Deposition of microparticles by neutrophils onto inflamed epithelium: a new mechanism to disrupt epithelial intercellular adhesions and promote transepithelial migration

A disease in Angus calves was characterised by shedding of the epidermis with ulceration and inflammation of the oral mucosa and the skin of carpus, metacarpal-phalangeal joints, phalanges, coronary border, and with partial separation of the hooves. The pathogenesis of these lesions involves a breakdown of intercellular adhesions associated with anomalous development of the desmosome-tonofilament complexes in the basal and prickle cells of the epidermis. The breeding and clinical history suggested a genetic cause. The disease was called ‘familial acantholysis of Angus calves’.

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Phosphatidylinositol-4,5 Bisphosphate Produced by PIP5KIγ Regulates Gelsolin, Actin Assembly, and Adhesion Strength of N-Cadherin Junctions

Molecular Biology of the Cell ◽

10.1091/mbc.e06-12-1159 ◽

2007 ◽

Vol 18 (8) ◽

pp. 3026-3038 ◽

Cited By ~ 50

Author(s):

T. Y. El Sayegh ◽

P. D. Arora ◽

K. Ling ◽

C. Laschinger ◽

P. A. Janmey ◽

...

Keyword(s):

Adhesion Strength ◽

Intercellular Adhesion ◽

Actin Binding ◽

Type I ◽

Actin Assembly ◽

Wild Type ◽

Binding Region ◽

A Cell ◽

Intercellular Adhesions ◽

Phosphatidylinositol 4

Phosphoinositides regulate several actin-binding proteins but their role at intercellular adhesions has not been defined. We found that phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) was generated at sites of N-cadherin–mediated intercellular adhesion and was a critical regulator of intercellular adhesion strength. Immunostaining for PI(4,5)P2 or transfection with GFP-PH-PLCδ showed that PI(4,5)P2 was enriched at sites of N-cadherin adhesions and this enrichment required activated Rac1. Isoform-specific immunostaining for type I phosphatidylinositol 4-phosphate 5 kinase (PIP5KI) showed that PIP5KIγ was spatially associated with N-cadherin–Fc beads. Association of PIP5KIγ with N-cadherin adhesions was in part dependent on the activation of RhoA. Transfection with catalytically inactive PIP5KIγ blocked the enrichment of PI(4,5)P2 around beads. Catalytically inactive PIP5KIγ or a cell-permeant peptide that mimics and competes for the PI(4,5)P2-binding region of the actin-binding protein gelsolin inhibited incorporation of actin monomers in response to N-cadherin ligation and reduced intercellular adhesion strength by more than twofold. Gelsolin null fibroblasts transfected with a gelsolin severing mutant containing an intact PI(4,5)P2 binding region, demonstrated intercellular adhesion strength similar to wild-type transfected controls. We conclude that PIP5KIγ-mediated generation of PI(4,5)P2 at sites of N-cadherin contacts regulates intercellular adhesion strength, an effect due in part to PI(4,5)P2-mediated regulation of gelsolin.

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Loss-of-Function Mutations in SERPINB8 Linked to Exfoliative Ichthyosis with Impaired Mechanical Stability of Intercellular Adhesions

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2016.06.004 ◽

2016 ◽

Vol 99 (2) ◽

pp. 430-436 ◽

Cited By ~ 12

Author(s):

Manuela Pigors ◽

Ofer Sarig ◽

Lisa Heinz ◽

Vincent Plagnol ◽

Judith Fischer ◽

...

Keyword(s):

Mechanical Stability ◽

Loss Of Function ◽

Intercellular Adhesions

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Building up actin at adherens junctions

The Journal of Cell Biology ◽

10.1083/jcb.1961if ◽

2012 ◽

Vol 196 (1) ◽

pp. 3-3

Author(s):

Ben Short

Keyword(s):

Adherens Junctions ◽

Biochemical Approach ◽

Intercellular Adhesions

A biochemical approach reveals that α-actinin-4 and Arp2/3 team up to assemble actin at intercellular adhesions.

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Identification of Desmoglein-2 as a novel target of Helicobacter pylori HtrA in epithelial cells

Cell Communication and Signaling ◽

10.1186/s12964-021-00788-x ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Sabine Bernegger ◽

Robert Vidmar ◽

Marko Fonovic ◽

Gernot Posselt ◽

Boris Turk ◽

...

