 (SH3) domain of TANGO1 was proposed to recognize collagen molecules, but how the SH3 domain recognizes various types of collagen is not understood. Moreover, how are large noncollagenous ECM molecules transported from the rER to the Golgi? Here we identify heat shock protein (Hsp) 47 as a guide molecule directing collagens to special vesicles by interacting with the SH3 domain of TANGO1. We also consider whether the collagen secretory model applies to other large ECM molecules.
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Michelson, Peter H., Margaret Tigue, and Jonathan C. R. Jones. "Human Bronchial Epithelial Cells Secrete Laminin 5, Express Hemidesmosomal Proteins, and Assemble Hemidesmosomes." Journal of Histochemistry & Cytochemistry 48, no. 4 (2000): 535–44. http://dx.doi.org/10.1177/002215540004800411.
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Epithelial cells attach to the basement membrane through adhesive contacts between the basal cells of the epithelium and the proteins of the extracellular matrix (ECM). The hemidesmosome (HD) is a specialized cell-ECM contact, that mediates the attachment of the epithelial cell basal surface to the ECM. In bronchial epithelial cells, the protein components that constitute the HD have not been demonstrated. Using immunohistochemical techniques, we determined that normal human bronchial epithelial (NHBE) cells express the HD cell surface integrin α6β4 and produce laminin 5, the ECM protein associated with HDs. Furthermore, expression of the HD-associated structural proteins, bullous pemphigoid antigens 1 (BPAG 1) and 2 (BPAG 2), was demonstrated in NHBE cells by immunofluorescence microscopy and immunoblot analyses. In addition, we confirmed the presence of laminin 5 in the basement membrane (BM) of bronchial epithelial biopsy specimens and of BP230, BP180, and the α6β4 integrin heterodimer at the site of bronchial epithelial cell-ECM interaction in vivo. Finally, using electron microscopy, we were able to demonstrate intact HDs in a glutaraldehyde-fixed NHBE cell monolayer. These findings suggest that bronchial epithelium forms HDs and that the laminin 5-α6β4 integrin interaction may be important in stabilizing epithelial cell adhesion to the BM in the lung.
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Kivelä, Riikka, Heikki Kyröläinen, Harri Selänne, Paavo V. Komi, Heikki Kainulainen, and Veikko Vihko. "A single bout of exercise with high mechanical loading induces the expression of Cyr61/CCN1 and CTGF/CCN2 in human skeletal muscle." Journal of Applied Physiology 103, no. 4 (2007): 1395–401. http://dx.doi.org/10.1152/japplphysiol.00531.2007.
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High mechanical loading was hypothesized to induce the expression of angiogenic and/or lymphangiogenic extracellular matrix (ECM) proteins in skeletal muscle. Eight men performed a strenuous exercise protocol, which consisted of 100 unilateral maximal drop jumps followed by submaximal jumping until exhaustion. Muscle biopsies were taken 30 min and 48 h postexercise from the vastus lateralis muscle and analyzed for the following parameters: mRNA and protein expression of ECM-associated CCN proteins [cysteine-rich angiogenic protein 61 (Cyr61)/CCN1, connective tissue growth factor (CTGF)/CCN2], and mRNA expression of vascular endothelial growth factors (VEGFs) and hypoxia-inducible factor-1α. The mRNA expression of Cyr61 and CTGF increased 30 min after the exercise (14- and 2.5-fold, respectively; P < 0.001). Cyr61 remained elevated 48 h postexercise (threefold; P < 0.05). The mRNA levels of VEGF-A, VEGF-B, VEGF-C, VEGF-D, or hypoxia-inducible factor-1α did not change significantly at either 30 min or 48 h postexercise; however, the variation between subjects increased markedly in VEGF-A and VEGF-B mRNA. Cyr61 protein levels were higher at both 30 min and 48 h after the exercise compared with the control ( P < 0.05). Cyr61 and CTGF proteins were localized to muscle fibers and the surrounding ECM by immunohistochemistry. Fast fibers stained more intensively than slow fibers. In conclusion, mechanical loading induces rapid expression of CCN proteins in human skeletal muscle. This may be one of the early mechanisms involved in skeletal muscle remodeling after exercise, since Cyr61 and CTGF regulate the expression of genes involved in angiogenesis and ECM remodeling.
