scholarly journals α2β1 integrins spatially restrict Cdc42 activity to stabilise adherens junctions

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jake D. Howden ◽  
Magdalene Michael ◽  
Willow Hight-Warburton ◽  
Maddy Parsons
Keyword(s):  
Adherens Junctions ◽  
External Environment ◽  
Transmembrane Receptors ◽  
Matrix Cell ◽  
Keratinocyte Cell ◽  
Cell Adhesions ◽  
Cytoskeletal Networks ◽  
Α2β1 Integrin ◽  
Integrin Family ◽  
Cell Cell

Abstract Background Keratinocytes form the main protective barrier in the skin to separate the underlying tissue from the external environment. In order to maintain this barrier, keratinocytes form robust junctions between neighbouring cells as well as with the underlying extracellular matrix. Cell–cell adhesions are mediated primarily through cadherin receptors, whereas the integrin family of transmembrane receptors is predominantly associated with assembly of matrix adhesions. Integrins have been shown to also localise to cell–cell adhesions, but their role at these sites remains unclear. Results Here we show that α2β1 integrins are enriched at mature keratinocyte cell–cell adhesions, where they play a crucial role in organising cytoskeletal networks to stabilize adherens junctions. Loss of α2β1 integrin has significant functional phenotypes associated with cell–cell adhesion destabilisation, including increased proliferation, reduced migration and impaired barrier function. Mechanistically, we show that α2β1 integrins suppress activity of Src and Shp2 at cell–cell adhesions leading to enhanced Cdc42–GDI interactions and stabilisation of junctions between neighbouring epithelial cells. Conclusion Our data reveals a new role for α2β1 integrins in controlling integrity of epithelial cell–cell adhesions.

scholarly journals Force transduction by cadherin adhesions in morphogenesis

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 1044 ◽  
Author(s):  
Willem-Jan Pannekoek ◽  
Johan de Rooij ◽  
Martijn Gloerich
Keyword(s):  
Adherens Junctions ◽  
Cell Behavior ◽  
Collective Cell Migration ◽  
Mechanical Forces ◽  
Cellular Behaviors ◽  
Intracellular Response ◽  
Cell Adhesions ◽  
Cell Intercalation ◽  
Cell Cell

Mechanical forces drive the remodeling of tissues during morphogenesis. This relies on the transmission of forces between cells by cadherin-based adherens junctions, which couple the force-generating actomyosin cytoskeletons of neighboring cells. Moreover, components of cadherin adhesions adopt force-dependent conformations that induce changes in the composition of adherens junctions, enabling transduction of mechanical forces into an intracellular response. Cadherin mechanotransduction can mediate reinforcement of cell–cell adhesions to withstand forces but also induce biochemical signaling to regulate cell behavior or direct remodeling of cell–cell adhesions to enable cell rearrangements. By transmission and transduction of mechanical forces, cadherin adhesions coordinate cellular behaviors underlying morphogenetic processes of collective cell migration, cell division, and cell intercalation. Here, we review recent advances in our understanding of this central role of cadherin adhesions in force-dependent regulation of morphogenesis.

scholarly journals Mechanosensitive EPLIN-dependent remodeling of adherens junctions regulates epithelial reshaping

2011 ◽  
Vol 194 (4) ◽  
pp. 643-656 ◽  
Author(s):  
Katsutoshi Taguchi ◽  
Takashi Ishiuchi ◽  
Masatoshi Takeichi
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Adherens Junctions ◽  
Adherens Junction ◽  
Mechanical Forces ◽  
Cell Adhesions ◽  
Cell Cell

The zonula adherens (ZA), a type of adherens junction (AJ), plays a major role in epithelial cell–cell adhesions. It remains unknown how the ZA is remodeled during epithelial reorganization. Here we found that the ZA was converted to another type of AJ with punctate morphology (pAJ) at the margins of epithelial colonies. The F-actin–stabilizing protein EPLIN (epithelial protein lost in neoplasm), which functions to maintain the ZA via its association with αE-catenin, was lost in the pAJs. Consistently, a fusion of αE-catenin and EPLIN contributed to the formation of ZA but not pAJs. We show that junctional tension was important for retaining EPLIN at AJs, and another force derived from actin fibers laterally attached to the pAJs inhibited EPLIN–AJ association. Vinculin was required for general AJ formation, and it cooperated with EPLIN to maintain the ZA. These findings suggest that epithelial cells remodel their junctional architecture by responding to mechanical forces, and the αE-catenin–bound EPLIN acts as a mechanosensitive regulator for this process.

