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Talin regulates integrin β1-dependent and -independent cell functions in ureteric bud development.
Mathew S, Palamuttam RJ, Mernaugh G, Ramalingam H, Lu Z, Zhang MZ, Ishibe S, Critchley DR, Fässler R, Pozzi A, Sanders CR, Carroll TJ, Zent R
(2017) Development 144: 4148-4158
MeSH Terms: Adherens Junctions, Amino Acid Motifs, Animals, Binding Sites, Cell Adhesion, Cell Membrane, Cell Polarity, Gene Expression Regulation, Developmental, Integrin beta1, Kidney Tubules, Collecting, Mice, Inbred C57BL, Morphogenesis, Mutation, Talin, Tight Junction Proteins, Ureter
Show Abstract · Added December 7, 2017
Kidney collecting system development requires integrin-dependent cell-extracellular matrix interactions. Integrins are heterodimeric transmembrane receptors consisting of α and β subunits; crucial integrins in the kidney collecting system express the β1 subunit. The β1 cytoplasmic tail has two NPxY motifs that mediate functions by binding to cytoplasmic signaling and scaffolding molecules. Talins, scaffolding proteins that bind to the membrane proximal NPxY motif, are proposed to activate integrins and to link them to the actin cytoskeleton. We have defined the role of talin binding to the β1 proximal NPxY motif in the developing kidney collecting system in mice that selectively express a Y-to-A mutation in this motif. The mice developed a hypoplastic dysplastic collecting system. Collecting duct cells expressing this mutation had moderate abnormalities in cell adhesion, migration, proliferation and growth factor-dependent signaling. In contrast, mice lacking talins in the developing ureteric bud developed kidney agenesis and collecting duct cells had severe cytoskeletal, adhesion and polarity defects. Thus, talins are essential for kidney collecting duct development through mechanisms that extend beyond those requiring binding to the β1 integrin subunit NPxY motif.
© 2017. Published by The Company of Biologists Ltd.
1 Communities
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16 MeSH Terms
Kindlin-2 cooperates with talin to activate integrins and induces cell spreading by directly binding paxillin.
Theodosiou M, Widmaier M, Böttcher RT, Rognoni E, Veelders M, Bharadwaj M, Lambacher A, Austen K, Müller DJ, Zent R, Fässler R
(2016) Elife 5: e10130
MeSH Terms: Animals, Cell Adhesion, Cell Line, Cell Movement, Cytoskeletal Proteins, Fibroblasts, Focal Adhesion Protein-Tyrosine Kinases, Integrin beta1, Manganese, Mice, Muscle Proteins, Paxillin, Protein Binding, Talin
Show Abstract · Added February 4, 2016
Integrins require an activation step prior to ligand binding and signaling. How talin and kindlin contribute to these events in non-hematopoietic cells is poorly understood. Here we report that fibroblasts lacking either talin or kindlin failed to activate β1 integrins, adhere to fibronectin (FN) or maintain their integrins in a high affinity conformation induced by Mn(2+). Despite compromised integrin activation and adhesion, Mn(2+) enabled talin- but not kindlin-deficient cells to initiate spreading on FN. This isotropic spreading was induced by the ability of kindlin to directly bind paxillin, which in turn bound focal adhesion kinase (FAK) resulting in FAK activation and the formation of lamellipodia. Our findings show that talin and kindlin cooperatively activate integrins leading to FN binding and adhesion, and that kindlin subsequently assembles an essential signaling node at newly formed adhesion sites in a talin-independent manner.
1 Communities
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14 MeSH Terms
Vinculin controls talin engagement with the actomyosin machinery.