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Liu, Jing, Wei Zhu, Chun-Ming Jiang, et al. "Mammalian Target of Rapamycin Complex 1 Activation Disrupts the Low-Density Lipoprotein Receptor Pathway: A Novel Mechanism for Extracellular Matrix Accumulation in Human Peritoneal Mesothelial Cells." American Journal of Nephrology 48, no. 5 (2018): 357–68. http://dx.doi.org/10.1159/000494144.
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Peritoneal fibrosis (PF) is characterized by progressive extracellular matrix (ECM) accumulation. Increasing evidence has suggested that ECM synthesis was increased in human peritoneal mesothelial cells (HPMCs) under high-glucose conditions, but the effects of high-glucose peritoneal dialysis solution (PDS) on ECM synthesis have not been fully elucidated. The aim of this study was to explore the potential mechanisms of high-glucose PDS-induced production of ECM in HPMCs. HPMCs were stimulated by high-glucose PDS. The activity of mammalian target of rapamycin complex 1 (mTORC1) was inhibited by rapamycin or regulatory-associated protein of mTOR (raptor) siRNA. Morphological changes in the cells were observed under an inverted microscope. Oil red O, filipin staining and high-performance liquid chromatography were used to examine lipid accumulation. The expression of low-density lipoprotein receptor (LDLr) regulation, the mTORC1 pathway and ECM-associated markers were assessed by real-time polymerase chain reaction and western blot analysis. The results showed that after treatment with PDS, HPMCs showed notable elongation consistent with the morphology of myofibroblasts, and the expression of ECM proteins such as α-smooth muscle actin, fibroblast specific protein-1 and collagen I was increased. In addition, there was a parallel increase in the ECM and lipid accumulation. Moreover, the effect of intracellular lipid deposition was closely correlated with the dysregulation of LDLr, which was mediated through the upregulation of LDLr, sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP), and SREBP-2 and through the enhanced coexpression of the SCAP with the Golgin. Further analysis showed that PDS enhanced the protein phosphorylation of mTOR, eukaryotic initiation factor 4E-binding protein 1, and p70 S6 kinase. Interestingly, blocking mTORC1 activity reversed the dysregulation of LDLr, even in the presence of PDS. These effects were also accompanied by a decrease in the expression of ECM components. Our findings demonstrated that increased mTORC1 activity exacerbated ECM formation in HPMCs by disrupting LDLr regulation, which contributed to lipid disorder-mediated PF.
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Rellmann, Yvonne, and Rita Dreier. "Different Forms of ER Stress in Chondrocytes Result in Short Stature Disorders and Degenerative Cartilage Diseases: New Insights by Cartilage-Specific ERp57 Knockout Mice." Oxidative Medicine and Cellular Longevity 2018 (December 17, 2018): 1–14. http://dx.doi.org/10.1155/2018/8421394.
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Cartilage is essential for skeletal development by endochondral ossification. The only cell type within the tissue, the chondrocyte, is responsible for the production of macromolecules for the extracellular matrix (ECM). Before proteins and proteoglycans are secreted, they undergo posttranslational modification and folding in the endoplasmic reticulum (ER). However, the ER folding capacity in the chondrocytes has to be balanced with physiological parameters like energy and oxygen levels. Specific cellular conditions, e.g., a high protein demand, or pathologic situations disrupt ER homeostasis and lead to the accumulation of poorly folded or misfolded proteins. This state is called ER stress and induces a cellular quality control system, the unfolded protein response (UPR), to restore homeostasis. Different mouse models with ER stress in chondrocytes display comparable skeletal phenotypes representing chondrodysplasias. Therefore, ER stress itself seems to be involved in the pathogenesis of these diseases. It is remarkable that chondrodysplasias with a comparable phenotype arise independent from the sources of ER stress, which are as follows: (1) mutations in ECM proteins leading to aggregation, (2) deficiencies in ER chaperones, (3) mutations in UPR signaling factors, or (4) deficiencies in the degradation of aggregated proteins. In any case, the resulting UPR substantially impairs ECM protein synthesis, chondrocyte proliferation, and/or differentiation or regulation of autophagy and apoptosis. Notably, chondrodysplasias arise no matter if single or multiple events are affected. We analyzed cartilage-specific ERp57 knockout mice and demonstrated that the deficiency of this single protein disulfide isomerase, which is responsible for formation of disulfide bridges in ECM glycoproteins, is sufficient to induce ER stress and to cause an ER stress-related bone phenotype. These mice therefore qualify as a novel model for the analysis of ER stress in chondrocytes. They give new insights in ER stress-related short stature disorders and enable the analysis of ER stress in other cartilage diseases, such as osteoarthritis.