Plakoglobin expression and localization in zebrafish embryo development

2004 ◽  
Vol 32 (5) ◽  
pp. 797-798 ◽  
Author(s):  
E.D. Martin ◽  
M. Grealy
Keyword(s):  
Confocal Microscopy ◽  
Embryo Development ◽  
Western Blotting ◽  
Protein Level ◽  
Adherens Junctions ◽  
Cell Junctions ◽  
Specific Cell ◽  
Heart Chamber ◽  
Heart Region ◽  
Cell Cell

Plakoglobin (γ-catenin) and β-catenin are major components of the adherens junctions and can be localized to the nucleus by activation of the Wnt signalling pathway. In addition, plakoglobin is also found in desmosomes, a vertebrate-specific cell–cell adhesion structure. Plakoglobin expression and localization were examined at the protein level during zebrafish embryonic development by Western blotting and confocal microscopy. Plakoglobin was expressed throughout embryo development at the protein level. Western blotting revealed that embryonic plakoglobin protein content increased between 12- and 24-h post-fertilization (hpf). Confocal microscopy showed that at stages up to 12 hpf, plakoglobin and β-catenin were co-localized and expressed in both the nucleus and in cell–cell junctions. At 24- and 72-hpf, separate patterns were seen for plakoglobin and β-catenin. These data indicate that plakoglobin localization in the heart region shifts from adherens junctions to desmosomes during heart chamber development.

scholarly journals Spatial and temporal relationships between cadherins and PECAM-1 in cell-cell junctions of human endothelial cells.

1994 ◽  
Vol 126 (1) ◽  
pp. 247-258 ◽  
Author(s):  
O Ayalon ◽  
H Sabanai ◽  
M G Lampugnani ◽  
E Dejana ◽  
B Geiger
Keyword(s):  
Endothelial Cells ◽  
Plasma Membrane ◽  
Vascular System ◽  
Adherens Junctions ◽  
Microscopic Analysis ◽  
Membrane Receptors ◽  
Temporal Organization ◽  
Cell Junctions ◽  
Short Treatment ◽  
Cell Cell

The integrity of the endothelial layer, which lines the entire cavity of the vascular system, depends on tight adhesion of the cells to the underlying basement membrane as well as to each other. It has been previously shown that such interactions occur via membrane receptors that determine the specificity, topology, and mechanical properties of the surface adhesion. Cell-cell junctions between endothelial cells, in culture and in situ, involve both Ca(2+)-dependent and -independent mechanisms that are mediated by distinct adhesion molecules. Ca(2+)-dependent cell-cell adhesion occurs mostly via members of the cadherin family, which locally anchor the microfilament system to the plasma membrane, in adherens junctions. Ca(2+)-independent adhesions were reported to mainly involve members of the Ig superfamily. In this study, we performed three-dimensional microscopic analysis of the relative subcellular distributions of these two endothelial intercellular adhesion systems. We show that cadherins are located at adjacent (usually more apical), yet clearly distinct domains of the lateral plasma membrane, compared to PECAM-1. Moreover, cadherins were first organized in adherens junctions within 2 h after seeding of endothelial cells, forming multiple lateral patches which developed into an extensive belt-like structure over a period of 24 h. PECAM-1 became associated with surface adhesions significantly later and became progressively associated with the cadherin-containing adhesions. Cadherins and PECAM-1 also differed in their detergent extractability, reflecting differences in their mode of association with the cytoskeleton. Moreover, the two adhesion systems could be differentially modulated since short treatment with the Ca2+ chelator EGTA, disrupted the cadherin junctions leaving PECAM-1 apparently intact. These results confirm that endothelial cells possess distinct intercellular contact mechanisms that differ in their spatial and temporal organization as well as in their functional properties.

scholarly journals Role of Nectin in Formation of E-Cadherin–based Adherens Junctions in Keratinocytes: Analysis with the N-Cadherin Dominant Negative Mutant

2003 ◽  
Vol 14 (4) ◽  
pp. 1597-1609 ◽  
Author(s):  
Yoshinari Tanaka ◽  
Hiroyuki Nakanishi ◽  
Shigeki Kakunaga ◽  
Noriko Okabe ◽  
Tomomi Kawakatsu ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Adherens Junctions ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Adhesion Activity ◽  
Negative Mutant ◽  
E Cadherin ◽  
Cell Cell

