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Interaction of phosphorylated Rab11-FIP2 with Eps15 regulates apical junction composition.
Lapierre LA, Manning EH, Mitchell KM, Caldwell CM, Goldenring JR
(2017) Mol Biol Cell 28: 1088-1100
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Cadherins, Carrier Proteins, Cell Polarity, Dogs, Endosomes, Epithelial Cells, Gene Knockout Techniques, HEK293 Cells, Humans, Intercellular Junctions, Madin Darby Canine Kidney Cells, Membrane Proteins, Occludin, Phosphorylation, Protein Binding, Protein Transport, rab GTP-Binding Proteins
Show Abstract · Added April 18, 2017
MARK2 regulates the establishment of polarity in Madin-Darby canine kidney (MDCK) cells in part through phosphorylation of serine 227 of Rab11-FIP2. We identified Eps15 as an interacting partner of phospho-S227-Rab11-FIP2 (pS227-FIP2). During recovery from low calcium, Eps15 localized to the lateral membrane before pS227-FIP2 arrival. Later in recovery, Eps15 and pS227-FIP2 colocalized at the lateral membrane. In MDCK cells expressing the pseudophosphorylated FIP2 mutant FIP2(S227E), during recovery from low calcium, Eps15 was trapped and never localized to the lateral membrane. Mutation of any of the three NPF domains within GFP-FIP2(S227E) rescued Eps15 localization at the lateral membrane and reestablished single-lumen cyst formation in GFP-FIP2(S227E)-expressing cells in three-dimensional (3D) culture. Whereas expression of GFP-FIP2(S227E) induced the loss of E-cadherin and occludin, mutation of any of the NPF domains of GFP-FIP2(S227E) reestablished both proteins at the apical junctions. Knockdown of Eps15 altered the spatial and temporal localization of pS227-FIP2 and also elicited formation of multiple lumens in MDCK 3D cysts. Thus an interaction of Eps15 and pS227-FIP2 at the appropriate time and location in polarizing cells is necessary for proper establishment of epithelial polarity.
© 2017 Lapierre et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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19 MeSH Terms
PTK7-Src signaling at epithelial cell contacts mediates spatial organization of actomyosin and planar cell polarity.
Andreeva A, Lee J, Lohia M, Wu X, Macara IG, Lu X
(2014) Dev Cell 29: 20-33
MeSH Terms: Actomyosin, Animals, Cell Differentiation, Cell Polarity, Cells, Cultured, Cochlea, Dogs, Epithelial Cells, Intercellular Junctions, Madin Darby Canine Kidney Cells, Mice, Phosphorylation, Receptor Protein-Tyrosine Kinases, Signal Transduction, rho-Associated Kinases
Show Abstract · Added May 30, 2014
Actomyosin contractility plays a key role in tissue morphogenesis. During mammalian development, PTK7 regulates epithelial morphogenesis and planar cell polarity (PCP) through modulation of actomyosin contractility, but the underlying mechanism is unknown. Here, we show that PTK7 interacts with the tyrosine kinase Src and stimulates Src signaling along cell-cell contacts. We further identify ROCK2 as a target of junctional PTK7-Src signaling. PTK7 knockdown in cultured epithelial cells reduced the level of active Src at cell-cell contacts, resulting in delocalization of ROCK2 from cell-cell contacts and decreased junctional contractility, with a concomitant increase in actomyosin on the basal surface. Moreover, we present in vivo evidence that Src family kinase (SFK) activity is critical for PCP regulation in the auditory sensory epithelium and that PTK7-SFK signaling regulates tyrosine phosphorylation of junctional ROCK2. Together, these results delineate a PTK7-Src signaling module for spatial regulation of ROCK activity, actomyosin contractility, and epithelial PCP.
Copyright © 2014 Elsevier Inc. All rights reserved.
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15 MeSH Terms
Trans-dimerization of JAM-A regulates Rap2 and is mediated by a domain that is distinct from the cis-dimerization interface.
