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Podocyte-associated talin1 is critical for glomerular filtration barrier maintenance.
Tian X, Kim JJ, Monkley SM, Gotoh N, Nandez R, Soda K, Inoue K, Balkin DM, Hassan H, Son SH, Lee Y, Moeckel G, Calderwood DA, Holzman LB, Critchley DR, Zent R, Reiser J, Ishibe S
(2014) J Clin Invest 124: 1098-113
MeSH Terms: Actin Cytoskeleton, Animals, Calpain, Cell Adhesion, Cells, Cultured, Focal Adhesions, Glomerular Filtration Barrier, Humans, Integrin beta1, Mice, Mice, Knockout, Nephrotic Syndrome, Podocytes, Proteinuria, Proteolysis, Renal Insufficiency, Talin
Show Abstract · Added February 25, 2014
Podocytes are specialized actin-rich epithelial cells that line the kidney glomerular filtration barrier. The interface between the podocyte and the glomerular basement membrane requires integrins, and defects in either α3 or β1 integrin, or the α3β1 ligand laminin result in nephrotic syndrome in murine models. The large cytoskeletal protein talin1 is not only pivotal for integrin activation, but also directly links integrins to the actin cytoskeleton. Here, we found that mice lacking talin1 specifically in podocytes display severe proteinuria, foot process effacement, and kidney failure. Loss of talin1 in podocytes caused only a modest reduction in β1 integrin activation, podocyte cell adhesion, and cell spreading; however, the actin cytoskeleton of podocytes was profoundly altered by the loss of talin1. Evaluation of murine models of glomerular injury and patients with nephrotic syndrome revealed that calpain-induced talin1 cleavage in podocytes might promote pathogenesis of nephrotic syndrome. Furthermore, pharmacologic inhibition of calpain activity following glomerular injury substantially reduced talin1 cleavage, albuminuria, and foot process effacement. Collectively, these findings indicate that podocyte talin1 is critical for maintaining the integrity of the glomerular filtration barrier and provide insight into the pathogenesis of nephrotic syndrome.
1 Communities
1 Members
0 Resources
17 MeSH Terms
The integrin β1 subunit regulates paracellular permeability of kidney proximal tubule cells.
Elias BC, Mathew S, Srichai MB, Palamuttam R, Bulus N, Mernaugh G, Singh AB, Sanders CR, Harris RC, Pozzi A, Zent R
(2014) J Biol Chem 289: 8532-44
MeSH Terms: Animals, Cadherins, Cell Membrane Permeability, Cells, Cultured, Claudin-2, Down-Regulation, Epithelial Cells, Gene Deletion, Integrin beta1, Kidney Tubules, Proximal, Mice, Permeability, Up-Regulation, Urine
Show Abstract · Added February 25, 2014
Epithelial cells lining the gastrointestinal tract and kidney have different abilities to facilitate paracellular and transcellular transport of water and solutes. In the kidney, the proximal tubule allows both transcellular and paracellular transport, while the collecting duct primarily facilitates transcellular transport. The claudins and E-cadherin are major structural and functional components regulating paracellular transport. In this study we present the novel finding that the transmembrane matrix receptors, integrins, play a role in regulating paracellular transport of renal proximal tubule cells. Deleting the integrin β1 subunit in these cells converts them from a "loose" epithelium, characterized by low expression of E-cadherin and claudin-7 and high expression of claudin-2, to a "tight" epithelium with increased E-cadherin and claudin-7 expression and decreased claudin-2 expression. This effect is mediated by the integrin β1 cytoplasmic tail and does not entail β1 heterodimerization with an α-subunit or its localization to the cell surface. In addition, we demonstrate that deleting the β1 subunit in the proximal tubule of the kidney results in a major urine-concentrating defect. Thus, the integrin β1 tail plays a key role in regulating the composition and function of tight and adherens junctions that define paracellular transport properties of terminally differentiated renal proximal tubule epithelial cells.
1 Communities
5 Members
1 Resources
14 MeSH Terms
Activation of Rac by Asef2 promotes myosin II-dependent contractility to inhibit cell migration on type I collagen.
