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Hung PF, Chung FP, Hung CL, Lin YJ, Kuo TT, Liao JN, Chen YY, Pan CH, Shaw KP, Chen SA. Decreased Expression of Plakophilin-2 and αT-Catenin in Arrhythmogenic Right Ventricular Cardiomyopathy: Potential Markers for Diagnosis. Int J Mol Sci 2022; 23:ijms23105529. [PMID: 35628349 PMCID: PMC9141850 DOI: 10.3390/ijms23105529] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/13/2022] [Accepted: 05/14/2022] [Indexed: 02/01/2023] Open
Abstract
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary disease of the heart muscle. Clinical challenges remain, however, in identifying patients with ARVC in the early or concealed stages with subtle clinical manifestations. Therefore, we wanted to identify potential targets by immunohistochemical (IHC) analysis in comparison with controls. Pathogenic mutations were identified in 11 of 37 autopsied patients with ARVC. As observed from IHC analysis of the RV, expression of αT-catenin and plakophilin-2 is significantly decreased in autopsied patients with ARVC as compared to controls, and the decreased expression is consistent in patients with and without pathogenic mutations. Furthermore, ARVC specimens demonstrated a reduced localization of αT-catenin, desmocollin-2, desmoglein-2, desmoplakin, and plakophilin-2 on intercalated discs. These findings have been validated by comparing RV specimens obtained via endomyocardial biopsy between patients with ARVC and those without. The pathogenic mutation was present in 3 of 5 clinical patients with ARVC. In HL-1 myocytes, siRNA was used to knockdown CTNNA3, and western blotting analysis demonstrated that the decline in αT-catenin expression was accompanied by a significant decline in the expression of plakophilin-2. The aforementioned effect was directed towards protein degradation rather than mRNA stability. Plakophilin-2 expression decreases concurrently with the decline in CTNNA3 expression. Therefore, the expression of αT-catenin and plakophilin-2 could be potential surrogates for the diagnosis of ARVC.
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Affiliation(s)
- Pei-Fang Hung
- Heart Rhythm Center and Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (P.-F.H.); (Y.-J.L.); (J.-N.L.); (Y.-Y.C.); (S.-A.C.)
| | - Fa-Po Chung
- Heart Rhythm Center and Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (P.-F.H.); (Y.-J.L.); (J.-N.L.); (Y.-Y.C.); (S.-A.C.)
- Institute of Clinical Medicine and Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan;
- Correspondence:
| | - Chung-Lieh Hung
- Department of Medicine, Mackay Medical College, New Taipei City 252005, Taiwan;
- Institute of Biomedical Sciences, Mackay Medical College, New Taipei City 252005, Taiwan
- Division of Cardiology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei 104217, Taiwan
| | - Yenn-Jiang Lin
- Heart Rhythm Center and Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (P.-F.H.); (Y.-J.L.); (J.-N.L.); (Y.-Y.C.); (S.-A.C.)
- Institute of Clinical Medicine and Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan;
| | - Tzu-Ting Kuo
- Institute of Clinical Medicine and Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan;
- Division of Cardiovascular Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112201, Taiwan
| | - Jo-Nan Liao
- Heart Rhythm Center and Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (P.-F.H.); (Y.-J.L.); (J.-N.L.); (Y.-Y.C.); (S.-A.C.)
- Institute of Clinical Medicine and Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan;
| | - Yun-Yu Chen
- Heart Rhythm Center and Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (P.-F.H.); (Y.-J.L.); (J.-N.L.); (Y.-Y.C.); (S.-A.C.)
- Institute of Epidemiology and Preventive Medicine College of Public Health, National Taiwan University, Taipei 100025, Taiwan
| | - Chih-Hsin Pan
- Institute of Forensic Medicine, Ministry of Justice, New Taipei City 235016, Taiwan; (C.-H.P.); (K.-P.S.)
| | - Kai-Ping Shaw
- Institute of Forensic Medicine, Ministry of Justice, New Taipei City 235016, Taiwan; (C.-H.P.); (K.-P.S.)
| | - Shih-Ann Chen
- Heart Rhythm Center and Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (P.-F.H.); (Y.-J.L.); (J.-N.L.); (Y.-Y.C.); (S.-A.C.)
- Institute of Clinical Medicine and Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan;
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Expression of ovine CTNNA3 and CAP2 genes and their association with growth traits. Gene 2022; 807:145949. [PMID: 34481004 DOI: 10.1016/j.gene.2021.145949] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 08/10/2021] [Accepted: 08/30/2021] [Indexed: 11/22/2022]
Abstract
Growth traits is a critical economic trait for animal husbandry. In this study, the SNPs of CTNNA3 and CAP2 genes were investigated to check whether they are associated with growth traits (body weight, body height, body length and chest circumference) in Hu sheep. The result of the association analysis indicated that the mutation in CTNNA3 (g.2018018 A > G) were associated significantly with body weight, body height, body length and chest circumference (P < 0.05), the mutation in CAP2 (g.8588 T > C) were associated significantly with body height at 140, 160, 180 days (P < 0.05), AA and CC of CTNNA3 and CAP2 were the dominant genotypes associated with growth traits in Hu sheep. Moreover, combined effect analyses indicated that the growth traits with combined genotypes AACTNNA3-CCCAP2 and AACTNNA3-CTCAP2 were higher than those with genotype GGCTNNA3-CTCAP2. RT-qPCR indicated that CTNNA3 expression levels were significantly higher in liver and lung than in other nine tissues (P < 0.05), CAP2 expression levels were significantly higher in bone, heart, liver, lung and duodenum than in other six tissues (P < 0.05). In conclusion, CTNNA3 and CAP2 polymorphisms could be used as genetic markers for improving growth traits in Hu sheep husbandry.