Monteiro AC, Luissint AC, Sumagin R, Lai C, Vielmuth F, Wolf MF, Laur O, Reiss K, Spindler V, Stehle T, Dermody TS, Nusrat A, Parkos CA
(2014) Mol Biol Cell 25: 1574-85
MeSH Terms: Amino Acid Substitution, Animals, Binding Sites, CHO Cells, Cell Adhesion, Cell Adhesion Molecules, Cell Aggregation, Cell Line, Cell Membrane, Cell Movement, Cricetulus, HEK293 Cells, Humans, Intercellular Junctions, Microscopy, Atomic Force, Mutation, Protein Multimerization, Protein Structure, Tertiary, RNA Interference, RNA, Small Interfering, Receptors, Cell Surface, Signal Transduction, Tight Junctions, rap GTP-Binding Proteins
Show Abstract · Added May 20, 2014
Junctional adhesion molecule-A (JAM-A) is a tight junction-associated signaling protein that regulates epithelial cell proliferation, migration, and barrier function. JAM-A dimerization on a common cell surface (in cis) has been shown to regulate cell migration, and evidence suggests that JAM-A may form homodimers between cells (in trans). Indeed, transfection experiments revealed accumulation of JAM-A at sites between transfected cells, which was lost in cells expressing cis- or predicted trans-dimerization null mutants. Of importance, microspheres coated with JAM-A containing alanine substitutions to residues 43NNP45 (NNP-JAM-A) within the predicted trans-dimerization site did not aggregate. In contrast, beads coated with cis-null JAM-A demonstrated enhanced clustering similar to that observed with wild-type (WT) JAM-A. In addition, atomic force microscopy revealed decreased association forces in NNP-JAM-A compared with WT and cis-null JAM-A. Assessment of effects of JAM-A dimerization on cell signaling revealed that expression of trans- but not cis-null JAM-A mutants decreased Rap2 activity. Furthermore, confluent cells, which enable trans-dimerization, had enhanced Rap2 activity. Taken together, these results suggest that trans-dimerization of JAM-A occurs at a unique site and with different affinity compared with dimerization in cis. Trans-dimerization of JAM-A may thus act as a barrier-inducing molecular switch that is activated when cells become confluent.
© 2014 Monteiro et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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24 MeSH Terms
Organization and execution of the epithelial polarity programme.
Rodriguez-Boulan E, Macara IG
(2014) Nat Rev Mol Cell Biol 15: 225-42
MeSH Terms: Animals, Cell Membrane, Cell Polarity, Epithelial Cells, Humans, Intercellular Junctions, Morphogenesis, Signal Transduction
Show Abstract · Added May 30, 2014
Epithelial cells require apical-basal plasma membrane polarity to carry out crucial vectorial transport functions and cytoplasmic polarity to generate different cell progenies for tissue morphogenesis. The establishment and maintenance of a polarized epithelial cell with apical, basolateral and ciliary surface domains is guided by an epithelial polarity programme (EPP) that is controlled by a network of protein and lipid regulators. The EPP is organized in response to extracellular cues and is executed through the establishment of an apical-basal axis, intercellular junctions, epithelial-specific cytoskeletal rearrangements and a polarized trafficking machinery. Recent studies have provided insight into the interactions of the EPP with the polarized trafficking machinery and how these regulate epithelial polarization and depolarization.
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8 MeSH Terms
N-cadherin regulates spatially polarized signals through distinct p120ctn and β-catenin-dependent signalling pathways.
Ouyang M, Lu S, Kim T, Chen CE, Seong J, Leckband DE, Wang F, Reynolds AB, Schwartz MA, Wang Y
(2013) Nat Commun 4: 1589
MeSH Terms: Actin Cytoskeleton, Animals, CHO Cells, Cadherins, Catenins, Cell Polarity, Chickens, Cricetinae, Embryo, Mammalian, Fibroblasts, Fluorescent Dyes, Integrins, Intercellular Junctions, Mice, Models, Biological, Phosphatidylinositol 3-Kinases, Protein Binding, RNA, Small Interfering, Rats, Recombinant Fusion Proteins, Signal Transduction, beta Catenin, rac GTP-Binding Proteins
Show Abstract · Added March 28, 2014
The spatial distribution of molecular signals within cells is crucial for cellular functions. Here, as a model to study the polarized spatial distribution of molecular activities, we used cells on micropatterned strips of fibronectin with one end free and the other end contacting a neighbouring cell. Phosphoinositide 3-kinase and the small GTPase Rac display greater activity at the free end, whereas myosin II light chain and actin filaments are enriched near the intercellular junction. Phosphoinositide 3-kinase and Rac polarization depend specifically on the N-cadherin-p120 catenin complex, whereas myosin II light chain and actin filament polarization depend on the N-cadherin-β-catenin complex. Integrins promote high phosphoinositide 3-kinase/Rac activities at the free end, and the N-cadherin-p120 catenin complex excludes integrin α5 at the junctions to suppress local phosphoinositide 3-kinase and Rac activity. We hence conclude that N-cadherin couples with distinct effectors to polarize phosphoinositide 3-kinase/Rac and myosin II light chain/actin filaments in migrating cells.