Jean L, Majumdar D, Shi M, Hinkle LE, Diggins NL, Ao M, Broussard JA, Evans JC, Choma DP, Webb DJ
(2013) J Cell Sci 126: 5585-97
MeSH Terms: Cell Adhesion, Cell Line, Tumor, Cell Movement, Collagen Type I, Guanine Nucleotide Exchange Factors, Humans, Integrin beta1, Myosin Type II, cdc42 GTP-Binding Protein, rac GTP-Binding Proteins
Show Abstract · Added May 20, 2014
Non-muscle myosin II (MyoII) contractility is central to the regulation of numerous cellular processes, including migration. Rho is a well-characterized modulator of actomyosin contractility, but the function of other GTPases, such as Rac, in regulating contractility is currently not well understood. Here, we show that activation of Rac by the guanine nucleotide exchange factor Asef2 (also known as SPATA13) impairs migration on type I collagen through a MyoII-dependent mechanism that enhances contractility. Knockdown of endogenous Rac or treatment of cells with a Rac-specific inhibitor decreases the amount of active MyoII, as determined by serine 19 (S19) phosphorylation, and negates the Asef2-promoted increase in contractility. Moreover, treatment of cells with blebbistatin, which inhibits MyoII activity, abolishes the Asef2-mediated effect on migration. In addition, Asef2 slows the turnover of adhesions in protrusive regions of cells by promoting large mature adhesions, which has been linked to actomyosin contractility, with increased amounts of active β1 integrin. Hence, our data reveal a new role for Rac activation, promoted by Asef2, in modulating actomyosin contractility, which is important for regulating cell migration and adhesion dynamics.
0 Communities
1 Members
0 Resources
10 MeSH Terms
Integrin β1 is critical for gastrin-releasing peptide receptor-mediated neuroblastoma cell migration and invasion.
Lee S, Qiao J, Paul P, Chung DH
(2013) Surgery 154: 369-75
MeSH Terms: Cell Line, Tumor, Cell Movement, Gastrin-Releasing Peptide, Humans, Integrin alpha2, Integrin alpha3, Integrin beta1, Neoplasm Invasiveness, Neuroblastoma, Receptors, Bombesin
Show Abstract · Added March 7, 2014
BACKGROUND - Gastrin-releasing peptide (GRP) and its receptor, GRP-R, are critically involved in neuroblastoma tumorigenesis; however, the molecular mechanisms and signaling pathways that are responsible for GRP/GRP-R-induced cell migration and invasion remain unclear. In this study, we sought to determine the cell signals involved in GRP/GRP-R-mediated neuroblastoma cell migration and invasion.
METHODS - Human neuroblastoma cell lines SK-N-SH, LAN-1, and IMR-32 were used for our study. Transwell migration and invasion assays were performed after GRP (10(-7) M) stimulation. The cDNA GEArray Microarray kit was used to determine GRP-R-induced gene expression changes. Protein and membrane expression of integrin subunits were confirmed by Western blotting and flow cytometry analysis. siRNA transfection was performed using Lipofectamine 2000. For scratch assay, a confluent monolayer of cells in 6-well plates were wounded with micropipette tip and observed microscopically at 24 to 72 h.
RESULTS - GRP increased neuroblastoma cell migration and expressions of MMP-2 whereas the TIMP-1 level decreased. GRP-R overexpression stimulated SK-N-SH cell migration and upregulated integrin α2, α3, and β1 protein as well as mRNA expression. Targeted silencing of integrin β1 inhibited cell migration.
CONCLUSION - GRP/GRP-R signaling contributes to neuroblastoma cell migration and invasion. Moreover, the integrin ß1 subunit critically regulates GRP-R-mediated neuroblastoma cell migration and invasion.
Copyright © 2013 Mosby, Inc. All rights reserved.
0 Communities
1 Members
0 Resources
10 MeSH Terms
Rab25 regulates integrin expression in polarized colonic epithelial cells.
Krishnan M, Lapierre LA, Knowles BC, Goldenring JR
(2013) Mol Biol Cell 24: 818-31
MeSH Terms: Adenovirus E1A Proteins, Caco-2 Cells, Cell Line, Tumor, Cell Movement, Cell Polarity, Claudin-1, Epithelial Cells, Gene Expression Regulation, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Integrin alpha2, Integrin alpha5, Integrin alpha5beta1, Integrin beta1, Integrins, Intestinal Mucosa, Microvilli, Neoplasm Invasiveness, Proto-Oncogene Proteins, RNA Interference, rab GTP-Binding Proteins
Show Abstract · Added October 7, 2013
Rab25 is a tumor suppressor for colon cancer in humans and mice. To identify elements of intestinal polarity regulated by Rab25, we developed Caco2-BBE cell lines stably expressing short hairpin RNA for Rab25 and lines rescuing Rab25 knockdown with reexpression of rabbit Rab25. Rab25 knockdown decreased α2-, α5-, and β1-integrin expression. We observed colocalization and direct association of Rab25 with α5β1-integrins. Rab25 knockdown also up-regulated claudin-1 expression, increased transepithelial resistance, and increased invasive behavior. Rab25-knockdown cells showed disorganized brush border microvilli with decreases in villin expression. All of these changes were reversed by reintroduction of rabbit Rab25. Rab25 knockdown altered the expression of 29 gene transcripts, including the loss of α5-integrin transcripts. Rab25 loss decreased expression of one transcription factor, ETV4, and overexpression of ETV4 in Rab25-knockdown cells reversed losses of α5β1-integrin. The results suggest that Rab25 controls intestinal cell polarity through the regulation of gene expression.