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Gordon-Weeks, Alex, and Arseniy Yuzhalin. "Cancer Extracellular Matrix Proteins Regulate Tumour Immunity." Cancers 12, no. 11 (2020): 3331. http://dx.doi.org/10.3390/cancers12113331.
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The extracellular matrix (ECM) plays an increasingly recognised role in the development and progression of cancer. Whilst significant progress has been made in targeting aspects of the tumour microenvironment such as tumour immunity and angiogenesis, there are no therapies that address the cancer ECM. Importantly, immune function relies heavily on the structure, physics and composition of the ECM, indicating that cancer ECM and immunity are mechanistically inseparable. In this review we highlight mechanisms by which the ECM shapes tumour immunity, identifying potential therapeutic targets within the ECM. These data indicate that to fully realise the potential of cancer immunotherapy, the cancer ECM requires simultaneous consideration.
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Kaufman, Gili, Laiz Nunes, Alex Eftimiades, and Wojtek Tutak. "Enhancing the Three-Dimensional Structure of Adherent Gingival Fibroblasts and Spheroids via a Fibrous Protein-Based Hydrogel Cover." Cells Tissues Organs 202, no. 5-6 (2016): 343–54. http://dx.doi.org/10.1159/000446821.
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Tissue engineering-based therapies rely on the delivery of monolayered fibroblasts on two-dimensional polystyrene-coated and extracellular matrix (ECM) surfaces to regenerate connective tissues. However, this approach may fail to mimic their three-dimensional (3D) native architecture and function. We hypothesize that ECM fibrous proteins, which direct the migration of cells in vivo, may attach and guide polystyrene- and Matrigel™-ECM (M-ECM)-adherent fibroblasts to rearrangement into large multicellular macrostructures with the ability to proliferate. Gingival monolayered fibroblasts and their derived spheroids were added and adhered to tissue culture polystyrene and M-ECM surfaces. The cells were covered with a layer of collagen1 hydrogel combined with vitronectin, fibronectin or fibrin, or 10% M-ECM. The development of 3D cell constructs was characterized by epifluorescence and confocal scanning microscope image analysis. The ECM turnover and the proliferative capabilities of the fibroblasts were determined via gene expression profiling of collagen1, fibronectin, matrix metalloproteinase/metallopeptidase 2, Nanog, and SRY (sex-determining region Y)-box2 (Sox2). Expression of the Sox2 protein was followed by immunostaining. The collagen1 protein had the strongest effect on monolayered and spheroid cell rearrangements, forming large spherical shapes and fused 3D macroconstructs. The addition of fibrin protein was typically required to achieve a similar effect on M-ECM-adherent monolayered fibroblasts. The spheroid fusion process was followed by an increase in cell density and the formation of tight clusters. The fused spheroids continued to maintain their intracellular ECM turnover and proliferation capacities. Collagen1 is a valuable component in the rearrangement of adherent fibroblast monolayers and spheroids. Fibroblast spheroids should preferably be used as basic building blocks to assemble multicellular connective tissue-like macrostructures.
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Subrahmanyam, Nithya, and Hamidreza Ghandehari. "Harnessing Extracellular Matrix Biology for Tumor Drug Delivery." Journal of Personalized Medicine 11, no. 2 (2021): 88. http://dx.doi.org/10.3390/jpm11020088.
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The extracellular matrix (ECM) plays an active role in cell life through a tightly controlled reciprocal relationship maintained by several fibrous proteins, enzymes, receptors, and other components. It is also highly involved in cancer progression. Because of its role in cancer etiology, the ECM holds opportunities for cancer therapy on several fronts. There are targets in the tumor-associated ECM at the level of signaling molecules, enzyme expression, protein structure, receptor interactions, and others. In particular, the ECM is implicated in invasiveness of tumors through its signaling interactions with cells. By capitalizing on the biology of the tumor microenvironment and the opportunities it presents for intervention, the ECM has been investigated as a therapeutic target, to facilitate drug delivery, and as a prognostic or diagnostic marker for tumor progression and therapeutic intervention. This review summarizes the tumor ECM biology as it relates to drug delivery with emphasis on design parameters targeting the ECM.
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Michel, Jean-Baptiste, Guillaume Jondeau, and Dianna M. Milewicz. "From genetics to response to injury: vascular smooth muscle cells in aneurysms and dissections of the ascending aorta." Cardiovascular Research 114, no. 4 (2018): 578–89. http://dx.doi.org/10.1093/cvr/cvy006.