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23 MeSH Terms
Lack of transforming growth factor-β signaling promotes collective cancer cell invasion through tumor-stromal crosstalk.
Matise LA, Palmer TD, Ashby WJ, Nashabi A, Chytil A, Aakre M, Pickup MW, Gorska AE, Zijlstra A, Moses HL
(2012) Breast Cancer Res 14: R98
MeSH Terms: Animals, Cadherins, Cell Communication, Cell Line, Tumor, Cell Movement, Epithelial-Mesenchymal Transition, Fibroblasts, Gene Expression Regulation, Neoplastic, Gene Knockout Techniques, Humans, Intercellular Junctions, Mice, Neoplasms, Phenotype, Protein Transport, Protein-Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Signal Transduction, Stromal Cells, Transforming Growth Factor beta, beta Catenin
Show Abstract · Added February 17, 2014
INTRODUCTION - Transforming growth factor beta (TGF-β) has a dual role during tumor progression, initially as a suppressor and then as a promoter. Epithelial TGF-β signaling regulates fibroblast recruitment and activation. Concurrently, TGF-β signaling in stromal fibroblasts suppresses tumorigenesis in adjacent epithelia, while its ablation potentiates tumor formation. Much is known about the contribution of TGF-β signaling to tumorigenesis, yet the role of TGF-β in epithelial-stromal migration during tumor progression is poorly understood. We hypothesize that TGF-β is a critical regulator of tumor-stromal interactions that promote mammary tumor cell migration and invasion.
METHODS - Fluorescently labeled murine mammary carcinoma cells, isolated from either MMTV-PyVmT transforming growth factor-beta receptor II knockout (TβRII KO) or TβRIIfl/fl control mice, were combined with mammary fibroblasts and xenografted onto the chicken embryo chorioallantoic membrane. These combinatorial xenografts were used as a model to study epithelial-stromal crosstalk. Intravital imaging of migration was monitored ex ovo, and metastasis was investigated in ovo. Epithelial RNA from in ovo tumors was isolated by laser capture microdissection and analyzed to identify gene expression changes in response to TGF-β signaling loss.
RESULTS - Intravital microscopy of xenografts revealed that mammary fibroblasts promoted two migratory phenotypes dependent on epithelial TGF-β signaling: single cell/strand migration or collective migration. At epithelial-stromal boundaries, single cell/strand migration of TβRIIfl/fl carcinoma cells was characterized by expression of α-smooth muscle actin and vimentin, while collective migration of TβRII KO carcinoma cells was identified by E-cadherin+/p120+/β-catenin+ clusters. TβRII KO tumors also exhibited a twofold greater metastasis than TβRIIfl/fl tumors, attributed to enhanced extravasation ability. In TβRII KO tumor epithelium compared with TβRIIfl/fl epithelium, Igfbp4 and Tspan13 expression was upregulated while Col1α2, Bmp7, Gng11, Vcan, Tmeff1, and Dsc2 expression was downregulated. Immunoblotting and quantitative PCR analyses on cultured cells validated these targets and correlated Tmeff1 expression with disease progression of TGF-β-insensitive mammary cancer.
CONCLUSION - Fibroblast-stimulated carcinoma cells utilize TGF-β signaling to drive single cell/strand migration but migrate collectively in the absence of TGF-β signaling. These migration patterns involve the signaling regulation of several epithelial-to-mesenchymal transition pathways. Our findings concerning TGF-β signaling in epithelial-stromal interactions are important in identifying migratory mechanisms that can be targeted as recourse for breast cancer treatment.
1 Communities
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22 MeSH Terms
Loss of glutathione S-transferase A4 accelerates obstruction-induced tubule damage and renal fibrosis.