1 Communities
2 Members
0 Resources
22 MeSH Terms
Pancreatic stellate cells: small cells with a big role in tissue homeostasis.
Means AL
(2013) Lab Invest 93: 4-7
MeSH Terms: Animals, Extracellular Matrix, Extracellular Matrix Proteins, Integrin beta1, Male, Pancreas, Exocrine
Added July 19, 2013
0 Communities
1 Members
0 Resources
6 MeSH Terms
β1 integrin NPXY motifs regulate kidney collecting-duct development and maintenance by induced-fit interactions with cytosolic proteins.
Mathew S, Lu Z, Palamuttam RJ, Mernaugh G, Hadziselimovic A, Chen J, Bulus N, Gewin LS, Voehler M, Meves A, Ballestrem C, Fässler R, Pozzi A, Sanders CR, Zent R
(2012) Mol Cell Biol 32: 4080-91
MeSH Terms: Amino Acid Motifs, Amino Acid Sequence, Animals, Cell Line, Cytosol, Humans, Integrin beta1, Integrin beta3, Kidney Tubules, Collecting, Membrane Proteins, Mice, Molecular Sequence Data, Mutation, Neoplasm Proteins, Protein Binding, Protein Conformation, Talin, Tyrosine
Show Abstract · Added February 24, 2014
Loss of β1 integrin expression inhibits renal collecting-system development. Two highly conserved NPXY motifs in the distal β1 tail regulate integrin function by associating with phosphtyrosine binding (PTB) proteins, such as talin and kindlin. Here, we define the roles of these two tyrosines in collecting-system development and delineate the structural determinants of the distal β1 tail using nuclear magnetic resonance (NMR). Mice carrying alanine mutations have moderate renal collecting-system developmental abnormalities relative to β1-null mice. Phenylalanine mutations did not affect renal collecting-system development but increased susceptibility to renal injury. NMR spectra in bicelles showed the distal β1 tail is disordered and does not interact with the model membrane surface. Alanine or phenylalanine mutations did not alter β1 structure or interactions between α and β1 subunit transmembrane/cytoplasmic domains; however, they did decrease talin and kindlin binding. Thus, these studies highlight the fact that the functional roles of the NPXY motifs are organ dependent. Moreover, the β1 cytoplasmic tail, in the context of the adjacent transmembrane domain in bicelles, is significantly different from the more ordered, membrane-associated β3 integrin tail. Finally, tyrosine mutations of β1 NPXY motifs induce phenotypes by disrupting their interactions with critical integrin binding proteins like talins and kindlins.
1 Communities
4 Members
1 Resources
18 MeSH Terms
Renal collecting system growth and function depend upon embryonic γ1 laminin expression.
Yang DH, McKee KK, Chen ZL, Mernaugh G, Strickland S, Zent R, Yurchenco PD
(2011) Development 138: 4535-44
MeSH Terms: Animals, Basement Membrane, Diabetes Insipidus, Female, Gene Expression Regulation, Developmental, Growth Substances, Heparitin Sulfate, Hydronephrosis, Integrin beta1, Kidney Tubules, Collecting, Laminin, Male, Mesoderm, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Morphogenesis, Pregnancy, Signal Transduction
Show Abstract · Added February 25, 2014
In order to understand the functions of laminins in the renal collecting system, the Lamc1 gene was inactivated in the developing mouse ureteric bud (UB). Embryos bearing null alleles exhibited laminin deficiency prior to mesenchymal tubular induction and either failed to develop a UB with involution of the mesenchyme, or developed small kidneys with decreased proliferation and branching, delayed renal vesicle formation and postnatal emergence of a water transport deficit. Embryonic day 12.5 kidneys revealed an almost complete absence of basement membrane proteins and reduced levels of α6 integrin and FGF2. mRNA levels for fibroblast growth factor 2 (FGF2) and mediators of the GDNF/RET and WNT11 signaling pathway were also decreased. Furthermore, collecting duct cells derived from laminin-deficient kidneys and grown in collagen gels were found to proliferate and branch slowly. The laminin-deficient cells exhibited decreased activation of growth factor- and integrin-dependent pathways, whereas heparin lyase-treated and β1 integrin-null cells exhibited more selective decreases. Collectively, these data support a requirement of γ1 laminins for assembly of the collecting duct system basement membrane, in which immobilized ligands act as solid-phase agonists to promote branching morphogenesis, growth and water transport functions.