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Danilova NV, Mikhailov IA, Oleynikova NA, Malkov PG. [E-cadherin expression in tumor emboli in gastric cancer]. Arkh Patol 2021; 83:11-19. [PMID: 34041891 DOI: 10.17116/patol20218303111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
OBJECTIVE To determine the level of E-cadherin expression in tumor emboli, to compare it with expression in a tumor, to determine the dependence of E-cadherin expression in tumor emboli on the clinical and morphological characteristics of gastric cancer. MATERIAL AND METHODS We used samples of surgical material from 280 patients with a verified diagnosis of gastric cancer. E-cadherin expression was determined by immunohistochemical method. The results of the reactions were assessed semi-quantitatively and compared with the main clinical and morphological characteristics of gastric cancer (histological type according to the WHO classification 2019, histological type according to the classification of P. Lauren, clinical stage, depth of invasion (T), number of metastases in lymph nodes (N), presence or/absence of distant metastases (M), tumor localization in the stomach). RESULTS Among 280 cases of cancer, emboli were detected only in 67 cases, used for further analysis. The rest of the samples were excluded from the analysis, since emboli did not get into the sections during the cutting of immunohistochemical preparations. The expression of E-cadherin in tumor emboli was significantly higher (p<0.001) than in tumor tissue. At the same time, no cases identified where the level of E-cadherin decreased in emboli compared to the tumor. A significant increase in the expression of E-cadherin in tumor emboli compared to the primary tumor was noted for all histological types according to WHO 2019, for intermediate and diffuse types according to the P. Lauren classification (p<0.001). Comparison of expression in emboli and tumors for neoplasms with different depths of invasion (T), different stages and different localizations did not reveal statistically significant differences. An increase in the expression of E-cadherin in emboli compared to tumors was characterized by a higher level of significance in the presence of metastases (N1, N2, N3a, N3b; p<0.001) than in the absence of metastases (N0; p=0.016). CONCLUSION The study revealed a statistically significant increase in the expression of E-cadherin in tumor emboli compared to the primary tumor, which is evidence of its important role in maintaining the integrity of emboli and tumor dissemination.
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Affiliation(s)
- N V Danilova
- Lomonosov Moscow State University, Moscow, Russia
| | | | | | - P G Malkov
- Lomonosov Moscow State University, Moscow, Russia.,Russian Medical Academy for Continuous Professional Education, Moscow, Russia
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Logan CM, Menko AS. Microtubules: Evolving roles and critical cellular interactions. Exp Biol Med (Maywood) 2019; 244:1240-1254. [PMID: 31387376 DOI: 10.1177/1535370219867296] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Microtubules are cytoskeletal elements known as drivers of directed cell migration, vesicle and organelle trafficking, and mitosis. In this review, we discuss new research in the lens that has shed light into further roles for stable microtubules in the process of development and morphogenesis. In the lens, as well as other systems, distinct roles for characteristically dynamic microtubules and stabilized populations are coming to light. Understanding the mechanisms of microtubule stabilization and the associated microtubule post-translational modifications is an evolving field of study. Appropriate cellular homeostasis relies on not only one cytoskeletal element, but also rather an interaction between cytoskeletal proteins as well as other cellular regulators. Microtubules are key integrators with actin and intermediate filaments, as well as cell–cell junctional proteins and other cellular regulators including myosin and RhoGTPases to maintain this balance.Impact statementThe role of microtubules in cellular functioning is constantly expanding. In this review, we examine new and exciting fields of discovery for microtubule’s involvement in morphogenesis, highlight our evolving understanding of differential roles for stabilized versus dynamic subpopulations, and further understanding of microtubules as a cellular integrator.
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Affiliation(s)
- Caitlin M Logan
- Pathology Anatomy and Cell Biology Department, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - A Sue Menko
- Pathology Anatomy and Cell Biology Department, Thomas Jefferson University, Philadelphia, PA 19107, USA
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Zhang T, Hsu FN, Xie XJ, Li X, Liu M, Gao X, Pei X, Liao Y, Du W, Ji JY. Reversal of hyperactive Wnt signaling-dependent adipocyte defects by peptide boronic acids. Proc Natl Acad Sci U S A 2017; 114:E7469-E7478. [PMID: 28827348 PMCID: PMC5594642 DOI: 10.1073/pnas.1621048114] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Deregulated Wnt signaling and altered lipid metabolism have been linked to obesity, diabetes, and various cancers, highlighting the importance of identifying inhibitors that can modulate Wnt signaling and aberrant lipid metabolism. We have established a Drosophila model with hyperactivated Wnt signaling caused by partial loss of axin, a key component of the Wnt cascade. The Axin mutant larvae are transparent and have severe adipocyte defects caused by up-regulation of β-catenin transcriptional activities. We demonstrate pharmacologic mitigation of these phenotypes in Axin mutants by identifying bortezomib and additional peptide boronic acids. We show that the suppressive effect of peptide boronic acids on hyperactive Wnt signaling is dependent on α-catenin; the rescue effect is completely abolished with the depletion of α-catenin in adipocytes. These results indicate that rather than targeting the canonical Wnt signaling pathway directly, pharmacologic modulation of β-catenin activity through α-catenin is a potentially attractive approach to attenuating Wnt signaling in vivo.
