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Results: 11 to 20 of 186

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Integrin alpha6 maintains the structural integrity of the kidney collecting system.
Viquez OM, Yazlovitskaya EM, Tu T, Mernaugh G, Secades P, McKee KK, Georges-Labouesse E, De Arcangelis A, Quaranta V, Yurchenco P, Gewin LC, Sonnenberg A, Pozzi A, Zent R
(2017) Matrix Biol 57-58: 244-257
MeSH Terms: Animals, Apoptosis, Basement Membrane, Cell Adhesion, Cell Movement, Cell Proliferation, Epithelial Cells, Fibrosis, Gene Expression Regulation, Humans, Integrin alpha6beta1, Integrin alpha6beta4, Kidney Tubules, Collecting, Laminin, Mice, Mice, Knockout, Protein Binding, Signal Transduction, Ureter, Ureteral Obstruction
Show Abstract · Added March 26, 2017
Laminins are a major constituent of the basement membranes of the kidney collecting system. Integrins, transmembrane receptors formed by non-covalently bound α and β subunits, serve as laminin receptors, but their role in development and homeostasis of the kidney collecting system is poorly defined. Integrin α3β1, one of the major laminin receptors, plays a minor role in kidney collecting system development, while the role of α6 containing integrins (α6β1 and α6β4), the other major laminin receptors, is unknown. Patients with mutations in α6 containing integrins not only develop epidermolysis bullosa, but also have abnormalities in the kidney collecting system. In this study, we show that selectively deleting the α6 or β4 integrin subunits at the initiation of ureteric bud development in mice does not affect morphogenesis. However, the collecting system becomes dilated and dysmorphic as the mice age. The collecting system in both null genotypes was also highly susceptible to unilateral ureteric obstruction injury with evidence of excessive tubule dilatation and epithelial cell apoptosis. Mechanistically, integrin α6-null collecting duct cells are unable to withstand high mechanical force when adhered to laminin. Thus, we conclude that α6 integrins are important for maintaining the integrity of the kidney collecting system by enhancing tight adhesion of the epithelial cells to the basement membrane. These data give a mechanistic explanation for the association between kidney collecting system abnormalities in patients and epidermolysis bullosa.
Copyright © 2017 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.
1 Communities
3 Members
1 Resources
20 MeSH Terms
The nature and biology of basement membranes.
Pozzi A, Yurchenco PD, Iozzo RV
(2017) Matrix Biol 57-58: 1-11
MeSH Terms: Agrin, Animals, Basement Membrane, Bone Diseases, Developmental, Collagen Type IV, Diabetic Nephropathies, Extracellular Matrix, Gene Expression Regulation, Heparan Sulfate Proteoglycans, Humans, Laminin, Lupus Nephritis, Mechanotransduction, Cellular, Membrane Glycoproteins, Mutation, Protein Isoforms
Show Abstract · Added March 26, 2017
Basement membranes are delicate, nanoscale and pliable sheets of extracellular matrices that often act as linings or partitions in organisms. Previously considered as passive scaffolds segregating polarized cells, such as epithelial or endothelial cells, from the underlying mesenchyme, basement membranes have now reached the center stage of biology. They play a multitude of roles from blood filtration to muscle homeostasis, from storing growth factors and cytokines to controlling angiogenesis and tumor growth, from maintaining skin integrity and neuromuscular structure to affecting adipogenesis and fibrosis. Here, we will address developmental, structural and biochemical aspects of basement membranes and discuss some of the pathogenetic mechanisms causing diseases linked to abnormal basement membranes.
Copyright © 2017 Elsevier B.V. All rights reserved.
0 Communities
0 Members
1 Resources
16 MeSH Terms
Lysyl Oxidase-like-2 Cross-links Collagen IV of Glomerular Basement Membrane.