1 Communities
1 Members
0 Resources
20 MeSH Terms
From touchdown to transcription: the reovirus cell entry pathway.
Danthi P, Guglielmi KM, Kirchner E, Mainou B, Stehle T, Dermody TS
(2010) Curr Top Microbiol Immunol 343: 91-119
MeSH Terms: Animals, Capsid Proteins, Cell Adhesion Molecules, Endocytosis, Humans, Immunity, Innate, Immunoglobulins, Integrin beta1, Receptors, Cell Surface, Reoviridae, Virion, Virus Assembly, Virus Attachment, Virus Internalization
Show Abstract · Added December 10, 2013
Mammalian orthoreoviruses (reoviruses) are prototype members of the Reoviridae family of nonenveloped viruses. Reoviruses contain ten double-stranded RNA gene segments enclosed in two concentric protein shells, outer capsid and core. These viruses serve as a versatile experimental system for studies of virus cell entry, innate immunity, and organ-specific disease. Reoviruses engage cells by binding to cell-surface carbohydrates and the immunoglobulin superfamily member, junctional adhesion molecule-A (JAM-A). JAM-A is a homodimer formed by extensive contacts between its N-terminal immunoglobulin-like domains. Reovirus attachment protein σ1 disrupts the JAM-A dimer, engaging a single JAM-A molecule by virtually the same interface used for JAM-A homodimerization. Following attachment to JAM-A and carbohydrate, reovirus internalization is promoted by β1 integrins, most likely via clathrin-dependent endocytosis. In the endocytic compartment, reovirus outer-capsid protein σ3 is removed by cathepsin proteases, which exposes the viral membrane-penetration protein, μ1. Proteolytic processing and conformational rearrangements of μ1 mediate endosomal membrane rupture and delivery of transcriptionally active reovirus core particles into the host cell cytoplasm. These events also allow the φ cleavage fragment of μ1 to escape into the cytoplasm where it activates NF-κB and elicits apoptosis. This review will focus on mechanisms of reovirus cell entry and activation of innate immune response signaling pathways.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Loss of Rab25 promotes the development of intestinal neoplasia in mice and is associated with human colorectal adenocarcinomas.
Nam KT, Lee HJ, Smith JJ, Lapierre LA, Kamath VP, Chen X, Aronow BJ, Yeatman TJ, Bhartur SG, Calhoun BC, Condie B, Manley NR, Beauchamp RD, Coffey RJ, Goldenring JR
(2010) J Clin Invest 120: 840-9
MeSH Terms: Adenocarcinoma, Animals, Cell Transformation, Neoplastic, Colorectal Neoplasms, Epithelial Cells, Female, Gene Expression Regulation, Neoplastic, Humans, Integrin beta1, Intestinal Polyps, Male, Mice, Mice, Knockout, Neoplasm Staging, Proteins, Smad3 Protein, Tumor Suppressor Proteins, rab GTP-Binding Proteins
Show Abstract · Added October 7, 2013
Transformation of epithelial cells is associated with loss of cell polarity, which includes alterations in cell morphology as well as changes in the complement of plasma membrane proteins. Rab proteins regulate polarized trafficking to the cell membrane and therefore represent potential regulators of this neoplastic transition. Here we have demonstrated a tumor suppressor function for Rab25 in intestinal neoplasia in both mice and humans. Human colorectal adenocarcinomas exhibited reductions in Rab25 expression independent of stage, with lower Rab25 expression levels correlating with substantially shorter patient survival. In wild-type mice, Rab25 was strongly expressed in cells luminal to the proliferating cells of intestinal crypts. While Rab25-deficient mice did not exhibit gross pathology, ApcMin/+ mice crossed onto a Rab25-deficient background showed a 4-fold increase in intestinal polyps and a 2-fold increase in colonic tumors compared with parental ApcMin/+ mice. Rab25-deficient mice had decreased beta1 integrin staining in the lateral membranes of villus cells, and this pattern was accentuated in Rab25-deficient mice crossed onto the ApcMin/+ background. Additionally, Smad3+/- mice crossed onto a Rab25-deficient background demonstrated a marked increase in colonic tumor formation. Taken together, these results suggest that Rab25 may function as a tumor suppressor in intestinal epithelial cells through regulation of protein trafficking to the cell surface.
3 Communities
4 Members
0 Resources
18 MeSH Terms