Liang A, Wang Y, Woodard LE, Wilson MH, Sharma R, Awasthi YC, Du J, Mitch WE, Cheng J
(2012) J Pathol 228: 448-58
MeSH Terms: Aldehydes, Animals, Autophagy, Cells, Cultured, DNA Transposable Elements, Fibroblasts, Fibrosis, Glutathione Transferase, Intercellular Junctions, Kidney Tubules, Lipid Peroxidation, Male, Mice, Knockout, RNA, Messenger, Snail Family Transcription Factors, Transcription Factors, Ureteral Obstruction
Show Abstract · Added December 8, 2017
Glutathione transferase isozyme A4 (GSTA4) exhibits high catalytic efficiency to metabolize 4-hydroxynonenal (4-HNE), a highly reactive lipid peroxidation product that has been implicated in the pathogenesis of various chronic diseases. We investigated the role of 4-HNE in the mechanisms of unilateral ureteral obstruction (UUO)-induced fibrosis and its modulation by GSTA4-4 in a mouse model. Our data indicate that after UUO, accumulation of 4-HNE and its adducts were increased in renal tissues, with a concomitant decrease in the expression of GSTA4-4 in mice. As compared to wild-type (WT) mice, UUO caused an increased expression of fibroblast markers in the interstitium of GSTA4 KO mice. Additionally, increased autophagy and tubular cell damage were more severe in UUO-treated GSTA4 KO mice than in WT mice. Furthermore, GSK-3β phosphorylation and expression of Snail, a regulator of E-cadherin and Occludin, was found to be significantly higher in UUO-inflicted GSTA4 KO mice. GSTA4 over-expression prevented 4-HNE-induced autophagy activation, tubular cell damage and Snail nuclear translocation in vitro. The effects of long-term expression of GSTA4 in restoration of UUO-induced damage in mice with the GSTA4 inducible transposon system indicated that release of obstruction after 3 days of UUO resulted in the attenuation of interstitial SMAα and collagen I expression. This transposon-delivered GSTA4 expression also suppressed UUO-induced loss of tubular cell junction markers and autophagy activation. Together, these results indicate that 4-HNE significantly contributes to the mechanisms of tubule injury and fibrosis and that these effects can be inhibited by the enhanced expression of GSTA4-4.
Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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17 MeSH Terms
A membrane fusion protein αSNAP is a novel regulator of epithelial apical junctions.
Naydenov NG, Brown B, Harris G, Dohn MR, Morales VM, Baranwal S, Reynolds AB, Ivanov AI
(2012) PLoS One 7: e34320
MeSH Terms: Adherens Junctions, Animals, Apoptosis, Catenins, Cattle, Cell Adhesion Molecules, Colon, Down-Regulation, Endoplasmic Reticulum, Epithelial Cells, Golgi Apparatus, Guanine Nucleotide Exchange Factors, Humans, Intercellular Junctions, Permeability, Protein Transport, Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins, Tight Junctions, beta Catenin
Show Abstract · Added March 28, 2014
Tight junctions (TJs) and adherens junctions (AJs) are key determinants of the structure and permeability of epithelial barriers. Although exocytic delivery to the cell surface is crucial for junctional assembly, little is known about the mechanisms controlling TJ and AJ exocytosis. This study was aimed at investigating whether a key mediator of exocytosis, soluble N-ethylmaleimide sensitive factor (NSF) attachment protein alpha (αSNAP), regulates epithelial junctions. αSNAP was enriched at apical junctions in SK-CO15 and T84 colonic epithelial cells and in normal human intestinal mucosa. siRNA-mediated knockdown of αSNAP inhibited AJ/TJ assembly and establishment of the paracellular barrier in SK-CO15 cells, which was accompanied by a significant down-regulation of p120-catenin and E-cadherin expression. A selective depletion of p120 catenin effectively disrupted AJ and TJ structure and compromised the epithelial barrier. However, overexpression of p120 catenin did not rescue the defects of junctional structure and permeability caused by αSNAP knockdown thereby suggesting the involvement of additional mechanisms. Such mechanisms did not depend on NSF functions or induction of cell death, but were associated with disruption of the Golgi complex and down-regulation of a Golgi-associated guanidine nucleotide exchange factor, GBF1. These findings suggest novel roles for αSNAP in promoting the formation of epithelial AJs and TJs by controlling Golgi-dependent expression and trafficking of junctional proteins.