E-Cadherin is a Ca2+-dependent cell-cell adhesion molecule at adherens junctions (AJs) of epithelial cells. A fragment of N-cadherin lacking its extracellular region serves as a dominant negative mutant (DN) and inhibits cell-cell adhesion activity of E-cadherin, but its mode of action remains to be elucidated. Nectin is a Ca2+-independent immunoglobulin-like cell-cell adhesion molecule at AJs and is associated with E-cadherin through their respective peripheral membrane proteins, afadin and catenins, which connect nectin and cadherin to the actin cytoskeleton, respectively. We showed here that overexpression of nectin capable of binding afadin, but not a mutant incapable of binding afadin, reduced the inhibitory effect of N-cadherin DN on the cell-cell adhesion activity of E-cadherin in keratinocytes. Overexpressed nectin recruited N-cadherin DN to the nectin-based cell-cell adhesion sites in an afadin-dependent manner. Moreover, overexpression of nectin enhanced the E-cadherin–based cell-cell adhesion activity. These results suggest that N-cadherin DN competitively inhibits the association of the endogenous nectin-afadin system with the endogenous E-cadherin-catenin system and thereby reduces the cell-cell adhesion activity of E-cadherin. Thus, nectin plays a role in the formation of E-cadherin–based AJs in keratinocytes.

scholarly journals Cortical Tension Initiates the Positive Feedback Loop Between E-cadherin and F-actin

2021 ◽  
Author(s):  
Qilin Yu ◽  
William R. Holmes ◽  
Jean P. Thiery ◽  
Rodney B. Luwor ◽  
Vijay Rajagopal
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
Adherens Junctions ◽  
Force Balance ◽  
Intercellular Junction ◽  
Cell Junctions ◽  
Positive Feedback Loop ◽  
Cortical Tension ◽  
E Cadherin ◽  
Cell Cell

AbstractAdherens junctions (AJs) physically link two cells at their contact interface via extracellular homophilic interactions between cadherin molecules and intracellular connections between cadherins and the actomyosin cortex. Both cadherin and actomyosin cytoskeletal dynamics are reciprocally regulated by mechanical and chemical signals, which subsequently determine the strength of cell-cell adhesions and the emergent organization and stiffness of the tissues they form. However, an understanding of the integrated system is lacking. We present a new mechanistic computational model of intercellular junction maturation in a cell doublet to investigate the mechano-chemical crosstalk that regulates AJ formation and homeostasis. The model couples a 2D lattice-based model of cadherin dynamics with a continuum, reaction-diffusion model of the reorganizing actomyosin network through its regulation by Rho signaling at the intercellular junction. We demonstrate that local immobilization of cadherin induces cluster formation in a cis less dependent manner. We further investigate how cadherin and actin regulate and cooperate. By considering the force balance during AJ maturation and the force-sensitive property of the cadherin/F-actin linking molecules, we show that cortical tension applied on the contact rim can explain the ring distribution of cadherin and F-actin on the cell-cell contact of the cell-doublet. Meanwhile, the positive feedback loop between cadherin and F-actin is necessary for maintenance of the ring. Different patterns of cadherin distribution can be observed as an emergent property of disturbances of this feedback loop. We discuss these findings in light of available experimental observations on underlying mechanisms related to cadherin/F-actin binding and the mechanical environment.Significance StatementThe formation, maintenance and disassembly of adherens junctions (AJs) is fundamental to organ development, tissue integrity as well as tissue function. E-cadherins and F-actin are two major players of the adherens junctions (AJs). Although it is well known that cadherins and F-actin affect each other, how these two players work together to maintain the intercellular contact is unclear. Using a novel mechano-chemical model of E-cadherin and F-actin remodeling, we demonstrate that a positive feedback loop between cadherins and F-actin allows them to stabilize each other locally. Mechanical and chemical stimuli applied to the cell adhesion change E-cadherin and F-actin distribution by consolidating or interrupting the feedback loop locally. Our study mechanistically links mechanical force to E-cadherin patterning at cell-cell junctions.

