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.

scholarly journals Immediate and Delayed Effects of E-Cadherin Inhibition on Gene Regulation and Cell Motility in Human Epidermoid Carcinoma Cells

2005 ◽  
Vol 25 (20) ◽  
pp. 9138-9150 ◽  
Author(s):  
Henriette Andersen ◽  
Jakob Mejlvang ◽  
Shaukat Mahmood ◽  
Irina Gromova ◽  
Pavel Gromov ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Cell Motility ◽  
Family Members ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Short Term ◽  
Mesenchymal Transition ◽  
Negative Mutant ◽  
E Cadherin ◽  
Cell Cell

ABSTRACT The invasion suppressor protein, E-cadherin, plays a central role in epithelial cell-cell adhesion. Loss of E-cadherin expression or function in various tumors of epithelial origin is associated with a more invasive phenotype. In this study, by expressing a dominant-negative mutant of E-cadherin (Ec1WVM) in A431 cells, we demonstrated that specific inhibition of E-cadherin-dependent cell-cell adhesion led to the genetic reprogramming of tumor cells. In particular, prolonged inhibition of cell-cell adhesion activated expression of vimentin and repressed cytokeratins, suggesting that the effects of Ec1WVM can be classified as epithelial-mesenchymal transition. Both short-term and prolonged expression of Ec1WVM resulted in morphological transformation and increased cell migration though to different extents. Short-term expression of Ec1WVM up-regulated two AP-1 family members, c-jun and fra-1, but was insufficient to induce complete mesenchymal transition. AP-1 activity induced by the short-term expression of Ec1WVM was required for transcriptional up-regulation of AP-1 family members and down-regulation of two other Ec1WVM-responsive genes, S100A4 and igfbp-3. Using a dominant-negative mutant of c-Jun (TAM67) and RNA interference-mediated silencing of c-Jun and Fra-1, we demonstrated that AP-1 was required for cell motility stimulated by the expression of Ec1WVM. In contrast, Ec1WVM-mediated changes in cell morphology were AP-1-independent. Our data suggest that mesenchymal transition induced by prolonged functional inhibition of E-cadherin is a slow and gradual process. At the initial step of this process, Ec1WVM triggers a positive autoregulatory mechanism that increases AP-1 activity. Activated AP-1 in turn contributes to Ec1WVM-mediated effects on gene expression and tumor cell motility. These data provide novel insight into the tumor suppressor function of E-cadherin.

scholarly journals Pancreatic Lineage Specifier PDX1 Increases Adhesion and Decreases Motility of Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4390
Author(s):  
Liya Kondratyeva ◽  
Igor Chernov ◽  
Eugene Kopantzev ◽  
Dmitry Didych ◽  
Alexey Kuzmich ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Cell Motility ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Progression ◽  
Ectopic Expression ◽  
Type I ◽  
Mesenchymal Transition ◽  
Tumor Cell Migration

Intercellular interactions involving adhesion factors are key operators in cancer progression. In particular, these factors are responsible for facilitating cell migration and metastasis. Strengthening of adhesion between tumor cells and surrounding cells or extracellular matrix (ECM), may provide a way to inhibit tumor cell migration. Recently, we demonstrated that PDX1 ectopic expression results in the reduction of pancreatic cancer line PANC-1 cell motility in vitro and in vivo, and we now provide experimental data confirming the hypothesis that suppression of migration may be related to the effect of PDX1 on cell adhesion. Cell migration analyses demonstrated decreased motility of pancreatic Colo357 and PANC-1 cell lines expressing PDX1. We observed decreased expression levels of genes associated with promoting cell migration and increased expression of genes negatively affecting cell motility. Expression of the EMT regulator genes was only mildly induced in cells expressing PDX1 during the simulation of the epithelial-mesenchymal transition (EMT) by the addition of TGFβ1 to the medium. PDX1-expressing cancer cell lines showed increased cell adhesion to collagen type I, fibronectin, and poly-lysine. We conclude that ectopic expression of PDX1 reduces the migration potential of cancer cells, by increasing the adhesive properties of cells and reducing the sensitivity to TGFβ1-induced EMT.

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 p120, a p120-related protein (p100), and the cadherin/catenin complex.

