Tuning epithelial cell-cell adhesion and collective dynamics with functional DNA-E-cadherin hybrid linkers

2021 ◽  
Author(s):  
Andreas Schoenit ◽  
Cristina Lo Giudice ◽  
Nina Hahnen ◽  
Dirk Ollech ◽  
Kevin Jahnke ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Epithelial Cells ◽  
Adhesion Strength ◽  
Control Cell ◽  
Dna Nanotechnology ◽  
Cell Dynamics ◽  
Binding Strength ◽  
Dna Sequence Design ◽  
E Cadherin ◽  
Cell Cell

The binding strength between epithelial cells is crucial for tissue integrity, signal transduction and collective cell dynamics. However, there is no experimental approach to precisely modulate cell-cell adhesion strength at the cellular and molecular level. Here, we establish DNA nanotechnology as tool to control cell-cell adhesion of epithelial cells. We designed a DNA-E-cadherin hybrid system consisting of complementary DNA strands covalently bound to a truncated E-cadherin with a modified extracellular domain. DNA sequence design allows to tune the DNA-E-cadherin hybrid molecular binding strength, while retaining its cytosolic interactions and downstream signaling capabilities. The DNA-E-cadherin hybrid facilitates strong and reversible cell-cell adhesion in E-cadherin deficient cells by forming mechanotransducive adherens junctions. We assess the direct influence of cell-cell adhesion strength on intracellular signaling and collective cell dynamics. This highlights the scope of DNA nanotechnology as a precision technology to study and engineer cell collectives.

scholarly journals Biogenesis of Polarized Epithelial Cells During Kidney Development In Situ: Roles of E-Cadherin–mediated Cell–Cell Adhesion and Membrane Cytoskeleton Organization

1998 ◽  
Vol 9 (11) ◽  
pp. 3161-3177 ◽  
Author(s):  
Peter A. Piepenhagen ◽  
W. James Nelson
Keyword(s):  
Cell Adhesion ◽  
Epithelial Cells ◽  
Kidney Development ◽  
Lateral Membrane ◽  
Membrane Cytoskeleton ◽  
Triton X ◽  
E Cadherin ◽  
Cell Cell

Organization of proteins into structurally and functionally distinct plasma membrane domains is an essential characteristic of polarized epithelial cells. Based on studies with cultured kidney cells, we have hypothesized that a mechanism for restricting Na/K-ATPase to the basal-lateral membrane involves E-cadherin–mediated cell–cell adhesion and integration of Na/K-ATPase into the Triton X-100–insoluble ankyrin- and spectrin-based membrane cytoskeleton. In this study, we examined the relevance of these in vitro observations to the generation of epithelial cell polarity in vivo during mouse kidney development. Using differential detergent extraction, immunoblotting, and immunofluorescence histochemistry, we demonstrate the following. First, expression of the 220-kDa splice variant of ankyrin-3 correlates with the development of resistance to Triton X-100 extraction for Na/K-ATPase, E-cadherin, and catenins and precedes maximal accumulation of Na/K-ATPase. Second, expression of the 190-kDa slice variant of ankyrin-3 correlates with maximal accumulation of Na/K-ATPase. Third, Na/K-ATPase, ankyrin-3, and fodrin specifically colocalize at the basal-lateral plasma membrane of all epithelial cells in which they are expressed and during all stages of nephrogenesis. Fourth, the relative immunofluorescence staining intensities of Na/K-ATPase, ankyrin-3, and fodrin become more similar during development until they are essentially identical in adult kidney. Thus, renal epithelial cells in vivo regulate the accumulation of E-cadherin–mediated adherens junctions, the membrane cytoskeleton, and Na/K-ATPase through sequential protein expression and assembly on the basal-lateral membrane. These results are consistent with a mechanism in which generation and maintenance of polarized distributions of these proteins in vivo and in vitro involve cell–cell adhesion, assembly of the membrane cytoskeleton complex, and concomitant integration and retention of Na/K-ATPase in this complex.

scholarly journals Syndecan-1 expression in mammary epithelial tumor cells is E-cadherin-dependent

1996 ◽  
Vol 109 (6) ◽  
pp. 1393-1403 ◽  
Author(s):  
S. Leppa ◽  
K. Vleminckx ◽  
F. Van Roy ◽  
M. Jalkanen
Keyword(s):  
Cell Adhesion ◽  
Epithelial Cells ◽  
Tumor Cells ◽  
Malignant Transformation ◽  
Mrna Levels ◽  
Epithelial Tumor ◽  
Cell Matrix ◽  
Epithelial Tumor Cells ◽  
E Cadherin ◽  
Cell Cell