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Affiliation(s)
- Tianyi Zhang
- Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637
| | - Fu-Ning Hsu
- Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, TX 77843
| | - Xiao-Jun Xie
- Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, TX 77843
| | - Xiao Li
- Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, TX 77843
| | - Mengmeng Liu
- Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, TX 77843
| | - Xinsheng Gao
- Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, TX 77843
| | - Xun Pei
- Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637
| | - Yang Liao
- Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637
| | - Wei Du
- Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637;
| | - Jun-Yuan Ji
- Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, TX 77843
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Muhamed I, Chowdhury F, Maruthamuthu V. Biophysical Tools to Study Cellular Mechanotransduction. Bioengineering (Basel) 2017; 4:E12. [PMID: 28952491 PMCID: PMC5590431 DOI: 10.3390/bioengineering4010012] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 01/30/2017] [Accepted: 02/02/2017] [Indexed: 01/25/2023] Open
Abstract
The cell membrane is the interface that volumetrically isolates cellular components from the cell's environment. Proteins embedded within and on the membrane have varied biological functions: reception of external biochemical signals, as membrane channels, amplification and regulation of chemical signals through secondary messenger molecules, controlled exocytosis, endocytosis, phagocytosis, organized recruitment and sequestration of cytosolic complex proteins, cell division processes, organization of the cytoskeleton and more. The membrane's bioelectrical role is enabled by the physiologically controlled release and accumulation of electrochemical potential modulating molecules across the membrane through specialized ion channels (e.g., Na⁺, Ca2+, K⁺ channels). The membrane's biomechanical functions include sensing external forces and/or the rigidity of the external environment through force transmission, specific conformational changes and/or signaling through mechanoreceptors (e.g., platelet endothelial cell adhesion molecule (PECAM), vascular endothelial (VE)-cadherin, epithelial (E)-cadherin, integrin) embedded in the membrane. Certain mechanical stimulations through specific receptor complexes induce electrical and/or chemical impulses in cells and propagate across cells and tissues. These biomechanical sensory and biochemical responses have profound implications in normal physiology and disease. Here, we discuss the tools that facilitate the understanding of mechanosensitive adhesion receptors. This article is structured to provide a broad biochemical and mechanobiology background to introduce a freshman mechano-biologist to the field of mechanotransduction, with deeper study enabled by many of the references cited herein.
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Affiliation(s)
- Ismaeel Muhamed
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27695, USA.
| | - Farhan Chowdhury
- Department of Mechanical Engineering and Energy Processes, Southern Illinois University Carbondale, Carbondale, IL 62901, USA.
| | - Venkat Maruthamuthu
- Department of Mechanical and Aerospace Engineering, Old Dominion University, Norfolk, VA 23529, USA.
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CCR6 expression in colon cancer is associated with advanced disease and supports epithelial-to-mesenchymal transition. Br J Cancer 2016; 114:1343-51. [PMID: 27149649 PMCID: PMC4984452 DOI: 10.1038/bjc.2016.113] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 03/22/2016] [Accepted: 03/29/2016] [Indexed: 12/11/2022] Open
Abstract
Background: Adjuvant chemotherapy offered to treat colon cancer is based on the TNM staging system, which often fails due to molecular heterogeneity and undefined molecular mechanisms independent of TNM. Therefore, identification of markers to better predict therapeutic option and outcome is needed. In this study we have characterised the clinical association of CCR6 with colon cancer and defined CCR6-mediated molecular pathway. Methods: Immunohistochemistry, RT-qPCR, western blot and FACS were used to determine expression of CCR6 and/or EMT markers in colon tissues/cells. BrdU assay and trans-well system were used to determine cell proliferation, migration and invasion in response to CCL20. Results: CCR6 was higher in cancer cases compared to normal adjacent tissue and expression was associated with nodal status and distant metastasis. Similarly, CCR6 expression was higher in cells derived from node-positive cases and highest expression was in cells derived from metastatic cases. Significant changes in EMT markers, that is, E-cadherin, vimentin, β-catenin, N-cadherin, α-SMA, SNAILl and ZEB1 were observed in response to CCL20 along with decreased proliferation, increased migratory and invasive potential. Conclusions: Results suggest CCR6 as a potential therapeutic target as well as biomarker in addition to nodal status for predicting therapeutic option.
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Shahbazi MN, Perez-Moreno M. Connections between cadherin-catenin proteins, spindle misorientation, and cancer. Tissue Barriers 2015; 3:e1045684. [PMID: 26451345 DOI: 10.1080/21688370.2015.1045684] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Revised: 04/18/2015] [Accepted: 04/21/2015] [Indexed: 10/25/2022] Open
Abstract
Cadherin-catenin mediated adhesion is an important determinant of tissue architecture in multicellular organisms. Cancer progression and maintenance is frequently associated with loss of their expression or functional activity, which not only leads to decreased cell-cell adhesion, but also to enhanced tumor cell proliferation and loss of differentiated characteristics. This review is focused on the emerging implications of cadherin-catenin proteins in the regulation of polarized divisions through their connections with the centrosomes, cytoskeleton, tissue tension and signaling pathways; and illustrates how alterations in cadherin-catenin levels or functional activity may render cells susceptible to transformation through the loss of their proliferation-differentiation balance.
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Affiliation(s)
- Marta N Shahbazi
- Department of Physiology, Development, and Neuroscience; University of Cambridge ; Cambridge, UK
| | - Mirna Perez-Moreno
- Epithelial Cell Biology Group; Cancer Cell Biology Program; Spanish National Cancer Research Centre ; Madrid, Spain
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Pelissier-Rota MA, Chartier NT, Jacquier-Sarlin MR. Dynamic Regulation of Adherens Junctions: Implication in Cell Differentiation and Tumor Development. INTERCELLULAR COMMUNICATION IN CANCER 2015:53-149. [DOI: 10.1007/978-94-017-7380-5_4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Wang X, Grunz-Borgmann EA, Parrish AR. Loss of α(E)-catenin potentiates cisplatin-induced nephrotoxicity via increasing apoptosis in renal tubular epithelial cells. Toxicol Sci 2014; 141:254-62. [PMID: 24973089 DOI: 10.1093/toxsci/kfu130] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Cisplatin is one of the most potent and widely used antitumor drugs. However, the use of cisplatin is limited by its side effect, nephrotoxicity. Evidence has shown an increased incidence and severity of acute kidney injury (AKI) in the elderly. Previous studies from our laboratory demonstrate a decrease in α(E)-catenin expression in aged kidney. In this study, we investigated whether the loss of α(E)-catenin may increase cisplatin nephrotoxicity. To study the effects of reduced α(E)-catenin, a cell line with stable knockdown of α(E)-catenin (C2 cells) was used; NT3 is nontargeted control. C2 cells exhibited a significant loss of viability as determined by MTT assay compared with NT3 cells after cisplatin challenge, but showed no difference in lactate dehydrogenase (LDH) leakage. Increased caspase 3/7 activation and PARP cleavage was observed in C2 cells after cisplatin treatment. Z-VAD, a pan-caspase inhibitor, abolished the difference in susceptibility between NT3 and C2 cells. Interestingly, the expression of α(E)-catenin was further decreased after cisplatin treatment. Furthermore, in vivo data demonstrated a significant increase in serum creatinine at 72 h after a single dose of cisplatin in 24-month-old rats, but not in 4-month-old rats. Increased expression of KIM-1 and in situ apoptosis were also detected in aged kidney after cisplatin challenge. Taken together, these data suggest that loss of α(E)-catenin increases apoptosis of tubular epithelial cells which may contribute to the increased nephrotoxicity induced by cisplatin in aged kidney.