1995 ◽  
Vol 130 (2) ◽  
pp. 369-381 ◽  
Author(s):  
J M Staddon ◽  
C Smales ◽  
C Schulze ◽  
F S Esch ◽  
L L Rubin
Keyword(s):  
Cell Adhesion ◽  
Epithelial Cells ◽  
Mdck Cells ◽  
Peptide Sequencing ◽  
Beta Catenin ◽  
Related Protein ◽  
P120 Catenin ◽  
Tissue Sections ◽  
Segment Polarity ◽  
Cell Cell

Cadherins and catenins play an important role in cell-cell adhesion. Two of the catenins, beta and gamma, are members of a group of proteins that contains a repeating amino acid motif originally described for the Drosophila segment polarity gene armadillo. Another member of this group is a 120-kD protein termed p120, originally identified as a substrate of the tyrosine kinase pp60src. In this paper, we show that endothelial and epithelial cells express p120 and p100, a 100-kD, p120-related protein. Peptide sequencing of p100 establishes it as highly related to p120. p120 and p100 both appear associated with the cadherin/catenin complex, but independent p120/catenin and p100/catenin complexes can be isolated. This association is shown by coimmunoprecipitation of cadherins and catenins with an anti-p120/p100 antibody, and of p120/p100 with cadherin or catenin antibodies. Immunocytochemical analysis with a p120-specific antibody reveals junctional colocalization of p120 and beta-catenin in epithelial cells. Catenins and p120/p100 also colocalize in endothelial and epithelial cells in culture and in tissue sections. The cellular content of p120/p100 and beta-catenin is similar in MDCK cells, but only approximately 20% of the p120/p100 pool associates with the cadherin/catenin complex. Our data provide further evidence for interactions among the different arm proteins and suggest that p120/p100 may participate in regulating the function of cadherins and, thereby, other processes influenced by cell-cell adhesion.

scholarly journals Integrin-linked kinase tunes cell-cell and cell-matrix adhesions to regulate the switch between apoptosis and EMT downstream of TGFβ1

2021 ◽  
pp. mbc.E20-02-0092
Author(s):  
Ayse Nihan Kilinc ◽  
Siyang Han ◽  
Lena Barrett ◽  
Niroshan Anandasivam ◽  
Celeste M. Nelson
Keyword(s):  
Cell Adhesion ◽  
Epithelial Cells ◽  
Focal Adhesions ◽  
Cell Phenotype ◽  
High Cell ◽  
Potent Inducer ◽  
Mesenchymal Transition ◽  
Cell Matrix ◽  
Integrin Linked Kinase ◽  
Cell Cell

Epithelial-mesenchymal transition (EMT) is a morphogenetic process that endows epithelial cells with migratory and invasive potential. Mechanical and chemical signals from the tumor microenvironment can activate the EMT program, thereby permitting cancer cells to invade the surrounding stroma and disseminate to distant organs. Transforming growth factor β1 (TGFβ1) is a potent inducer of EMT that can also induce apoptosis depending on the microenvironmental context. In particular, stiff microenvironments promote EMT while softer ones promote apoptosis. Here, we investigated the molecular signaling downstream of matrix stiffness that regulates the phenotypic switch in response to TGFβ1, and uncovered a critical role for integrin-linked kinase (ILK). Specifically, depleting ILK from mammary epithelial cells precludes their ability to sense the stiffness of their microenvironment. In response to treatment with TGFβ1, ILK-depleted cells undergo apoptosis on both soft and stiff substrata. We found that knockdown of ILK decreases focal adhesions and increases cell-cell adhesions, thus shifting the balance from cell-matrix to cell-cell adhesion. High cell-matrix adhesion promotes EMT whereas high cell-cell adhesion promotes apoptosis downstream of TGFβ1. These results highlight an important role for ILK in controlling cell phenotype by regulating adhesive connections to the local microenvironment.

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.

Expression and role of E- and P-cadherin adhesion molecules in embryonic histogenesis. I. Lung epithelial morphogenesis

Development ◽  
1989 ◽  
Vol 105 (2) ◽  
pp. 263-270 ◽  
Author(s):  
Y. Hirai ◽  
A. Nose ◽  
S. Kobayashi ◽  
M. Takeichi
Keyword(s):  
Monoclonal Antibody ◽  
Cell Adhesion ◽  
Epithelial Cells ◽  
Adhesion Molecules ◽  
Lung Epithelial Cells ◽  
Early Developmental Stage ◽  
Subtle Effect ◽  
Lung Epithelial ◽  
Cell Cell

The role of Ca2+-dependent cell-cell adhesion molecules, E- and P-cadherins, in the histogenesis of mouse embryonic lung was studied. All epithelial cells of the lung express both E- and P-cadherin at the early developmental stage. P-cadherin, however, gradually disappears during development, initially from the main bronchi and eventually from all epithelial cells. When a monoclonal antibody to E-cadherin (ECCD-1) was added to monolayer cultures of lung epithelial cells, it induced a partial disruption of their cell-cell adhesion, while a monoclonal antibody to P-cadherin (PCD-1) showed a subtle effect. A mixture of the two antibodies, however, displayed a synergistic effect. We then tested the effect of the antibodies on the morphogenesis of lung primordia using an organ culture system. In control media, the explants formed typical bronchial trees. In the presence of ECCD-1, the explants grew up at the same rate as in the control, but their morphogenesis was affected. The control explants formed round epithelial lobules with an open luminal space at the tips of the bronchial trees, whereas the lobules of explants incubated with ECCD-1 tended to be flat and devoid of the luminal space. PCD-1 showed a similar but very small effect. A mixture of the two antibodies, however, showed a stronger effect: the branching of epithelia was partially suppressed and the arrangement of epithelial cells was distorted in many places. These results suggest that E- and P-cadherin have a synergistic role in the organization of epithelial cells in lung morphogenesis.