E-cadherin is a Ca(2+)-dependent cell-cell adhesion molecule, which is mainly expressed in epithelial cells. Recent studies have shown that E-cadherin has an important role as an invasion suppressor molecule in epithelial tumor cells. Syndecan-1 is a cell surface proteoglycan that has been implicated in a number of cellular functions including cell-cell adhesion, cell-matrix anchorage and growth factor presentation for signalling receptors. Its suppression has also been shown to be associated with malignant transformation of epithelial cells. In order to better understand the coordinated regulation of cell-cell and cell-matrix interactions during malignant transformation, we have studied the expression of syndecan-1 in malignant mammary tumor cells genetically manipulated for E-cadherin expression. In invasive NM-e-ras-MAC1 cells, where E-cadherin was partially downregulated by specific antisense RNA, syndecan-1 expression was suppressed. Furthermore, transfection of E-cadherin cDNA into invasive NM-f-ras-TD cells resulted in the upregulation of syndecan-1 expression in association with decreased invasiveness. In both cases, regulation of syndecan-1 occurred post-transcriptionally, since syndecan-1 mRNA levels remained unchanged. Instead, a translational regulation is suggested, since syndecan-1 core protein synthesis was E-cadherin dependent. Another cell adhesion protein, beta 1-integrin was not affected by E-cadherin expression. The data provide an example of coordinated changes in the expression of two cell adhesion molecules, syndecan-1 and E-cadherin during epithelial cell transformation.

scholarly journals Involvement of LMO7 in the Association of Two Cell-Cell Adhesion Molecules, Nectin and E-cadherin, through Afadin and α-Actinin in Epithelial Cells

2004 ◽  
Vol 279 (30) ◽  
pp. 31365-31373 ◽  
Author(s):  
Takako Ooshio ◽  
Kenji Irie ◽  
Koji Morimoto ◽  
Atsunori Fukuhara ◽  
Toshio Imai ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Epithelial Cells ◽  
Adhesion Molecules ◽  
Cell Adhesion Molecules ◽  
E Cadherin ◽  
Cell Cell

scholarly journals Expression of N-cadherin by human squamous carcinoma cells induces a scattered fibroblastic phenotype with disrupted cell-cell adhesion.

1996 ◽  
Vol 135 (6) ◽  
pp. 1643-1654 ◽  
Author(s):  
S Islam ◽  
T E Carey ◽  
G T Wolf ◽  
M J Wheelock ◽  
K R Johnson
Keyword(s):  
Cell Adhesion ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Cell Line ◽  
Squamous Cell ◽  
Epithelial Cell Line ◽  
Squamous Epithelial Cell ◽  
Squamous Carcinoma Cells ◽  
E Cadherin ◽  
Cell Cell

E-cadherin is a transmembrane glycoprotein that mediates calcium-dependent, homotypic cell-cell adhesion and plays an important role in maintaining the normal phenotype of epithelial cells. Disruption of E-cadherin activity in epithelial cells correlates with formation of metastatic tumors. Decreased adhesive function may be implemented in a number of ways including: (a) decreased expression of E-cadherin; (b) mutations in the gene encoding E-cadherin; or (c) mutations in the genes that encode the catenins, proteins that link the cadherins to the cytoskeleton and are essential for cadherin mediated cell-cell adhesion. In this study, we explored the possibility that inappropriate expression of a nonepithelial cadherin by an epithelial cell might also result in disruption of cell-cell adhesion. We showed that a squamous cell carcinoma-derived cell line expressed N-cadherin and displayed a scattered fibroblastic phenotype along with decreased expression of E- and P-cadherin. Transfection of this cell line with antisense N-cadherin resulted in reversion to a normal-appearing squamous epithelial cell with increased E- and P-cadherin expression. In addition, transfection of a normal-appearing squamous epithelial cell line with N-cadherin resulted in downregulation of both E- and P-cadherin and a scattered fibroblastic phenotype. In all cases, the levels of expression of N-cadherin and E-cadherin were inversely related to one another. In addition, we showed that some squamous cell carcinomas expressed N-cadherin in situ and those tumors expressing N-cadherin were invasive. These studies led us to propose a novel mechanism for tumorigenesis in squamous epithelial cells; i.e., inadvertent expression of a nonepithelial cadherin.

scholarly journals The cell-cell adhesion protein JAM3 determines nuclear deformability by regulating microtubule organization

2019 ◽  
Author(s):  
Mar Arias-Garcia ◽  
Rebecca Rickman ◽  
Julia Sero ◽  
Yinyin Yuan ◽  
Chris Bakal
Keyword(s):  
Cell Adhesion ◽  
Epithelial Cells ◽  
Control Cell ◽  
Nuclear Shape ◽  
Microtubule Organization ◽  
Cell Fates ◽  
Adhesion Protein ◽  
Confined Spaces ◽  
Cell Adhesion Protein ◽  
Cell Cell