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Affiliation(s)
- Xinhui Wang
- Department of Medical Pharmacology and Physiology, School of Medicine, University, of Missouri, Columbia, Missouri 65212
| | - Elizabeth A Grunz-Borgmann
- Department of Medical Pharmacology and Physiology, School of Medicine, University, of Missouri, Columbia, Missouri 65212
| | - Alan R Parrish
- Department of Medical Pharmacology and Physiology, School of Medicine, University, of Missouri, Columbia, Missouri 65212
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Li J. Alterations in cell adhesion proteins and cardiomyopathy. World J Cardiol 2014; 6:304-313. [PMID: 24944760 PMCID: PMC4062122 DOI: 10.4330/wjc.v6.i5.304] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Revised: 02/27/2014] [Accepted: 03/14/2014] [Indexed: 02/06/2023] Open
Abstract
Cell adhesive junction is specialized intercellular structure composed of cell adhesion proteins. They are essential to connect adjacent heart muscle cell and make heart contraction effectively and properly. Clinical and genetic studies have revealed close relationship between cell adhesive proteins and the occurrence of various cardiomyopathies. Here we will review recent development on the disease phenotype, potential cellular and molecular mechanism related to cell adhesion molecules, with particular disease pathogenesis learned from genetic manipulated murine models.
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Nichols LA, Slusarz A, Grunz-Borgmann EA, Parrish AR. α(E)-catenin regulates BMP-7 expression and migration in renal epithelial cells. Am J Nephrol 2014; 39:409-17. [PMID: 24818804 DOI: 10.1159/000362250] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Accepted: 03/11/2014] [Indexed: 01/29/2023]
Abstract
BACKGROUND The aging kidney has a decreased ability to repair following injury. We have shown a loss in expression of α-catenin in the aging rat kidney and hypothesize that decreased α-catenin expression in tubular epithelial cells results in diminished repair capacity. METHODS In an effort to elucidate alterations due to the loss of α-catenin, we generated NRK-52E cell lines with stable knockdown of α(E)-catenin. RESULTS α(E)-catenin knockdown resulted in decreased wound repair due to alterations in cell migration. Analysis of gene expression in the α(E)-catenin knockdown cells demonstrated almost a complete loss of bone morphogenetic protein-7 (BMP-7) expression that was associated with decreased phospho-Smad1/5/8 staining. However, addition of exogenous BMP-7 increased phospho-Smad1/5/8, suggesting that the BMP-7 pathway remained intact in C2 cells. Given the potential role of BMP-7 in repair, we investigated its role in wound repair. Inhibition of BMP-7 decreased repair in non-targeted control cells; conversely, exogenous BMP-7 restored repair in α(E)-catenin knockdown cells to control levels. CONCLUSIONS Taken together, the data suggests that the loss of α(E)-catenin expression and subsequent downregulation of BMP-7 is a mechanism underlying the altered migration of tubular epithelial cells that contributes to the inability of the aging kidney to repair following injury.
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Affiliation(s)
- LaNita A Nichols
- Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Mo., USA
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Li MWM, Cheng CY, Mruk DD. Sertolin mediates blood-testis barrier restructuring. Endocrinology 2014; 155:1520-31. [PMID: 24467744 PMCID: PMC3959606 DOI: 10.1210/en.2013-1850] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2013] [Accepted: 01/14/2014] [Indexed: 01/12/2023]
Abstract
Two important events that occur during mammalian spermatogenesis are the release of elongated spermatids at late stage VIII of the seminiferous epithelial cycle and the restructuring of the blood-testis barrier (BTB) during stages VIII-XI. Still, it is not completely understood how these cellular events are accomplished within the seminiferous epithelium. In the present study, we investigate how sertolin, a protein that was initially identified, cloned, and partially characterized by our laboratory, functions in these critical events. Sertolin was found at the BTB, as well as at the apical ectoplasmic specialization and apical tubulobulbar complex, where it colocalized with epidermal growth factor receptor kinase substrate 8 and actin-related protein 3, two actin-regulatory proteins. Knockdown of sertolin by RNA interference showed Sertoli cell barrier function to be enhanced when assessed by transepithelial electrical resistance measurements and immunolocalization experiments. By contrast, the integrity of the BTB was disrupted when sertolin was overexpressed in vitro and in vivo. Sertolin overexpression also prompted germ cell loss from the seminiferous epithelium. Taken collectively, these results suggest that sertolin may be involved in coordinating spermatid release and BTB restructuring during spermatogenesis in the rat.
