scholarly journals A Model for the Homotypic Interaction between Na+,K+-ATPase β1 Subunits Reveals the Role of Extracellular Residues 221–229 in Its Ig-Like Domain

2019 ◽  
Vol 20 (18) ◽  
pp. 4538
Author(s):  
Omar Páez ◽  
Marlet Martínez-Archundia ◽  
Nicolás Villegas-Sepúlveda ◽  
María Luisa Roldan ◽  
José Correa-Basurto ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Fusion Proteins ◽  
Cell Adhesion Molecule ◽  
Protein Docking ◽  
Epithelial Cell Adhesion Molecule ◽  
Animal Cells ◽  
Extracellular Region ◽  
Dynamics Simulations

The Na+, K+-ATPase transports Na+ and K+ across the membrane of all animal cells. In addition to its ion transporting function, the Na+, K+-ATPase acts as a homotypic epithelial cell adhesion molecule via its β1 subunit. The extracellular region of the Na+, K+-ATPase β1 subunit includes a single globular immunoglobulin-like domain. We performed Molecular Dynamics simulations of the ectodomain of the β1 subunit and a refined protein-protein docking prediction. Our results show that the β1 subunit Ig-like domain maintains an independent structure and dimerizes in an antiparallel fashion. Analysis of the putative interface identified segment Lys221-Tyr229. We generated triple mutations on YFP-β1 subunit fusion proteins to assess the contribution of these residues. CHO fibroblasts transfected with mutant β1 subunits showed a significantly decreased cell-cell adhesion. Association of β1 subunits in vitro was also reduced, as determined by pull-down assays. Altogether, we conclude that two Na+, K+-ATPase molecules recognize each other by a large interface spanning residues 221–229 and 198–207 on their β1 subunits.

scholarly journals Expression and role of epithelial cell adhesion molecule in dysplastic nodule and hepatocellular carcinoma

2012 ◽  
Vol 41 (6) ◽  
pp. 2150-2158 ◽  
Author(s):  
JUN SANG BAE ◽  
SANG JAE NOH ◽  
KYU YUN JANG ◽  
HO SUNG PARK ◽  
MYOUNG JA CHUNG ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Adhesion ◽  
Epithelial Cell ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Dysplastic Nodule ◽  
Epithelial Cell Adhesion Molecule

In vitro and in vivo evaluation of therapy targeting epithelial-cell adhesion-molecule aptamers for non-small cell lung cancer

2015 ◽  
Vol 209 ◽  
pp. 88-100 ◽  
Author(s):  
Mona Alibolandi ◽  
Mohammad Ramezani ◽  
Khalil Abnous ◽  
Fatemeh Sadeghi ◽  
Fatemeh Atyabi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Adhesion ◽  
Epithelial Cell ◽  
Cell Adhesion Molecule ◽  
Small Cell ◽  
Epithelial Cell Adhesion Molecule ◽  
Small Cell Lung ◽  
In Vivo Evaluation

scholarly journals Antidiabetic DPP-4 Inhibitors Reprogram Tumor Microenvironment That Facilitates Murine Breast Cancer Metastasis Through Interaction With Cancer Cells via a ROS–NF-кB–NLRP3 Axis

2021 ◽  
Vol 11 ◽  
Author(s):  
Rui Li ◽  
Xin Zeng ◽  
Meihua Yang ◽  
Jinmei Feng ◽  
Xiaohui Xu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Adhesion ◽  
Tumor Microenvironment ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Diabetic Patients ◽  
Dipeptidyl Peptidase 4 Inhibitors ◽  
Cell Adhesion Molecule 1