Keyword(s):

Helicobacter Pylori ◽

Epithelial Cells ◽

Intercellular Junctions ◽

Matrix Metalloproteases ◽

Proteomic Profiling ◽

Proteomic Approach ◽

Group I ◽

H Pylori ◽

Intercellular Adhesions

Abstract Background High temperature requirement A (HtrA) is an active serine protease secreted by the group-I carcinogen Helicobacter pylori (H. pylori). The human cell adhesion protein and tumor suppressor E-cadherin (hCdh1) expressed on the surface of gastric epithelial cells was identified as the first HtrA substrate. HtrA-mediated hCdh1 cleavage and subsequent disruption of intercellular adhesions are considered as important steps in H. pylori pathogenesis. In this study, we performed a proteomic profiling of H. pylori HtrA (HpHtrA) to decipher the complex mechanism of H. pylori interference with the epithelial barrier integrity. Results Using a proteomic approach we identified human desmoglein-2 (hDsg2), neuropilin-1, ephrin-B2, and semaphorin-4D as novel extracellular HpHtrA substrates and confirmed the well characterized target hCdh1. HpHtrA-mediated hDsg2 cleavage was further analyzed by in vitro cleavage assays using recombinant proteins. In infection experiments, we demonstrated hDsg2 shedding from H. pylori-colonized MKN28 and NCI-N87 cells independently of pathogen-induced matrix-metalloproteases or ADAM10 and ADAM17. Conclusions Characterizing the substrate specificity of HpHtrA revealed efficient hDsg2 cleavage underlining the importance of HpHtrA in opening intercellular junctions.

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Phosphorylation of N-Cadherin-associated Cortactin by Fer Kinase Regulates N-Cadherin Mobility and Intercellular Adhesion Strength

Molecular Biology of the Cell ◽

10.1091/mbc.e05-05-0410 ◽

2005 ◽

Vol 16 (12) ◽

pp. 5514-5527 ◽

Cited By ~ 44

Author(s):

Tarek Y. El Sayegh ◽

Pamela D. Arora ◽

Lingzhi Fan ◽

Carol A. Laschinger ◽

Peter A. Greer ◽

...

Keyword(s):

Tyrosine Phosphorylation ◽

Adhesion Strength ◽

Fluorescence Recovery After Photobleaching ◽

Kinase Activity ◽

Intercellular Adhesion ◽

Wild Type ◽

Nonreceptor Tyrosine Kinase ◽

Junction Formation ◽

Intercellular Adhesions ◽

Dependent Mechanism

Cortactin regulates the strength of nascent N-cadherin-mediated intercellular adhesions through a tyrosine phosphorylation-dependent mechanism. Currently, the functional significance of cortactin phosphorylation and the kinases responsible for the regulation of adhesion strength are not defined. We show that the nonreceptor tyrosine kinase Fer phosphorylates cadherin-associated cortactin and that this process is involved in mediating intercellular adhesion strength. In wild-type fibroblasts N-cadherin ligation-induced transient phosphorylation of Fer, indicating that junction formation activates Fer kinase. Tyrosine phosphorylation of cortactin after N-cadherin ligation was strongly reduced in fibroblasts expressing only catalytically inactive Fer (D743R), compared with wild-type cells. In wild-type cells, N-cadherin-coated bead pull-off assays induced fourfold greater endogenous N-cadherin association than in D743R cells. Fluorescence recovery after photobleaching showed that GFP-N-cadherin mobility at nascent contacts was 50% faster in wild-type than D743R cells. In shear wash-off assays, nascent intercellular adhesion strength was twofold higher in wild-type than D743R cells. Cortactin recruitment to adhesions was independent of Fer kinase activity, but was impacted by N-cadherin ligation-provoked Rac activation. We conclude that N-cadherin ligation induces Rac-dependent cortactin recruitment and Fer-dependent cortactin phosphorylation, which in turn promotes enhanced mobilization and interaction of surface expressed N-cadherin in contacting cells.

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Modeling the two-way feedback between contractility and matrix realignment reveals a nonlinear mode of cancer cell invasion

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1617037114 ◽

2017 ◽

Vol 114 (9) ◽

pp. E1617-E1626 ◽

Cited By ~ 76

Author(s):

Hossein Ahmadzadeh ◽

Marie R. Webster ◽

Reeti Behera ◽

Angela M. Jimenez Valencia ◽

Denis Wirtz ◽

...

Keyword(s):

Cancer Cell ◽

Cell Invasion ◽

Cell Movement ◽

Cell Polarization ◽

Cancer Cell Invasion ◽

Collagen Matrices ◽

Primary Tumors ◽

Cell Contractility ◽

The Matrix ◽

Intercellular Adhesions

Cancer cell invasion from primary tumors is mediated by a complex interplay between cellular adhesions, actomyosin-driven contractility, and the physical characteristics of the extracellular matrix (ECM). Here, we incorporate a mechanochemical free-energy–based approach to elucidate how the two-way feedback loop between cell contractility (induced by the activity of chemomechanical interactions such as Ca2+and Rho signaling pathways) and matrix fiber realignment and strain stiffening enables the cells to polarize and develop contractile forces to break free from the tumor spheroids and invade into the ECM. Interestingly, through this computational model, we are able to identify a critical stiffness that is required by the matrix to break intercellular adhesions and initiate cell invasion. Also, by considering the kinetics of the cell movement, our model predicts a biphasic invasiveness with respect to the stiffness of the matrix. These predictions are validated by analyzing the invasion of melanoma cells in collagen matrices of varying concentration. Our model also predicts a positive correlation between the elongated morphology of the invading cells and the alignment of fibers in the matrix, suggesting that cell polarization is directly proportional to the stiffness and alignment of the matrix. In contrast, cells in nonfibrous matrices are found to be rounded and not polarized, underscoring the key role played by the nonlinear mechanics of fibrous matrices. Importantly, our model shows that mechanical principles mediated by the contractility of the cells and the nonlinearity of the ECM behavior play a crucial role in determining the phenotype of the cell invasion.