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Affiliation(s)
- Michelle W M Li
- Center for Biomedical Research, Population Council, New York, New York 10065
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Miller RK, Hong JY, Muñoz WA, McCrea PD. Beta-catenin versus the other armadillo catenins: assessing our current view of canonical Wnt signaling. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2013; 116:387-407. [PMID: 23481204 DOI: 10.1016/b978-0-12-394311-8.00017-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The prevailing view of canonical Wnt signaling emphasizes the role of beta-catenin acting downstream of Wnt activation to regulate transcriptional activity. However, emerging evidence indicates that other armadillo catenins in vertebrates, such as members of the p120 subfamily, convey parallel signals to the nucleus downstream of canonical Wnt pathway activation. Their study is thus needed to appreciate the networked mechanisms of canonical Wnt pathway transduction, especially as they may assist in generating the diversity of Wnt effects observed in development and disease. In this chapter, we outline evidence of direct canonical Wnt effects on p120 subfamily members in vertebrates and speculate upon these catenins' roles in conjunction with or aside from beta-catenin.
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Affiliation(s)
- Rachel K Miller
- Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Ivanov AI, Naydenov NG. Dynamics and regulation of epithelial adherens junctions: recent discoveries and controversies. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2013; 303:27-99. [PMID: 23445808 DOI: 10.1016/b978-0-12-407697-6.00002-7] [Citation(s) in RCA: 90] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Adherens junctions (AJs) are evolutionarily conserved plasma-membrane structures that mediate cell-cell adhesions in multicellular organisms. They are organized by several types of adhesive integral membrane proteins, most notably cadherins and nectins that are clustered and stabilized by a number of cytoplasmic scaffolds. AJs are key regulators of tissue architecture and dynamics via control of cell proliferation, polarity, shape, motility, and survival. They are absolutely critical for normal tissue morphogenesis and their disruption results in pathological abnormalities in different tissues. Although the field of adherens-junction research dramatically progressed in recent years, a number of important questions remain controversial and poorly understood. This review outlines basic principles that regulate organization of AJs in mammalian epithelia and discusses recent advances and standing controversies in the field. A special attention is paid to the regulation of AJs by vesicle trafficking and the intracellular cytoskeleton as well as roles and mechanisms of adherens-junction disruption during tumor progression and tissue inflammation.
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Affiliation(s)
- Andrei I Ivanov
- Department of Human and Molecular Genetics, Virginia Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
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Hollestelle A, Peeters JK, Smid M, Timmermans M, Verhoog LC, Westenend PJ, Heine AAJ, Chan A, Sieuwerts AM, Wiemer EAC, Klijn JGM, van der Spek PJ, Foekens JA, Schutte M, den Bakker MA, Martens JWM. Loss of E-cadherin is not a necessity for epithelial to mesenchymal transition in human breast cancer. Breast Cancer Res Treat 2013; 138:47-57. [PMID: 23338761 DOI: 10.1007/s10549-013-2415-3] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2012] [Accepted: 01/11/2013] [Indexed: 11/25/2022]
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17
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Polato NR, Altman NS, Baums IB. Variation in the transcriptional response of threatened coral larvae to elevated temperatures. Mol Ecol 2013; 22:1366-82. [DOI: 10.1111/mec.12163] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2012] [Revised: 10/30/2012] [Accepted: 11/02/2012] [Indexed: 12/30/2022]
Affiliation(s)
- Nicholas R. Polato
- Department of Biology; The Pennsylvania State University; 208 Mueller Laboratory University Park PA 16802 USA
| | - Naomi S. Altman
- Department of Statistics; The Pennsylvania State University; 312 Thomas Building University Park PA 16802 USA
| | - Iliana B. Baums
- Department of Biology; The Pennsylvania State University; 208 Mueller Laboratory University Park PA 16802 USA
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18
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Canel M, Serrels A, Frame MC, Brunton VG. E-cadherin-integrin crosstalk in cancer invasion and metastasis. J Cell Sci 2013; 126:393-401. [PMID: 23525005 DOI: 10.1242/jcs.100115] [Citation(s) in RCA: 480] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
E-cadherin is a single-pass transmembrane protein that mediates homophilic cell-cell interactions. Tumour progression is often associated with the loss of E-cadherin function and the transition to a more motile and invasive phenotype. This requires the coordinated regulation of both E-cadherin-mediated cell-cell adhesions and integrin-mediated adhesions that contact the surrounding extracellular matrix (ECM). Regulation of both types of adhesion is dynamic as cells respond to external cues from the tumour microenvironment that regulate polarity, directional migration and invasion. Here, we review the mechanisms by which tumour cells control the cross-regulation between dynamic E-cadherin-mediated cell-cell adhesions and integrin-mediated cell-matrix contacts, which govern the invasive and metastatic potential of tumours. In particular, we will discuss the role of the adhesion-linked kinases Src, focal adhesion kinase (FAK) and integrin-linked kinase (ILK), and the Rho family of GTPases.
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Affiliation(s)
- Marta Canel
- Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK
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19
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Centralspindlin and α-catenin regulate Rho signalling at the epithelial zonula adherens. Nat Cell Biol 2012; 14:818-828. [PMID: 22750944 DOI: 10.1038/ncb2532] [Citation(s) in RCA: 203] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2011] [Accepted: 05/25/2012] [Indexed: 12/17/2022]
Abstract
The biological impact of Rho depends critically on the precise subcellular localization of its active, GTP-loaded form. This can potentially be determined by the balance between molecules that promote nucleotide exchange or GTP hydrolysis. However, how these activities may be coordinated is poorly understood. We now report a molecular pathway that achieves exactly this coordination at the epithelial zonula adherens. We identify an extramitotic activity of the centralspindlin complex, better understood as a cytokinetic regulator, which localizes to the interphase zonula adherens by interacting with the cadherin-associated protein, α-catenin. Centralspindlin recruits the RhoGEF, ECT2, to activate Rho and support junctional integrity through myosin IIA. Centralspindlin also inhibits the junctional localization of p190 B RhoGAP, which can inactivate Rho. Thus, a conserved molecular ensemble that governs Rho activation during cytokinesis is used in interphase cells to control the Rho GTPase cycle at the zonula adherens.