Improvement of understanding of the safety profile and biological significance of antidiabetic agents in breast cancer (BC) progression may shed new light on minimizing the unexpected side effect of antidiabetic reagents in diabetic patients with BC. Our recent finding showed that Saxagliptin (Sax) and Sitagliptin (Sit), two common antidiabetic dipeptidyl peptidase-4 inhibitors (DPP-4i) compounds, promoted murine BC 4T1 metastasis via a ROS–NRF2–HO-1 axis in nonobese diabetic–severe combined immunodeficiency (NOD-SCID) mice. However, the potential role of DPP-4i in BC progression under immune-competent status remains largely unknown. Herein, we extended our investigation and revealed that Sax and Sit also accelerated murine BC 4T1 metastasis in orthotopic, syngeneic, and immune-competent BALB/c mice. Mechanically, we found that DPP-4i not only activated ROS–NRF2–HO-1 axis but also triggered reactive oxygen species (ROS)-dependent nuclear factor kappa B (NF-κB) activation and its downstream metastasis-associated gene levels in vitro and in vivo, while NF-кB inhibition significantly abrogated DPP-4i-driven BC metastasis in vitro. Meanwhile, inhibition of NRF2–HO-1 activation attenuated DPP-4i-driven NF-кB activation, while NRF2 activator ALA enhanced NF-кB activation, indicating an essential role of ROS–NRF2–HO-1 axis in DPP-4i-driven NF-кB activation. Furthermore, we also found that DPP-4i increased tumor-infiltrating CD45, MPO, F4/80, CD4, and Foxp3-positive cells and myeloid-derived suppressor cells (MDSCs), and decreased CD8-positive lymphocytes in metastatic sites, but did not significantly alter cell viability, apoptosis, differentiation, and suppressive activation of 4T1-induced splenic MDSCs. Moreover, we revealed that DPP-4i triggered ROS-NF-κB-dependent NLRP3 inflammasome activation in BC cells, leading to increase in inflammation cytokines such as interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor (VEGF), intercellular cell adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), IL-1β and IL-33, and MDSCs inductors granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, and M-CSF, which play a crucial role in the remodeling of tumor immune-suppressive microenvironment. Thus, our findings suggest that antidiabetic DPP-4i reprograms tumor microenvironment that facilitates murine BC metastasis by interaction with BC cells via a ROS–NRF2–HO-1–NF-κB–NLRP3 axis. This finding not only provides a mechanistic insight into the oncogenic ROS–NRF2–HO-1 in DPP-4i-driven BC progression but also offers novel insights relevant for the improvement of tumor microenvironment to alleviate DPP-4i-induced BC metastasis.

scholarly journals Pivotal role of epithelial cell adhesion molecule in the survival of lung cancer cells

2011 ◽  
Vol 102 (8) ◽  
pp. 1493-1500 ◽  
Author(s):  
Tetsunari Hase ◽  
Mitsuo Sato ◽  
Kenya Yoshida ◽  
Luc Girard ◽  
Yoshihiro Takeyama ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Adhesion ◽  
Epithelial Cell ◽  
Cancer Cells ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Pivotal Role ◽  
Lung Cancer Cells ◽  
Epithelial Cell Adhesion Molecule

scholarly journals Functional analysis of posttranslational cleavage products of the neuron-glia cell adhesion molecule, Ng-CAM.

1995 ◽  
Vol 130 (3) ◽  
pp. 733-744 ◽  
Author(s):  
M P Burgoon ◽  
R B Hazan ◽  
G R Phillips ◽  
K L Crossin ◽  
G M Edelman ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Neurite Outgrowth ◽  
Adhesion Molecule ◽  
Fusion Proteins ◽  
Cell Adhesion Molecule ◽  
Proteolytic Cleavage ◽  
Neural Regeneration ◽  
Glia Cell ◽  
L Cells ◽  
Extracellular Region