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Abstract Vascular smooth muscle cells (vSMCs) play a crucial role in both the pathogenesis of Aneurysms and Dissections of the ascending thoracic aorta (TAAD) in humans and in the associated adaptive compensatory responses, since thrombosis and inflammatory processes are absent in the majority of cases. Aneurysms and dissections share numerous characteristics, including aetiologies and histopathological alterations: vSMC disappearance, medial areas of mucoid degeneration, and extracellular matrix (ECM) breakdown. Three aetiologies predominate in TAAD in humans: (i) genetic causes in heritable familial forms, (ii) an association with bicuspid aortic valves, and (iii) a sporadic degenerative form linked to the aortic aging process. Genetic forms include mutations in vSMC genes encoding for molecules of the ECM or the TGF-β pathways, or participating in vSMC tone. On the other hand, aneurysms and dissections, whatever their aetiologies, are characterized by an increase in wall permeability leading to transmural advection of plasma proteins which could interact with vSMCs and ECM components. In this context, blood-borne plasminogen appears to play an important role, because its outward convection through the wall is increased in TAAD, and it could be converted to active plasmin at the vSMC membrane. Active plasmin can induce vSMC disappearance, proteolysis of adhesive proteins, activation of MMPs and release of TGF-β from its ECM storage sites. Conversely, vSMCs could respond to aneurysmal biomechanical and proteolytic injury by an epigenetic phenotypic switch, including constitutional overexpression and nuclear translocation of Smad2 and an increase in antiprotease and ECM protein synthesis. In contrast, such an epigenetic phenomenon is not observed in dissections. In this context, dysfunction of proteins involved in vSMC tone are interesting to study, particularly in interaction with plasma protein transport through the wall and TGF-β activation, to establish the relationship between these dysfunctions and ECM proteolysis.
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Chaqour, Brahim, and Charles Karrasch. "Eyeing the Extracellular Matrix in Vascular Development and Microvascular Diseases and Bridging the Divide between Vascular Mechanics and Function." International Journal of Molecular Sciences 21, no. 10 (2020): 3487. http://dx.doi.org/10.3390/ijms21103487.
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The extracellular matrix (ECM) is critical in all aspects of vascular development and health: supporting cell anchorage, providing structure, organization and mechanical stability, and serving as a sink for growth factors and sustained survival signals. Abnormal changes in ECM protein expression, organization, and/or properties, and the ensuing changes in vascular compliance affect vasodilator responses, microvascular pressure transmission, and collateral perfusion. The changes in microvascular compliance are independent factors initiating, driving, and/or exacerbating a plethora of microvascular diseases of the eye including diabetic retinopathy (DR) and vitreoretinopathy, retinopathy of prematurity (ROP), wet age-related macular degeneration (AMD), and neovascular glaucoma. Congruently, one of the major challenges with most vascular regenerative therapies utilizing localized growth factor, endothelial progenitor, or genetically engineered cell delivery, is the regeneration of blood vessels with physiological compliance properties. Interestingly, vascular cells sense physical forces, including the stiffness of their ECM, through mechanosensitive integrins, their associated proteins and the actomyosin cytoskeleton, which generates biochemical signals that culminate in a rapid expression of matricellular proteins such as cellular communication network 1 (CCN1) and CCN2 (aka connective tissue growth factor or CTGF). Loss or gain of function of these proteins alters genetic programs of cell growth, ECM biosynthesis, and intercellular signaling, that culminate in changes in cell behavior, polarization, and barrier function. In particular, the function of the matricellular protein CCN2/CTGF is critical during retinal vessel development and regeneration wherein new blood vessels form and invest a preformed avascular neural retina following putative gradients of matrix stiffness. These observations underscore the need for further in-depth characterization of the ECM-derived cues that dictate structural and functional properties of the microvasculature, along with the development of new therapeutic strategies addressing the ECM-dependent regulation of pathophysiological stiffening of blood vessels in ischemic retinopathies.
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Liu, Kathleen D., Anirban Datta, Wei Yu, et al. "Rac1 is required for reorientation of polarity and lumen formation through a PI 3-kinase-dependent pathway." American Journal of Physiology-Renal Physiology 293, no. 5 (2007): F1633—F1640. http://dx.doi.org/10.1152/ajprenal.00053.2007.