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20
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Epifano C, Perez-Moreno M. Crossroads of integrins and cadherins in epithelia and stroma remodeling. Cell Adh Migr 2012; 6:261-73. [PMID: 22568988 DOI: 10.4161/cam.20253] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Adhesion events mediated by cadherin and integrin adhesion receptors have fundamental roles in the maintenance of the physiological balance of epithelial tissues, and it is well established that perturbations in their normal functional activity and/or changes in their expression are associated with tumorigenesis. Over the last decades, increasing evidence of a dynamic collaborative interaction between these complexes through their shared interactions with cytoskeletal proteins and common signaling pathways has emerged not only as an important regulator of several aspects of epithelial cell behavior, but also as a coordinated adhesion module that senses and transmits signals from and to the epithelia surrounding microenvironment. The tight regulation of their crosstalk is particularly important during epithelial remodeling events that normally take place during morphogenesis and tissue repair, and when defective it leads to cell transformation and aggravated responses of the tumor microenvironment that contribute to tumorigenesis. In this review we highlight some of the interactions that regulate their crosstalk and how this could be implicated in regulating signals across epithelial tissues to sustain homeostasis.
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Affiliation(s)
- Carolina Epifano
- Epithelial Cell Biology Group, BBVA Foundation-Cancer Cell Biology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
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21
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Fiore C, Bailey D, Conlon N, Wu X, Martin N, Fiorentino M, Finn S, Fall K, Andersson SO, Andren O, Loda M, Flavin R. Utility of multispectral imaging in automated quantitative scoring of immunohistochemistry. J Clin Pathol 2012; 65:496-502. [PMID: 22447914 DOI: 10.1136/jclinpath-2012-200734] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
BACKGROUND Automated scanning devices and image analysis software provide a means to overcome the limitations of manual semiquantitative scoring of immunohistochemistry. Common drawbacks to automated imaging systems include an inability to classify tissue type and an inability to segregate cytoplasmic and nuclear staining. METHODS Immunohistochemistry for the membranous marker α-catenin, the cytoplasmic marker stathmin and the nuclear marker Ki-67 was performed on tissue microarrays (TMA) of archival formalin-fixed paraffin-embedded tissue comprising 471 (α-catenin and stathmin) and 511 (Ki-67) cases of prostate adenocarcinoma. These TMA were quantitatively analysed using two commercially available automated image analysers, the Ariol SL-50 system and the Nuance system from CRi. Both systems use brightfield microscopy for automated, unbiased and standardised quantification of immunohistochemistry, while the Nuance system has spectral deconvolution capabilities. RESULTS Overall concordance between scores from both systems was excellent (r=0.90; 0.83-0.95). The software associated with the multispectral imager allowed accurate automated classification of tissue type into epithelial glandular structures and stroma, and a single-step segmentation of staining into cytoplasmic or nuclear compartments allowing independent evaluation of these areas. The Nuance system, however, was not able to distinguish reliably between tumour and non-tumour tissue. In addition, variance in the labour and time required for analysis between the two systems was also noted. CONCLUSION Despite limitations, this study suggests some beneficial role for the use of a multispectral imaging system in automated analysis of immunohistochemistry.
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Affiliation(s)
- Christopher Fiore
- Center for Molecular Oncologic Pathology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
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22
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Li J, Goossens S, van Hengel J, Gao E, Cheng L, Tyberghein K, Shang X, De Rycke R, van Roy F, Radice GL. Loss of αT-catenin alters the hybrid adhering junctions in the heart and leads to dilated cardiomyopathy and ventricular arrhythmia following acute ischemia. J Cell Sci 2012; 125:1058-67. [PMID: 22421363 DOI: 10.1242/jcs.098640] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
It is generally accepted that the intercalated disc (ICD) required for mechano-electrical coupling in the heart consists of three distinct junctional complexes: adherens junctions, desmosomes and gap junctions. However, recent morphological and molecular data indicate a mixing of adherens junctional and desmosomal components, resulting in a 'hybrid adhering junction' or 'area composita'. The α-catenin family member αT-catenin, part of the N-cadherin-catenin adhesion complex in the heart, is the only α-catenin that interacts with the desmosomal protein plakophilin-2 (PKP2). Thus, it has been postulated that αT-catenin might serve as a molecular integrator of the two adhesion complexes in the area composita. To investigate the role of αT-catenin in the heart, gene targeting technology was used to delete the Ctnna3 gene, encoding αT-catenin, in the mouse. The αT-catenin-null mice are viable and fertile; however, the animals exhibit progressive cardiomyopathy. Adherens junctional and desmosomal proteins were unaffected by loss of αT-catenin, with the exception of the desmosomal protein PKP2. Immunogold labeling at the ICD demonstrated in the αT-catenin-null heart a preferential reduction of PKP2 at the area composita compared with the desmosome. Furthermore, gap junction protein Cx43 was reduced at the ICD, including its colocalization with N-cadherin. Gap junction remodeling in αT-catenin-knockout hearts was associated with an increased incidence of ventricular arrhythmias after acute ischemia. This novel animal model demonstrates for the first time how perturbation in αT-catenin can affect both PKP2 and Cx43 and thereby highlights the importance of understanding the crosstalk between the junctional proteins of the ICD and its implications for arrhythmogenic cardiomyopathy.