Añazco C, López-Jiménez AJ, Rafi M, Vega-Montoto L, Zhang MZ, Hudson BG, Vanacore RM
(2016) J Biol Chem 291: 25999-26012
MeSH Terms: Amino Acid Oxidoreductases, Animals, Collagen Type IV, Extracellular Matrix, Glomerular Basement Membrane, HEK293 Cells, Humans, Mice
Show Abstract · Added October 30, 2016
The 7S dodecamer is recognized as an important structural cross-linking domain of collagen IV networks that provide mechanical stability to basement membranes, a specialized form of extracellular matrix essential for the development and maintenance of tissue architecture. Although the 7S dodecamer is stabilized by covalent cross-linking, the molecular mechanism by which such cross-links are formed has not been revealed. Here, we aimed to identify the enzyme(s) that cross-links the 7S dodecamer and characterize its expression in the kidney glomerulus. Pharmacological inhibition of candidate extracellular matrix enzymes revealed that lysyl oxidase activity is required for cross-linking of 7S polypeptides. Among all lysyl oxidase family members, lysyl oxidase-like-2 (LOXL2) was identified as the isoform cross-linking collagen IV in mouse embryonal PFHR-9 cells. Biochemical analyses revealed that LOXL2 readily promoted the formation of lysyl-derived cross-links in the 7S dodecamer but not in the NC1 domain. We also established that LOXL2 is the main lysyl oxidase family member present in the glomerular extracellular matrix. Altogether, we demonstrate that LOXL2 is a novel component of the molecular machinery that forms cross-linked collagen IV networks, which are essential for glomerular basement membrane stability and molecular ultrafiltration function.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
1 Communities
1 Members
1 Resources
8 MeSH Terms
Proprotein Convertase Processing Enhances Peroxidasin Activity to Reinforce Collagen IV.
Colon S, Bhave G
(2016) J Biol Chem 291: 24009-24016
MeSH Terms: Basement Membrane, Collagen Type IV, Extracellular Matrix Proteins, HEK293 Cells, Humans, Peroxidase, Proprotein Convertases, Protein Domains
Show Abstract · Added March 3, 2020
The basement membrane (BM) is a form of extracellular matrix that underlies cell layers in nearly all animal tissues. Type IV collagen, a major constituent of BMs, is critical for tissue development and architecture. The enzyme peroxidasin (Pxdn), an extracellular matrix-associated protein, catalyzes the formation of structurally reinforcing sulfilimine cross-links within the collagen IV network, an event essential to basement membrane integrity. Although the catalytic function of Pxdn is known, the regulation of its activity remains unclear. In this work we show through N-terminal sequencing, pharmacologic studies, and mutational analysis that proprotein convertases (PCs) proteolytically process human Pxdn at Arg-1336, a location relatively close to its C terminus. PC processing enhances the enzymatic activity of Pxdn and facilitates the formation of sulfilimine cross-links in collagen IV. Thus, PC processing of Pxdn is a key regulatory step that contributes to its function and, therefore, supports BM integrity and homeostasis.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
0 Communities
1 Members
0 Resources
MeSH Terms
Embryo implantation triggers dynamic spatiotemporal expression of the basement membrane toolkit during uterine reprogramming.
Jones-Paris CR, Paria S, Berg T, Saus J, Bhave G, Paria BC, Hudson BG
(2017) Matrix Biol 57-58: 347-365
MeSH Terms: Animals, Basement Membrane, Collagen Type IV, Embryo Implantation, Extracellular Matrix Proteins, Female, Fluorescent Antibody Technique, Gene Expression Regulation, Injections, Laminin, Mice, Peptide Fragments, Peroxidase, Pregnancy, Protein-Serine-Threonine Kinases, RNA, Messenger, Sesame Oil, Uterus
Show Abstract · Added October 30, 2016
Basement membranes (BMs) are specialized extracellular scaffolds that influence behaviors of cells in epithelial, endothelial, muscle, nervous, and fat tissues. Throughout development and in response to injury or disease, BMs are fine-tuned with specific protein compositions, ultrastructure, and localization. These features are modulated through implements of the BM toolkit that is comprised of collagen IV, laminin, perlecan, and nidogen. Two additional proteins, peroxidasin and Goodpasture antigen-binding protein (GPBP), have recently emerged as potential members of the toolkit. In the present study, we sought to determine whether peroxidasin and GPBP undergo dynamic regulation in the assembly of uterine tissue BMs in early pregnancy as a tractable model for dynamic adult BMs. We explored these proteins in the context of collagen IV and laminin that are known to extensively change for decidualization. Electron microscopic analyses revealed: 1) a smooth continuous layer of BM in between the epithelial and stromal layers of the preimplantation endometrium; and 2) interrupted, uneven, and progressively thickened BM within the pericellular space of the postimplantation decidua. Quantification of mRNA levels by qPCR showed changes in expression levels that were complemented by immunofluorescence localization of peroxidasin, GPBP, collagen IV, and laminin. Novel BM-associated and subcellular spatiotemporal localization patterns of the four components suggest both collective pericellular functions and distinct functions in the uterus during reprogramming for embryo implantation.
Copyright © 2016 Elsevier B.V. All rights reserved.
1 Communities
2 Members
3 Resources
18 MeSH Terms
Glomerular basement membrane heparan sulfate in health and disease: A regulator of local complement activation.