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HB-EGF promotes intestinal restitution by affecting integrin–extracellular matrix interactions and intercellular adhesions

Growth Factors ◽

10.3109/08977194.2012.755966 ◽

2013 ◽

Vol 31 (1) ◽

pp. 39-55 ◽

Cited By ~ 21

Author(s):

Yanwei Su ◽

Jixin Yang ◽

Gail E. Besner

Keyword(s):

Extracellular Matrix ◽

Matrix Interactions ◽

Intercellular Adhesions ◽

Extracellular Matrix Interactions

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Numb controls E-cadherin endocytosis through p120 catenin with aPKC

Molecular Biology of the Cell ◽

10.1091/mbc.e11-03-0274 ◽

2011 ◽

Vol 22 (17) ◽

pp. 3103-3119 ◽

Cited By ~ 69

Author(s):

Kazuhide Sato ◽

Takashi Watanabe ◽

Shujie Wang ◽

Mai Kakeno ◽

Kenji Matsuzawa ◽

...

Keyword(s):

Epithelial Cells ◽

Apical Membrane ◽

Dominant Negative ◽

Binding Ability ◽

P120 Catenin ◽

Adhesion Sites ◽

Kinase C ◽

Apicobasal Polarity ◽

Intercellular Adhesions ◽

E Cadherin

Cadherin trafficking controls tissue morphogenesis and cell polarity. The endocytic adaptor Numb participates in apicobasal polarity by acting on intercellular adhesions in epithelial cells. However, it remains largely unknown how Numb controls cadherin-based adhesion. Here, we found that Numb directly interacted with p120 catenin (p120), which is known to interact with E-cadherin and prevent its internalization. Numb accumulated at intercellular adhesion sites and the apical membrane in epithelial cells. Depletion of Numb impaired E-cadherin internalization, whereas depletion of p120 accelerated internalization. Expression of the Numb-binding fragment of p120 inhibited E-cadherin internalization in a dominant-negative fashion, indicating that Numb interacts with the E-cadherin/p120 complex and promotes E-cadherin endocytosis. Impairment of Numb induced mislocalization of E-cadherin from the lateral membrane to the apical membrane. Atypical protein kinase C (aPKC), a member of the PAR complex, phosphorylated Numb and inhibited its association with p120 and α-adaptin. Depletion or inhibition of aPKC accelerated E-cadherin internalization. Wild-type Numb restored E-cadherin internalization in the Numb-depleted cells, whereas a phosphomimetic mutant or a mutant with defective α-adaptin-binding ability did not restore the internalization. Thus, we propose that aPKC phosphorylates Numb to prevent its binding to p120 and α-adaptin, thereby attenuating E-cadherin endocytosis to maintain apicobasal polarity.

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Assay of intercellular adhesiveness using cell-coated Sephadex beads as collecting particles

Journal of Cell Science ◽

10.1242/jcs.22.3.657 ◽

1976 ◽

Vol 22 (3) ◽

pp. 657-670

Author(s):

K. Vosbeck ◽

S. Roth

Keyword(s):

Precise Determination ◽

Intercellular Adhesion ◽

Previous Method ◽

Precise Method ◽

Large Numbers ◽

Cell Layers ◽

Confluent Cell ◽

Intercellular Adhesions ◽

Short Time

A simple, rapid and precise method, based on a previous method, for measuring relative rates of intercellular adhesion is described. DEAE-Sephadex beads were treated with nitrocellulose in order to allow cells to grow on their surfaces. Balb/c 3T3 and Balb/c 3T12 cells were used to characterize the assay. They formed confluent cell layers on nitrocellulose-treated DEAE-Sephadex. These cell-coated beads were employed to collect 32P-labelled cells from single cell suspensions. Since they formed statistically uniform, large collecting surfaces, the collection of labelled cells was markedly improved as compared to the original assay. The cell-coated beads collected a large percentage of the labelled cells in a short time. The percentage of cells collected was independent of the concentration of labelled cells in the assay mixture, and the collection was linear for approximately 60 min. The variability between replicate assays was usually +/− 5%. The assay allows the rapid and precise determination of intercellular adhesion in large numbers of individual samples. These features make it useful to screen for effects of different treatments on intercellular adhesions.

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