Neuron-glia cell adhesion molecule (Ng-CAM) mediates cell adhesion between neurons homophilically and between neurons and glia heterophilically; it also promotes neurite outgrowth. In the chick brain, Ng-CAM is detected as glycoproteins of 190 and 210 kD (Ng-CAM200) with posttranslational cleavage products of 135 kD (F135, which contains most of the extracellular region) and 80 kD (F80, which includes the transmembrane and the cytoplasmic domains). To examine the functions of each of these components, we have expressed Ng-CAM200, F135, and F80 in murine L cells, and F135 and F80 as GST fusion proteins in the pGEX vector in bacteria. Appropriately transfected L cells expressed each of these proteins on their surfaces; F135 was also found in the media of cells transfected with Ng-CAM200 and F135. In addition to binding homophilically, cells transfected with Ng-CAM200 and F135 bound heterophilically to untransfected L cells, suggesting that there is a ligand for Ng-CAM on fibroblasts that may be related to the glial ligand. Detailed studies using the transfected cells and the fusion proteins indicated that both the homophilic and the heterophilic binding activities of Ng-CAM are localized in the F135 fragment of the molecule. The results also indicated that proteolytic cleavage of Ng-CAM200 is not required either for its expression on the cell surface or for cell adhesion and that there is an "anchor" for F135 on L cells (and presumably on neurons). In contrast to the cell binding results, the F80 but not the F135 fusion protein enhanced the outgrowth of neurites from dorsal root ganglion cells; this activity was associated with the FnIII repeats of F80. The observations that a protein corresponding to F135 contains the cell aggregation sites whereas one corresponding to the F80 has the ability to promote neurite outgrowth suggest that proteolytic cleavage may be an important event in regulating these Ng-CAM activities during embryonic development and neural regeneration.

scholarly journals Enteroids expressing a disease-associated mutant of EpCAM are a model for congenital tufting enteropathy

2019 ◽  
Vol 317 (5) ◽  
pp. G580-G591 ◽  
Author(s):  
Barun Das ◽  
Kevin Okamoto ◽  
John Rabalais ◽  
Philip A. Kozan ◽  
Ronald R. Marchelletta ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Epithelial Cell ◽  
Adhesion Molecule ◽  
Barrier Function ◽  
Cell Adhesion Molecule ◽  
Ex Vivo ◽  
Goblet Cells ◽  
Epithelial Cell Adhesion Molecule ◽  
Epcam Gene

Congenital tufting enteropathy (CTE) is an autosomal recessive disease characterized by severe intestinal failure in infancy and mutations in the epithelial cell adhesion molecule ( EPCAM) gene. Previous studies of CTE in mice expressing mutant EpCAM show neonatal lethality. Hence, to study the cellular, molecular, and physiological alterations that result from EpCAM mutation, a tamoxifen-inducible mutant EpCAM enteroid model has been generated. The presence of mutant EpCAM in the model was confirmed at both mRNA and protein levels. Immunofluorescence microscopy demonstrated the reduced expression of mutant EpCAM. Mutant enteroids had reduced budding potential as well as significantly decreased mRNA expression for epithelial lineage markers ( Mucin 2, lysozyme, sucrase-isomaltase), proliferation marker Ki67, and secretory pathway transcription factors ( Atoh1, Hnf1b). Significantly decreased numbers of Paneth and goblet cells were confirmed by staining. These findings were correlated with intestinal tissue from CTE patients and the mutant mice model that had significantly fewer Paneth and goblet cells than in healthy counterparts. FITC-dextran studies demonstrated significantly impaired barrier function in monolayers derived from mutant enteroids compared with control monolayers. In conclusion, we have established an ex vivo CTE model. The role of EpCAM in the budding potential, differentiation, and barrier function of enteroids is noted. Our study establishes new facets of EpCAM biology that will aid in understanding the pathophysiology of CTE and role of EpCAM in health and disease. NEW & NOTEWORTHY Here, we develop a novel ex vivo enteroid model for congenital tufting enteropathy (CTE) based on epithelial cell adhesion molecule ( EPCAM) gene mutations found in patients. With this model we demonstrate the role of EpCAM in maintaining the functional homeostasis of the intestinal epithelium, including differentiation, proliferation, and barrier integrity. This study further establishes a new direction in EpCAM biology that will help in understanding the detailed pathophysiology of CTE and role of EpCAM.

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