Aquaporin-5 regulation of cell-cell adhesion proteins: an elusive "tail" story

2020 ◽  
Author(s):  
Frédéric H. Login ◽  
Johan Palmfeldt ◽  
Joleen Cheah ◽  
Soichiro Yamada ◽  
Lene N. Nejsum
Keyword(s):  
Cell Adhesion ◽  
Water Transport ◽  
Epithelial Mesenchymal Transition ◽  
Tail Domain ◽  
Aquaporin 5 ◽  
Mesenchymal Transition ◽  
Cancer Spread ◽  
Aqp5 Expression ◽  
Migration Capacity ◽  
Cell Cell

Aquaporins (AQPs) are water channels that facilitate transport of water across cellular membranes. AQPs are overexpressed in several cancers. Especially in breast cancer, AQP5 overexpression correlates with spread to lymph nodes and poor prognosis. Previously, we showed that AQP5 expression reduced cell-cell adhesion by reducing levels of adherens and tight junction proteins (e.g., ZO1, plakoglobin and β-catenin) at the actual junctions. Here, we show that when targeted to the plasma membrane, the AQP5 C-terminal tail domain regulated junctional proteins. Moreover, that AQP5 interacted with ZO1, plakoglobin, β-catenin and desmoglein-2, which were all reduced at junctions upon AQP5 overexpression. Thus, our data suggest that AQP5 mediates the effect on cell-cell adhesion via interactions with junctional protein independently of AQP5 mediated water transport. AQP5 overexpression in cancers may thus contribute to carcinogenesis and cancer spread by two independent mechanisms: reduced cell-cell adhesion, a characteristic of epithelial-mesenchymal transition, and increased cell migration capacity via water transport.

scholarly journals Lipid Phosphate Phosphatase 3 Stabilization of β-Catenin Induces Endothelial Cell Migration and Formation of Branching Point Structures

2010 ◽  
Vol 30 (7) ◽  
pp. 1593-1606 ◽  
Author(s):  
Joseph O. Humtsoe ◽  
Mingyao Liu ◽  
Asrar B. Malik ◽  
Kishore K. Wary
Keyword(s):  
Cell Adhesion ◽  
Endothelial Cell ◽  
De Novo ◽  
Endothelial Cell Migration ◽  
Dependent Manner ◽  
P120 Catenin ◽  
Branching Point ◽  
Lipid Phosphate ◽  
Underlying Mechanisms ◽  
Cell Cell

ABSTRACT Endothelial cell (EC) migration, cell-cell adhesion, and the formation of branching point structures are considered hallmarks of angiogenesis; however, the underlying mechanisms of these processes are not well understood. Lipid phosphate phosphatase 3 (LPP3) is a recently described p120-catenin-associated integrin ligand localized in adherens junctions (AJs) of ECs. Here, we tested the hypothesis that LPP3 stimulates β-catenin/lymphoid enhancer binding factor 1 (β-catenin/LEF-1) to induce EC migration and formation of branching point structures. In subconfluent ECs, LPP3 induced expression of fibronectin via β-catenin/LEF-1 signaling in a phosphatase and tensin homologue (PTEN)-dependent manner. In confluent ECs, depletion of p120-catenin restored LPP3-mediated β-catenin/LEF-1 signaling. Depletion of LPP3 resulted in destabilization of β-catenin, which in turn reduced fibronectin synthesis and deposition, which resulted in inhibition of EC migration. Accordingly, reexpression of β-catenin but not p120-catenin in LPP3-depleted ECs restored de novo synthesis of fibronectin, which mediated EC migration and formation of branching point structures. In confluent ECs, however, a fraction of p120-catenin associated and colocalized with LPP3 at the plasma membrane, via the C-terminal cytoplasmic domain, thereby limiting the ability of LPP3 to stimulate β-catenin/LEF-1 signaling. Thus, our study identified a key role for LPP3 in orchestrating PTEN-mediated β-catenin/LEF-1 signaling in EC migration, cell-cell adhesion, and formation of branching point structures.

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