Borza DB
(2017) Matrix Biol 57-58: 299-310
MeSH Terms: Agrin, Animals, Collagen Type IV, Complement Activation, Complement C3b, Complement Factor H, Gene Expression Regulation, Glomerular Basement Membrane, Glomerulonephritis, Membranous, Heparitin Sulfate, Humans, Laminin, Lupus Nephritis, Membrane Glycoproteins, Signal Transduction, Static Electricity
Show Abstract · Added December 2, 2016
The glomerular basement membrane (GBM) is an essential component of the glomerular filtration barrier. Heparan sulfate proteoglycans such as agrin are major components of the GBM, along with α345(IV) collagen, laminin-521 and nidogen. A loss of GBM heparan sulfate chains is associated with proteinuria in several glomerular diseases and may contribute to the underlying pathology. As the major determinants of the anionic charge of the GBM, heparan sulfate chains have been thought to impart charge selectivity to the glomerular filtration, a view challenged by the negligible albuminuria in mice that lack heparan sulfate in the GBM. Recent studies provide increasing evidence that heparan sulfate chains modulate local complement activation by recruiting complement regulatory protein factor H, the major inhibitor of the alternative pathway in plasma. Factor H selectively inactivates C3b bound to surfaces bearing host-specific polyanions such as heparan sulfate, thus limiting complement activation on self surfaces such as the GBM, which are not protected by cell-bound complement regulators. We discuss mechanisms whereby the acquired loss of GBM heparan sulfate can impair the local regulation of the alternative pathway, exacerbating complement activation and glomerular injury in immune-mediated kidney diseases such as membranous nephropathy and lupus nephritis.
Copyright © 2016 Elsevier B.V. All rights reserved.
1 Communities
1 Members
0 Resources
16 MeSH Terms
Extracellular chloride signals collagen IV network assembly during basement membrane formation.
Cummings CF, Pedchenko V, Brown KL, Colon S, Rafi M, Jones-Paris C, Pokydeshava E, Liu M, Pastor-Pareja JC, Stothers C, Ero-Tolliver IA, McCall AS, Vanacore R, Bhave G, Santoro S, Blackwell TS, Zent R, Pozzi A, Hudson BG
(2016) J Cell Biol 213: 479-94
MeSH Terms: Amino Acid Sequence, Animals, Basement Membrane, Cattle, Cell Line, Tumor, Chlorides, Collagen Type IV, Humans, Phylogeny, Protein Conformation, Protein Structure, Tertiary, Protein Subunits
Show Abstract · Added June 14, 2016
Basement membranes are defining features of the cellular microenvironment; however, little is known regarding their assembly outside cells. We report that extracellular Cl(-) ions signal the assembly of collagen IV networks outside cells by triggering a conformational switch within collagen IV noncollagenous 1 (NC1) domains. Depletion of Cl(-) in cell culture perturbed collagen IV networks, disrupted matrix architecture, and repositioned basement membrane proteins. Phylogenetic evidence indicates this conformational switch is a fundamental mechanism of collagen IV network assembly throughout Metazoa. Using recombinant triple helical protomers, we prove that NC1 domains direct both protomer and network assembly and show in Drosophila that NC1 architecture is critical for incorporation into basement membranes. These discoveries provide an atomic-level understanding of the dynamic interactions between extracellular Cl(-) and collagen IV assembly outside cells, a critical step in the assembly and organization of basement membranes that enable tissue architecture and function. Moreover, this provides a mechanistic framework for understanding the molecular pathobiology of NC1 domains.
© 2016 Cummings et al.
1 Communities
5 Members
3 Resources
12 MeSH Terms
Antibodies to α5 chain of collagen IV are pathogenic in Goodpasture's disease.