The Molecular Architecture of Cell–Cell Adhesions

2016 ◽  
pp. 181-191 ◽  
Author(s):  
B. Geiger ◽  
R. Zaidel-Bar ◽  
M. Vaman Rao
Keyword(s):  
Molecular Architecture ◽  
Cell Adhesions ◽  
Cell Cell

scholarly journals Myosin-1c regulates the dynamic stability of E-cadherin–based cell–cell contacts in polarized Madin–Darby canine kidney cells

2013 ◽  
Vol 24 (18) ◽  
pp. 2820-2833 ◽  
Author(s):  
Hiroshi Tokuo ◽  
Lynne M. Coluccio
Keyword(s):  
Dynamic Stability ◽  
Motor Function ◽  
Kidney Cells ◽  
Madin Darby Canine Kidney ◽  
Cell Contacts ◽  
Cell Adhesions ◽  
Darby Canine Kidney ◽  
Canine Kidney ◽  
E Cadherin ◽  
Cell Cell

Cooperation between cadherins and the actin cytoskeleton controls the formation and maintenance of cell–cell adhesions in epithelia. We find that the molecular motor protein myosin-1c (Myo1c) regulates the dynamic stability of E-cadherin–based cell–cell contacts. In Myo1c-depleted Madin–Darby canine kidney cells, E-cadherin localization was dis­organized and lateral membranes appeared less vertical with convoluted edges versus control cells. In polarized monolayers, Myo1c-knockdown (KD) cells were more sensitive to reduced calcium concentration. Myo1c separated in the same plasma membrane fractions as E-cadherin, and Myo1c KD caused a significant reduction in the amount of E-cadherin recovered in one peak fraction. Expression of green fluorescent protein (GFP)–Myo1c mutants revealed that the phosphatidylinositol-4,5-bisphosphate–binding site is necessary for its localization to cell–cell adhesions, and fluorescence recovery after photobleaching assays with GFP-Myo1c mutants revealed that motor function was important for Myo1c dynamics at these sites. At 18°C, which inhibits vesicle recycling, Myo1c-KD cells accumulated more E-cadherin–positive vesicles in their cytoplasm, suggesting that Myo1c affects E-cadherin endocytosis. Studies with photoactivatable GFP–E-cadherin showed that Myo1c KD reduced the stability of E-cadherin at cell–cell adhesions. We conclude that Myo1c stabilizes E-cadherin at adherens junctions in polarized epithelial cells and that the motor function and ability of Myo1c to bind membrane are critical.

scholarly journals A role for the E-cadherin cell-cell adhesion molecule during tumor progression of mouse epidermal carcinogenesis.

1991 ◽  
Vol 115 (2) ◽  
pp. 517-533 ◽  
Author(s):  
P Navarro ◽  
M Gómez ◽  
A Pizarro ◽  
C Gamallo ◽  
M Quintanilla ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Cell Lines ◽  
Spindle Cell ◽  
Inverse Correlation ◽  
Malignant Cell ◽  
Mouse Tumors ◽  
Keratinocyte Cell ◽  
Well Differentiated ◽  
E Cadherin ◽  
Cell Cell

The expression of the cell-cell adhesion molecules E- and P-cadherin has been analyzed in seven mouse epidermal keratinocyte cell lines representative of different stages of epidermal carcinogenesis. An inverse correlation between the amount of E-cadherin protein and tumorigenicity of the cell lines has been found, together with a complete absence of E-cadherin protein and mRNA expression in three carcinoma cell lines (the epithelioid HaCa4 and the fibroblastoid CarB and CarC cells). A similar result has been detected in tumors induced in nude mice by the cell lines, where induction of E-cadherin expression takes place in moderately differentiated squamous cell carcinomas induced by HaCa4 cells, although at much lower levels than in well-differentiated tumors induced by the epithelial PDV or PDVC57 cell lines. Complete absence of E-cadherin expression has been observed in spindle cell carcinomas induced by CarB or CarC cells. P-cadherin protein was detected in all cell lines that exhibit an epithelial (MCA3D, AT5, PDV, and PDVC57) or epithelioid (HaCa4) morphology, as well as in nude mouse tumors, independent of their tumorigenic capabilities. However, complete absence of P-cadherin was observed in the fibroblast-like cells (CarB and CarC) and in spindle cell carcinomas. The introduction of an exogenous E-cadherin cDNA into HaCa4 cells, or reactivation of the endogenous E-cadherin gene, leads to a partial suppression of the tumorigenicity of this highly malignant cell line. These results suggest a role for E-cadherin in the progression to malignancy of mouse epidermal carcinogenesis. They also suggest that the loss of both E- and P-cadherin could be associated to the final stage of carcinogenesis, the development of spindle cell carcinomas.

scholarly journals A PAK6–IQGAP1 complex promotes disassembly of cell–cell adhesions

2013 ◽  
Vol 71 (14) ◽  
pp. 2759-2773 ◽  
Author(s):  
Sally Fram ◽  
Helen King ◽  
David B. Sacks ◽  
Claire M. Wells
Keyword(s):  
Cell Adhesions ◽  
Cell Cell
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