AbstractThe shape, size, and architecture of the nucleus determines the output of transcriptional programmes. As such, the ability of the nucleus to resist deformation and maintain its shape is essential for homeostasis. Conversely, changes in nuclear shape can alter transcription and cell state. The ability of cells to deform their nuclei is also essential for cells to invade confined spaces. But how cells set the extent of nuclear deformability in response to their environment is unclear. Here we show that the cell-cell adhesion protein JAM3 regulates nuclear shape. In epithelial cells, JAM3 is required for maintenance of nuclear shape by organizing microtubule polymers and promoting LMNA stabilization in the nuclear membrane. Depletion of JAM3 in normal epithelial cells leads to dysmorphic nuclei, which leads to differentiation into a mesenchymal-like state. Inhibiting the actions of kinesins in JAM3 depleted cells restores nuclear morphology and prevents differentiation into the mesenchymal-like state. Critically, JAM3 expression is predictive of disease progression. Thus JAM3 is a molecule which allows cells to control cell fates in response to the presence of neighbouring cells by tuning the extent of nuclear deformability.

scholarly journals PAR1b Promotes Cell–Cell Adhesion and Inhibits Dishevelled-mediated Transformation of Madin-Darby Canine Kidney Cells

2006 ◽  
Vol 17 (8) ◽  
pp. 3345-3355 ◽  
Author(s):  
Maya Elbert ◽  
David Cohen ◽  
Anne Müsch
Keyword(s):  
Cell Adhesion ◽  
Epithelial Cells ◽  
Wnt Signaling ◽  
Mdck Cells ◽  
Madin Darby Canine Kidney ◽  
Darby Canine Kidney ◽  
Canine Kidney ◽  
E Cadherin ◽  
Cell Cell

Mammalian Par1 is a family of serine/threonine kinases comprised of four homologous isoforms that have been associated with tumor suppression and differentiation of epithelial and neuronal cells, yet little is known about their cellular functions. In polarizing kidney epithelial (Madin-Darby canine kidney [MDCK]) cells, the Par1 isoform Par1b/MARK2/EMK1 promotes the E-cadherin–dependent compaction, columnarization, and cytoskeletal organization characteristic of differentiated columnar epithelia. Here, we identify two functions of Par1b that likely contribute to its role as a tumor suppressor in epithelial cells. 1) The kinase promotes cell–cell adhesion and resistance of E-cadherin to extraction by nonionic detergents, a measure for the association of the E-cadherin cytoplasmic domain with the actin cytoskeleton, which is critical for E-cadherin function. 2) Par1b attenuates the effect of Dishevelled (Dvl) expression, an inducer of wnt signaling that causes transformation of epithelial cells. Although Dvl is a known Par1 substrate in vitro, we determined, after mapping the PAR1b-phosphorylation sites in Dvl, that PAR1b did not antagonize Dvl signaling by phosphorylating the wnt-signaling molecule. Instead, our data suggest that both proteins function antagonistically to regulate the assembly of functional E-cadherin–dependent adhesion complexes.

scholarly journals p120 Catenin Is Required for Growth Factor–dependent Cell Motility and Scattering in Epithelial Cells

2003 ◽  
Vol 14 (5) ◽  
pp. 1964-1977 ◽  
Author(s):  
Mauro Cozzolino ◽  
Venturina Stagni ◽  
Laura Spinardi ◽  
Nadia Campioni ◽  
Carla Fiorentini ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Epithelial Cells ◽  
Cell Motility ◽  
Control Cell ◽  
Ectopic Expression ◽  
Receptor Activation ◽  
P120 Catenin ◽  
Mesenchymal Transition ◽  
Rhoa Activation ◽  
Cell Cell

Cadherin-mediated cell–cell adhesion is dynamically modulated during epithelial–mesenchymal transition triggered by activation of receptor tyrosine kinases (RTK) in epithelial cells. Several cadherin-binding proteins have been identified that control cell–cell adhesion. However, the mechanisms by which intercellular adhesion and cell motility are coregulated are still unknown. Here, we delineate a hitherto uncharted cooperation between RTKs, RhoA GTPase, and p120 catenin in instructing a motile behavior to epithelial cells. We found that expression of an N-terminus–deleted p120 catenin in a variety of epithelial cell types, including primary keratinocytes, effectively competes for endogenous p120 at cadherin binding sites and abrogates EGF-stimulated cell motility as well as HGF-induced cell scattering. The deleted mutant also inhibits the PI3K-dependent RhoA activation ensuing receptor activation. Conversely, we also show that the ectopic expression of full-length p120 in epithelial cells promotes cytoskeletal changes, stimulates cell motility, and activates RhoA. Both motogenic response to p120 and RhoA activation require coactivation of signaling downstream of RTKs as they are suppressed by ablation of the Ras/PI3K pathway. These studies demonstrate that p120 catenin is a necessary target of RTKs in regulating cell motility and help define a novel pathway leading to RhoA activation, which may contribute to the early steps of metastatic invasion.

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