Cui Z, Zhao MH, Jia XY, Wang M, Hu SY, Wang SX, Yu F, Brown KL, Hudson BG, Pedchenko V
(2016) J Autoimmun 70: 1-11
MeSH Terms: Aged, Amino Acid Sequence, Animals, Anti-Glomerular Basement Membrane Disease, Autoantibodies, Autoantigens, Autoimmunity, Biopsy, Case-Control Studies, Cell Line, Tumor, Collagen Type IV, Disease Models, Animal, Epitope Mapping, Epitopes, Female, Humans, Kidney Glomerulus, Male, Models, Molecular, Protein Conformation, Protein Subunits, Rats, Rats, Inbred WKY
Show Abstract · Added June 14, 2016
Autoantibody against glomerular basement membrane (GBM) plays a direct role in the initiation and development of Goodpasture's (GP) disease. The principal autoantigen is the non-collagenous domain 1 (NC1) of α3 chain of collagen IV, with two immunodominant epitopes, EA-α3 and EB-α3. We recently demonstrated that antibodies targeting α5NC1 are bound to kidneys in GP patients, suggesting their pathogenic relevance. In the present study, we sought to assess the pathogenicity of the α5 autoantibody with clinical and animal studies. Herein, we present a special case of GP disease with circulating autoantibody reactive exclusively to the α5NC1 domain. This autoantibody reacted with conformational epitopes within GBM collagen IV hexamer and produced a linear IgG staining on frozen sections of human kidney. The antibody binds to the two regions within α5NC1 domain, EA and EB, and inhibition ELISA indicates that they are targeted by distinct sub-populations of autoantibodies. Sequence analysis highlights five residues that determine specificity of antibody targeting EA and EB epitopes of α5NC1 over homologous regions in α3NC1. Furthermore, immunization with recombinant α5NC1 domain induced crescentic glomerulonephritis and alveolar hemorrhage in Wistar-Kyoto rats. Thus, patient data and animal studies together reveal the pathogenicity of α5 antibodies. Given previously documented cases of GP disease with antibodies selectively targeting α3NC1 domain, our data presents a conundrum of why α3-specific antibodies developing in majority of GP patients, with α5-specific antibodies emerged in isolated cases, the answer for which is critical for understanding of etiology and progression of the GP disease.
Copyright © 2016 Elsevier Ltd. All rights reserved.
1 Communities
1 Members
1 Resources
23 MeSH Terms
BMP signaling and cellular dynamics during regeneration of airway epithelium from basal progenitors.
Tadokoro T, Gao X, Hong CC, Hotten D, Hogan BL
(2016) Development 143: 764-73
MeSH Terms: Animals, Apoptosis, Basement Membrane, Bone Morphogenetic Proteins, Cell Differentiation, Cell Proliferation, Epithelial Cells, Green Fluorescent Proteins, Ligands, Lung, Male, Mice, Mice, Inbred C57BL, Pyrazoles, Pyrimidines, Regeneration, Respiratory Mucosa, Signal Transduction, Stem Cells, Trachea
Show Abstract · Added February 22, 2016
The pseudostratified epithelium of the lung contains ciliated and secretory luminal cells and basal stem/progenitor cells. To identify signals controlling basal cell behavior we screened factors that alter their self-renewal and differentiation in a clonal organoid (tracheosphere) assay. This revealed that inhibitors of the canonical BMP signaling pathway promote proliferation but do not affect lineage choice, whereas exogenous Bmp4 inhibits proliferation and differentiation. We therefore followed changes in BMP pathway components in vivo in the mouse trachea during epithelial regeneration from basal cells after injury. The findings suggest that BMP signaling normally constrains proliferation at steady state and this brake is released transiently during repair by the upregulation of endogenous BMP antagonists. Early in repair, the packing of epithelial cells along the basal lamina increases, but density is later restored by active extrusion of apoptotic cells. Systemic administration of the BMP antagonist LDN-193189 during repair initially increases epithelial cell number but, following the shedding phase, normal density is restored. Taken together, these results reveal crucial roles for both BMP signaling and cell shedding in homeostasis of the respiratory epithelium.
© 2016. Published by The Company of Biologists Ltd.
1 Communities
1 Members
0 Resources
20 MeSH Terms
Cell Receptor-Basement Membrane Interactions in Health and Disease: A Kidney-Centric View.
Borza CM, Chen X, Zent R, Pozzi A
(2015) Curr Top Membr 76: 231-53
MeSH Terms: Animals, Basement Membrane, Epithelial Cells, Humans, Kidney, Kidney Diseases, Protein Binding, Receptors, Cell Surface
Show Abstract · Added February 4, 2016
Cell-extracellular matrix (ECM) interactions are essential for tissue development, homeostasis, and response to injury. Basement membranes (BMs) are specialized ECMs that separate epithelial or endothelial cells from stromal components and interact with cells via cellular receptors, including integrins and discoidin domain receptors. Disruption of cell-BM interactions due to either injury or genetic defects in either the ECM components or cellular receptors often lead to irreversible tissue injury and loss of organ function. Animal models that lack specific BM components or receptors either globally or in selective tissues have been used to help with our understanding of the molecular mechanisms whereby cell-BM interactions regulate organ function in physiological and pathological conditions. We review recently published works on animal models that explore how cell-BM interactions regulate kidney homeostasis in both health and disease.
Copyright © 2015 Elsevier Inc. All rights reserved.
1 Communities
2 Members
1 Resources
8 MeSH Terms