Atherton P, Stutchbury B, Wang DY, Jethwa D, Tsang R, Meiler-Rodriguez E, Wang P, Bate N, Zent R, Barsukov IL, Goult BT, Critchley DR, Ballestrem C
(2015) Nat Commun 6: 10038
MeSH Terms: Actin Cytoskeleton, Actins, Actomyosin, Animals, Cell Polarity, Focal Adhesions, Mice, NIH 3T3 Cells, Protein Binding, Protein Structure, Tertiary, Talin, Vinculin
Show Abstract · Added February 4, 2016
The link between extracellular-matrix-bound integrins and intracellular F-actin is essential for cell spreading and migration. Here, we demonstrate how the actin-binding proteins talin and vinculin cooperate to provide this link. By expressing structure-based talin mutants in talin null cells, we show that while the C-terminal actin-binding site (ABS3) in talin is required for adhesion complex assembly, the central ABS2 is essential for focal adhesion (FA) maturation. Thus, although ABS2 mutants support cell spreading, the cells lack FAs, fail to polarize and exert reduced force on the surrounding matrix. ABS2 is inhibited by the preceding mechanosensitive vinculin-binding R3 domain, and deletion of R2R3 or expression of constitutively active vinculin generates stable force-independent FAs, although cell polarity is compromised. Our data suggest a model whereby force acting on integrin-talin complexes via ABS3 promotes R3 unfolding and vinculin binding, activating ABS2 and locking talin into an actin-binding configuration that stabilizes FAs.
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12 MeSH Terms
Extracellular rigidity sensing by talin isoform-specific mechanical linkages.
Austen K, Ringer P, Mehlich A, Chrostek-Grashoff A, Kluger C, Klingner C, Sabass B, Zent R, Rief M, Grashoff C
(2015) Nat Cell Biol 17: 1597-606
MeSH Terms: Actin Cytoskeleton, Actins, Animals, Biosensing Techniques, Blotting, Western, Cell Adhesion, Cells, Cultured, Extracellular Matrix, Fibroblasts, Fluorescence Resonance Energy Transfer, Focal Adhesions, Luminescent Proteins, Mechanical Phenomena, Mice, Knockout, Mice, Transgenic, Microfilament Proteins, Microscopy, Confocal, Microscopy, Fluorescence, Optical Tweezers, Peptides, Protein Binding, Talin, Vinculin
Show Abstract · Added February 4, 2016
The ability of cells to adhere and sense differences in tissue stiffness is crucial for organ development and function. The central mechanisms by which adherent cells detect extracellular matrix compliance, however, are still unknown. Using two single-molecule-calibrated biosensors that allow the analysis of a previously inaccessible but physiologically highly relevant force regime in cells, we demonstrate that the integrin activator talin establishes mechanical linkages following cell adhesion, which are indispensable for cells to probe tissue stiffness. Talin linkages are exposed to a range of piconewton forces and bear, on average, 7-10 pN during cell adhesion depending on their association with F-actin and vinculin. Disruption of talin's mechanical engagement does not impair integrin activation and initial cell adhesion but prevents focal adhesion reinforcement and thus extracellular rigidity sensing. Intriguingly, talin mechanics are isoform specific so that expression of either talin-1 or talin-2 modulates extracellular rigidity sensing.
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23 MeSH Terms
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
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17 MeSH Terms
Dictyostelium cells migrate similarly on surfaces of varying chemical composition.
McCann CP, Rericha EC, Wang C, Losert W, Parent CA
(2014) PLoS One 9: e87981
MeSH Terms: Alkanes, Cell Adhesion, Cell Membrane, Cell Movement, Cell Polarity, Dictyostelium, Glass, Myosin Type II, Polylysine, Serum Albumin, Bovine, Silanes, Surface Properties, Talin
Show Abstract · Added April 29, 2016
During cell migration, cell-substrate binding is required for pseudopod anchoring to move the cell forward, yet the interactions with the substrate must be sufficiently weak to allow parts of the cell to de-adhere in a controlled manner during typical protrusion/retraction cycles. Mammalian cells actively control cell-substrate binding and respond to extracellular conditions with localized integrin-containing focal adhesions mediating mechanotransduction. We asked whether mechanotransduction also occurs during non-integrin mediated migration by examining the motion of the social amoeba Dictyostelium discoideum, which is thought to bind non-specifically to surfaces. We discovered that Dictyostelium cells are able to regulate forces generated by the actomyosin cortex to maintain optimal cell-surface contact area and adhesion on surfaces of various chemical composition and that individual cells migrate with similar speed and contact area on the different surfaces. In contrast, during collective migration, as observed in wound healing and metastasis, the balance between surface forces and protrusive forces is altered. We found that Dictyostelium collective migration dynamics are strongly affected when cells are plated on different surfaces. These results suggest that the presence of cell-cell contacts, which appear as Dictyostelium cells enter development, alter the mechanism cells use to migrate on surfaces of varying composition.