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Affiliation(s)
- Jifen Li
- Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA
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23
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Rhee J, Ryu JH, Kim JH, Chun CH, Chun JS. α-Catenin inhibits β-catenin-T-cell factor/lymphoid enhancing factor transcriptional activity and collagen type II expression in articular chondrocytes through formation of Gli3R.α-catenin.β-catenin ternary complex. J Biol Chem 2012; 287:11751-60. [PMID: 22298781 DOI: 10.1074/jbc.m111.281014] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Chondrocytes, a unique cell type in cartilage tissue, are responsible for the regulation of anabolic and catabolic homeostasis in cartilage-specific extracellular matrix synthesis. Activation of Wnt/β-catenin signaling induces dedifferentiation of articular chondrocytes, resulting in suppression of type II collagen expression. We have shown previously that α-catenin inhibits β-catenin-Tcf/Lef (T-cell factor/lymphoid-enhancing factor) transcriptional activity in articular chondrocytes with a concomitant recovery of type II collagen expression. In the current study, we elucidated the mechanism underlying this inhibition of β-catenin-Tcf/Lef transcriptional activity by α-catenin, showing that it requires direct interaction between α-catenin and β-catenin. We further showed that it involves recruitment of Gli3R, the short transcription-repressing form of the transcription factor Gli3, to β-catenin by α-catenin. The resulting inhibition of β-catenin transcriptional activity leads to increased expression of type II collagen. Gli3R and α-catenin actions are co-dependent: both are necessary for the observed inhibitory effects on β-catenin transcriptional activity. Reducing Gli3R expression levels through activation of Indian Hedgehog (Ihh) signaling also is sufficient to activate β-catenin transcriptional activity, suggesting that the ternary complex, Gli3R·α-catenin·β-catenin, mediates Ihh-dependent activation of Wnt/β-catenin signaling in articular chondrocytes. Collectively, this study shows that α-catenin functions as a nuclear factor that recruits the transcriptional repressor Gli3R to β-catenin to inhibit β-catenin transcriptional activity and dedifferentiation of articular chondrocytes. Finally, osteoarthritic cartilage showed elevated levels of β-catenin and decreased levels of α-catenin and Gli3R, suggesting that decreased levels of α-catenin and Gli3R levels contribute to increased β-catenin transcriptional activity during osteoarthritic cartilage destruction.
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Affiliation(s)
- Jinseol Rhee
- Cell Dynamics Research Center and School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea
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24
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Niessen CM, Leckband D, Yap AS. Tissue organization by cadherin adhesion molecules: dynamic molecular and cellular mechanisms of morphogenetic regulation. Physiol Rev 2011; 91:691-731. [PMID: 21527735 DOI: 10.1152/physrev.00004.2010] [Citation(s) in RCA: 287] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
This review addresses the cellular and molecular mechanisms of cadherin-based tissue morphogenesis. Tissue physiology is profoundly influenced by the distinctive organizations of cells in organs and tissues. In metazoa, adhesion receptors of the classical cadherin family play important roles in establishing and maintaining such tissue organization. Indeed, it is apparent that cadherins participate in a range of morphogenetic events that range from support of tissue integrity to dynamic cellular rearrangements. A comprehensive understanding of cadherin-based morphogenesis must then define the molecular and cellular mechanisms that support these distinct cadherin biologies. Here we focus on four key mechanistic elements: the molecular basis for adhesion through cadherin ectodomains, the regulation of cadherin expression at the cell surface, cooperation between cadherins and the actin cytoskeleton, and regulation by cell signaling. We discuss current progress and outline issues for further research in these fields.
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Affiliation(s)
- Carien M Niessen
- Department of Dermatology, Center for Molecular Medicine, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
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25
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Chalasani K, Brewster RM. N-cadherin-mediated cell adhesion restricts cell proliferation in the dorsal neural tube. Mol Biol Cell 2011; 22:1505-15. [PMID: 21389116 PMCID: PMC3084673 DOI: 10.1091/mbc.e10-08-0675] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Neural progenitors are organized as a pseudostratified epithelium held together by adherens junctions (AJs), multiprotein complexes composed of cadherins and α- and β-catenin. Catenins are known to control neural progenitor division; however, it is not known whether they function in this capacity as cadherin binding partners, as there is little evidence that cadherins themselves regulate neural proliferation. We show here that zebrafish N-cadherin (N-cad) restricts cell proliferation in the dorsal region of the neural tube by regulating cell-cycle length. We further reveal that N-cad couples cell-cycle exit and differentiation, as a fraction of neurons are mitotic in N-cad mutants. Enhanced proliferation in N-cad mutants is mediated by ligand-independent activation of Hedgehog (Hh) signaling, possibly caused by defective ciliogenesis. Furthermore, depletion of Hh signaling results in the loss of junctional markers. We therefore propose that N-cad restricts the response of dorsal neural progenitors to Hh and that Hh signaling limits the range of its own activity by promoting AJ assembly. Taken together, these observations emphasize a key role for N-cad-mediated adhesion in controlling neural progenitor proliferation. In addition, these findings are the first to demonstrate a requirement for cadherins in synchronizing cell-cycle exit and differentiation and a reciprocal interaction between AJs and Hh signaling.
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Affiliation(s)
- Kavita Chalasani
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250, USA
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26
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Watanabe T, Sato K, Kaibuchi K. Cadherin-mediated intercellular adhesion and signaling cascades involving small GTPases. Cold Spring Harb Perspect Biol 2010; 1:a003020. [PMID: 20066109 DOI: 10.1101/cshperspect.a003020] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Epithelia form physical barriers that separate the internal milieu of the body from its external environment. The biogenesis of functional epithelia requires the precise coordination of many cellular processes. One of the key events in epithelial biogenesis is the establishment of cadherin-dependent cell-cell contacts, which initiate morphological changes and the formation of other adhesive structures. Cadherin-mediated adhesions generate intracellular signals that control cytoskeletal reorganization, polarity, and vesicle trafficking. Among such signaling pathways, those involving small GTPases play critical roles in epithelial biogenesis. Assembly of E-cadherin activates several small GTPases and, in turn, the activated small GTPases control the effects of E-cadherin-mediated adhesions on epithelial biogenesis. Here, we focus on small GTPase signaling at E-cadherin-mediated epithelial junctions.