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Epithelial cells are characterized by the ability to form sheets of cells that surround fluid-filled lumens. Cells in these sheets exhibit a characteristic subcellular polarity, with an apical pole that faces the lumen and a basolateral pole that is in contact with other cells and the extracellular matrix (ECM). To investigate the signaling events required for polarization and lumen formation, we have taken advantage of the ability of Madin-Darby canine kidney (MDCK) cells to dynamically remodel their polarity in response to changes in ECM cues. When MDCK cells are grown in suspension culture, they form multicellular “inside-out” cysts with apical proteins found on the peripheral surface and basolateral markers on the interior surface. When these inside-out cysts are embedded in ECM, they rapidly reorient their polarity: apical proteins become localized to the inside surface, and basolateral proteins are found on the surface that contacts ECM. Here we have characterized the signaling requirements for these early molecular reorientation events. Specifically, expression of a dominant-negative form of Rac1 (DN-Rac1) blocks the reorientation of polarity. Phosphoinositide 3′-kinase is required for apical membrane protein remodeling from the initial apical membrane surface. Cells expressing DN-Rac1 fail to detectably activate the PI 3-kinase/protein kinase B pathway. Last, we found that atypical protein kinase C (aPKC) is also required for reorientation of polarity, since an inhibitor of atypical PKC blocks reorientation. This effect cannot be overcome by constitutively active Rac1, demonstrating that both Rac1 and atypical PKC are required for reorientation of cellular polarity.
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Ge, Gaoxiang, та Daniel S. Greenspan. "BMP1 controls TGFβ1 activation via cleavage of latent TGFβ-binding protein". Journal of Cell Biology 175, № 1 (2006): 111–20. http://dx.doi.org/10.1083/jcb.200606058.
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Transforming growth factor β1 (TGFβ1), an important regulator of cell behavior, is secreted as a large latent complex (LLC) in which it is bound to its cleaved prodomain (latency-associated peptide [LAP]) and, via LAP, to latent TGFβ-binding proteins (LTBPs). The latter target LLCs to the extracellular matrix (ECM). Bone morphogenetic protein 1 (BMP1)–like metalloproteinases play key roles in ECM formation, by converting precursors into mature functional proteins, and in morphogenetic patterning, by cleaving the antagonist Chordin to activate BMP2/4. We provide in vitro and in vivo evidence that BMP1 cleaves LTBP1 at two specific sites, thus liberating LLC from ECM and resulting in consequent activation of TGFβ1 via cleavage of LAP by non–BMP1-like proteinases. In mouse embryo fibroblasts, LAP cleavage is shown to be predominantly matrix metalloproteinase 2 dependent. TGFβ1 is a potent inducer of ECM formation and of BMP1 expression. Thus, a role for BMP1-like proteinases in TGFβ1 activation completes a novel fast-forward loop in vertebrate tissue remodeling.
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Martinez-Garcia, Francisco Drusso, Roderick Harold Jan de Hilster, Prashant Kumar Sharma, et al. "Architecture and Composition Dictate Viscoelastic Properties of Organ-Derived Extracellular Matrix Hydrogels." Polymers 13, no. 18 (2021): 3113. http://dx.doi.org/10.3390/polym13183113.
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The proteins and polysaccharides of the extracellular matrix (ECM) provide architectural support as well as biochemical and biophysical instruction to cells. Decellularized, ECM hydrogels replicate in vivo functions. The ECM’s elasticity and water retention renders it viscoelastic. In this study, we compared the viscoelastic properties of ECM hydrogels derived from the skin, lung and (cardiac) left ventricle and mathematically modelled these data with a generalized Maxwell model. ECM hydrogels from the skin, lung and cardiac left ventricle (LV) were subjected to a stress relaxation test under uniaxial low-load compression at a 20%/s strain rate and the viscoelasticity determined. Stress relaxation data were modelled according to Maxwell. Physical data were compared with protein and sulfated GAGs composition and ultrastructure SEM. We show that the skin-ECM relaxed faster and had a lower elastic modulus than the lung-ECM and the LV-ECM. The skin-ECM had two Maxwell elements, the lung-ECM and the LV-ECM had three. The skin-ECM had a higher number of sulfated GAGs, and a highly porous surface, while both the LV-ECM and the lung-ECM had homogenous surfaces with localized porous regions. Our results show that the elasticity of ECM hydrogels, but also their viscoelastic relaxation and gelling behavior, was organ dependent. Part of these physical features correlated with their biochemical composition and ultrastructure.