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13 MeSH Terms
Critical role for the advanced glycation end-products receptor in pulmonary arterial hypertension etiology.
Meloche J, Courchesne A, Barrier M, Carter S, Bisserier M, Paulin R, Lauzon-Joset JF, Breuils-Bonnet S, Tremblay É, Biardel S, Racine C, Courture C, Bonnet P, Majka SM, Deshaies Y, Picard F, Provencher S, Bonnet S
(2013) J Am Heart Assoc 2: e005157
MeSH Terms: Adult, Aged, Animals, Apoptosis, Arterial Pressure, Bone Morphogenetic Protein Receptors, Type II, Case-Control Studies, Cell Proliferation, Cells, Cultured, Disease Models, Animal, Familial Primary Pulmonary Hypertension, Female, Glycation End Products, Advanced, Humans, Hypertension, Pulmonary, Hypertrophy, Right Ventricular, Hypoxia, Indoles, Male, Middle Aged, Monocrotaline, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, PPAR gamma, Pulmonary Artery, Pyrroles, RNA Interference, Rats, Rats, Sprague-Dawley, Receptor for Advanced Glycation End Products, Receptors, Immunologic, S100 Proteins, STAT3 Transcription Factor, Signal Transduction, Transfection, Up-Regulation
Show Abstract · Added August 4, 2015
BACKGROUND - Pulmonary arterial hypertension (PAH) is a vasculopathy characterized by enhanced pulmonary artery smooth muscle cell (PASMC) proliferation and suppressed apoptosis. This results in both increase in pulmonary arterial pressure and pulmonary vascular resistance. Recent studies have shown the implication of the signal transducer and activator of transcription 3 (STAT3)/bone morphogenetic protein receptor 2 (BMPR2)/peroxisome proliferator-activated receptor gamma (PPARγ) in PAH. STAT3 activation induces BMPR2 downregulation, decreasing PPARγ, which both contribute to the proproliferative and antiapoptotic phenotype seen in PAH. In chondrocytes, activation of this axis has been attributed to the advanced glycation end-products receptor (RAGE). As RAGE is one of the most upregulated proteins in PAH patients' lungs and a strong STAT3 activator, we hypothesized that by activating STAT3, RAGE induces BMPR2 and PPARγ downregulation, promoting PAH-PASMC proliferation and resistance to apoptosis.
METHODS AND RESULTS - In vitro, using PASMCs isolated from PAH and healthy patients, we demonstrated that RAGE is overexpressed in PAH-PASMC (6-fold increase), thus inducing STAT3 activation (from 10% to 40% positive cells) and decrease in BMPR2 and PPARγ levels (>50% decrease). Pharmacological activation of RAGE in control cells by S100A4 recapitulates the PAH phenotype (increasing RAGE by 6-fold, thus activating STAT3 and decreasing BMPR2 and PPARγ). In both conditions, this phenotype is totally reversed on RAGE inhibition. In vivo, RAGE inhibition in monocrotaline- and Sugen-induced PAH demonstrates therapeutic effects characterized by PA pressure and right ventricular hypertrophy decrease (control rats have an mPAP around 15 mm Hg, PAH rats have an mPAP >40 mm Hg, and with RAGE inhibition, mPAP decreases to 20 and 28 mm Hg, respectively, in MCT and Sugen models). This was associated with significant improvement in lung perfusion and vascular remodeling due to decrease in proliferation (>50% decrease) and BMPR2/PPARγ axis restoration (increased by ≥60%).
CONCLUSION - We have demonstrated the implications of RAGE in PAH etiology. Thus, RAGE constitutes a new attractive therapeutic target for PAH.