1 Communities
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19 MeSH Terms
Association of Rho-associated protein kinase 1 with E-cadherin complexes is mediated by p120-catenin.
Smith AL, Dohn MR, Brown MV, Reynolds AB
(2012) Mol Biol Cell 23: 99-110
MeSH Terms: Actins, Cadherins, Catenins, Cell Line, Gene Knockdown Techniques, Guanine Nucleotide Exchange Factors, Humans, Intercellular Junctions, Microscopy, Fluorescence, Multiprotein Complexes, Protein Binding, Protein Interaction Mapping, Protein Transport, RNA Interference, Repressor Proteins, rho-Associated Kinases
Show Abstract · Added March 5, 2014
The dynamic functional linkage of cadherins with the underlying actin cytoskeleton is tightly regulated to achieve proper cell-cell adhesion. p120-catenin (p120) regulates both cadherin stability and actin dynamics, but the relationship between these two functions remains unclear. Using a novel proteomic approach called reversible cross-link immunoprecipitation, or ReCLIP, we previously identified a physical interaction between p120 and Rho-associated protein kinase 1 (ROCK1), a major effector of RhoA. In this paper, we show that a discrete fraction of cellular ROCK1 coimmunoprecipitates with p120 and precisely colocalizes to adherens junctions (AJs). Manipulation of AJs using a calcium-switch assay and cadherin-blocking antibodies indicates direct recruitment of ROCK1 to newly forming junctions. Importantly, we find that p120 links ROCK1 to the cadherin complex, as ROCK1 coimmunoprecipitates with wild-type but not p120-uncoupled E-cadherin. Moreover, depletion of ROCK1 using short-hairpin RNA results in dramatic mislocalization of the cadherin complex and junctional actin. These data are consistent with a model in which p120 dynamically regulates Rho-GTPase activity at the cadherin complex through transient interaction with several of its up- and downstream effectors, including ROCK1.
1 Communities
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16 MeSH Terms
IQGAP1 is a novel CXCR2-interacting protein and essential component of the "chemosynapse".
Neel NF, Sai J, Ham AJ, Sobolik-Delmaire T, Mernaugh RL, Richmond A
(2011) PLoS One 6: e23813
MeSH Terms: Chemotaxis, Chromatography, Liquid, HEK293 Cells, HL-60 Cells, Humans, Intercellular Junctions, Interleukin-8, Mass Spectrometry, Protein Binding, Proteomics, Receptors, Interleukin-8B, cdc42 GTP-Binding Protein, ras GTPase-Activating Proteins
Show Abstract · Added June 6, 2013
BACKGROUND - Chemotaxis is essential for a number of physiological processes including leukocyte recruitment. Chemokines initiate intracellular signaling pathways necessary for chemotaxis through binding seven transmembrane G protein-couple receptors. Little is known about the proteins that interact with the intracellular domains of chemokine receptors to initiate cellular signaling upon ligand binding. CXCR2 is a major chemokine receptor expressed on several cell types, including endothelial cells and neutrophils. We hypothesize that multiple proteins interact with the intracellular domains of CXCR2 upon ligand stimulation and these interactions comprise a "chemosynapse", and play important roles in transducing CXCR2 mediated signaling processes.
METHODOLOGY/PRINCIPAL FINDINGS - In an effort to define the complex of proteins that assemble upon CXCR2 activation to relay signals from activated chemokine receptors, a proteomics approach was employed to identify proteins that co-associate with CXCR2 with or without ligand stimulation. The components of the CXCR2 "chemosynapse" are involved in processes ranging from intracellular trafficking to cytoskeletal modification. IQ motif containing GTPase activating protein 1 (IQGAP1) was among the novel proteins identified to interact directly with CXCR2. Herein, we demonstrate that CXCR2 co-localizes with IQGAP1 at the leading edge of polarized human neutrophils and CXCR2 expressing differentiated HL-60 cells. Moreover, amino acids 1-160 of IQGAP1 directly interact with the carboxyl-terminal domain of CXCR2 and stimulation with CXCL8 enhances IQGAP1 association with Cdc42.
CONCLUSIONS - Our studies indicate that IQGAP1 is a novel essential component of the CXCR2 "chemosynapse".
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13 MeSH Terms