1 Communities
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36 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
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18 MeSH Terms
New isoform-specific monoclonal antibodies reveal different sub-cellular localisations for talin1 and talin2.
Praekelt U, Kopp PM, Rehm K, Linder S, Bate N, Patel B, Debrand E, Manso AM, Ross RS, Conti F, Zhang MZ, Harris RC, Zent R, Critchley DR, Monkley SJ
(2012) Eur J Cell Biol 91: 180-91
MeSH Terms: Animals, Antibodies, Monoclonal, Antibody Specificity, Fibronectins, Focal Adhesions, Gene Knockdown Techniques, Humans, Macrophages, Mice, Mice, Inbred BALB C, NIH 3T3 Cells, Protein Isoforms, RNA, Small Interfering, Rats, Talin
Show Abstract · Added February 26, 2014
Talins are adaptor proteins that connect the integrin family of cell adhesion receptors to cytoskeletal actin. Vertebrates express two closely related talins encoded by separate genes, and while it is well established that talin1 plays a key role in cell adhesion and spreading, little is known about the role of talin2. To facilitate such studies, we report the characterisation of 4 new isoform-specific talin mouse monoclonal antibodies that work in Western blotting, immuno-precipitation, immuno-fluorescence and immuno-histochemistry. Using these antibodies, we show that talin1 and talin2 do not form heterodimers, and that they are differentially localised within the cell. Talin1 was concentrated in peripheral focal adhesions while talin2 was observed in both focal and fibrillar adhesions, and knock-down of talin2 compromised fibronectin fibrillogenesis. Although differentiated human macrophages express both isoforms, only talin1 showed discrete staining and was localised to the ring structure of podosomes. However, siRNA-mediated knock-down of macrophage talin2 led to a significant reduction in podosomal matrix degradation. We have also used the antibodies to localise each isoform in tissue sections using both cryostat and paraffin-embedded material. In skeletal muscle talin2 was localised to both myotendinous junctions and costameres while talin1 was restricted to the former structure. In contrast, both isoforms co-localised in kidney with staining of the glomerulus, and the tubular epithelial and interstitial cells of the cortex and medulla. We anticipate that these antibodies will form a valuable resource for future studies on the function of the two major talin isoforms.
Copyright © 2012 Elsevier GmbH. All rights reserved.
1 Communities
3 Members
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15 MeSH Terms
Integrin adhesion and force coupling are independently regulated by localized PtdIns(4,5)2 synthesis.
Legate KR, Takahashi S, Bonakdar N, Fabry B, Boettiger D, Zent R, Fässler R
(2011) EMBO J 30: 4539-53
MeSH Terms: Animals, Carrier Proteins, Cell Adhesion, Cells, Cultured, Focal Adhesions, Integrins, Membrane Proteins, Mice, Phosphatidylinositol 4,5-Diphosphate, Phosphotransferases (Alcohol Group Acceptor), Protein Binding, Talin, Vinculin
Show Abstract · Added February 25, 2014
The 90-kDa isoform of the lipid kinase PIP kinase Type I γ (PIPKIγ) localizes to focal adhesions (FAs), where it provides a local source of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)). Although PtdIns(4,5)P(2) regulates the function of several FA-associated molecules, the role of the FA-specific pool of PtdIns(4,5)P(2) is not known. We report that the genetic ablation of PIPKIγ specifically from FAs results in defective integrin-mediated adhesion and force coupling. Adhesion defects in cells deficient in FAPtdIns(4,5)P(2) synthesis are corrected within minutes while integrin-actin force coupling remains defective over a longer period. Talin and vinculin, but not kindlin, are less efficiently recruited to new adhesions in these cells. These data demonstrate that the specific depletion of PtdIns(4,5)P(2) from FAs temporally separates integrin-ligand binding from integrin-actin force coupling by regulating talin and vinculin recruitment. Furthermore, it suggests that force coupling relies heavily on locally generated PtdIns(4,5)P(2) rather than bulk membrane PtdIns(4,5)P(2).
1 Communities
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13 MeSH Terms