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Affiliation(s)
- Takashi Watanabe
- Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya 466-8550, Japan
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27
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Libusova L, Stemmler MP, Hierholzer A, Schwarz H, Kemler R. N-cadherin can structurally substitute for E-cadherin during intestinal development but leads to polyp formation. Development 2010; 137:2297-305. [DOI: 10.1242/dev.048488] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
We conditionally substituted E-cadherin (E-cad; cadherin 1) with N-cadherin (N-cad; cadherin 2) during intestine development by generating mice in which an Ncad cDNA was knocked into the Ecad locus. Mutant mice were born, demonstrating that N-cad can structurally replace E-cad and establish proper organ architecture. After birth, mutant mice gradually developed a mutant phenotype in both the small and large intestine and died at ~2-3 weeks of age, probably due to malnutrition during the transition to solid food. Molecular analysis revealed an extended domain of cells from the crypt into the villus region, with nuclear localization of β-catenin (β-cat; Ctnnb1) and enhanced expression of several β-cat target genes. In addition, the BMP signaling pathway was suppressed in the intestinal epithelium of the villi, suggesting that N-cad might interfere with BMP signaling in the intestinal epithelial cell layer. Interestingly, mutant mice developed severe dysplasia and clusters of cells with neoplastic features scattered along the crypt-villus axis in the small and large intestine. Our experimental model indicates that, in the absence of E-cad, the sole expression of N-cad in an epithelial environment is sufficient to induce neoplastic transformations.
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Affiliation(s)
- Lenka Libusova
- Department of Molecular Embryology, Max-Planck Institute of Immunobiology, Stuebeweg 51, D-79108 Freiburg, Germany
| | - Marc P. Stemmler
- Department of Molecular Embryology, Max-Planck Institute of Immunobiology, Stuebeweg 51, D-79108 Freiburg, Germany
| | - Andreas Hierholzer
- Department of Molecular Embryology, Max-Planck Institute of Immunobiology, Stuebeweg 51, D-79108 Freiburg, Germany
| | - Heinz Schwarz
- Max-Planck Institute of Developmental Biology, Spemannstr. 35, D-72076 Tübingen, Germany
| | - Rolf Kemler
- Department of Molecular Embryology, Max-Planck Institute of Immunobiology, Stuebeweg 51, D-79108 Freiburg, Germany
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28
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Affiliation(s)
- Pierre D McCrea
- Department of Biochemistry and Molecular Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
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29
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Abstract
Background: The Coxsackie and adenovirus receptor (CAR) has been shown to inhibit cancer cell proliferation, migration, and invasion. The underlying mechanisms, however, are poorly understood. Methods: The differential gene expression in the human colon cancer cell line DLD1 on RNAi-mediated functional CAR knockdown was analysed using oligo-array technology. Expression of α-catenin was determined by quantitative RT-PCR and western blotting. Proliferation, migration, and invasion after CAR knockdown were assessed by in vitro assays, and cell morphology in a three-dimensional context was evaluated using matrigel. Results: Oligo-array technology identified α-catenin as the strongest downregulated gene after CAR knockdown. Western blotting and quantitative RT-PCR confirmed a reduced α-catenin expression after CAR knockdown in DLD1 cells and in the rat intestinal cell line IEC-6. Functionally, both cell lines showed a marked increase in proliferation, migration, and invasion on CAR knockdown. In matrigel, both cell lines formed amorphous cell clusters in contrast to well-organised three-dimensional structures of CAR-expressing vector controls. Ectopic ‘re’-expression of α-catenin in DLD1 and IEC-6 CAR knockdown cells reversed these functional and morphological effects. Conclusion These data suggest that an interaction of CAR and α-catenin mediates the impact of CAR on cell proliferation, migration, invasion, and morphology.
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30
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Popoff MR, Geny B. Multifaceted role of Rho, Rac, Cdc42 and Ras in intercellular junctions, lessons from toxins. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2009; 1788:797-812. [PMID: 19366594 DOI: 10.1016/j.bbamem.2009.01.011] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2008] [Revised: 01/20/2009] [Accepted: 01/22/2009] [Indexed: 12/20/2022]
Abstract
Tight junctions (TJs) and adherens junctions (AJs) are dynamic structures linked to the actin cytoskeleton, which control the paracellular permeability of epithelial and endothelial barriers. TJs and AJs are strictly regulated in a spatio-temporal manner by a complex signaling network, including Rho/Ras-GTPases, which have a pivotal role. Rho preferentially regulates TJs by controlling the contraction of apical acto-myosin filaments, whereas Rac/Cdc42 mainly coordinate the assembly-disassembly of AJ components. However, a subtle balance of Rho/Ras-GTPase activity and interplay between these molecules is required to maintain an optimal organization and function of TJs and AJs. Conversely, integrity of intercellular junctions generates signals through Rho-GTPases, which are involved in the regulation of multiple cellular processes. Rho/Ras-GTPases and the control of intercellular junctions are the target of various bacterial toxins responsible for severe diseases in man and animals, and are part of their mechanism of action. This review focuses on the regulation of TJs and AJs by Rho/Ras-GTPases through molecular approaches and bacterial toxins.
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Affiliation(s)
- Michel R Popoff
- Institut Pasteur, Unité des Bactéries anaérobies et Toxines, 75724 Paris cedex151, France.
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31
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Jeanes A, Gottardi CJ, Yap AS. Cadherins and cancer: how does cadherin dysfunction promote tumor progression? Oncogene 2009; 27:6920-9. [PMID: 19029934 DOI: 10.1038/onc.2008.343] [Citation(s) in RCA: 595] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
It has long been recognized that the cell-cell adhesion receptor, E-cadherin, is an important determinant of tumor progression, serving as a suppressor of invasion and metastasis in many contexts. Yet how the loss of E-cadherin function promotes tumor progression is poorly understood. In this review, we focus on three potential underlying mechanisms: the capacity of E-cadherin to regulate beta-catenin signaling in the canonical Wnt pathway; its potential to inhibit mitogenic signaling through growth factor receptors and the possible links between cadherins and the molecular determinants of epithelial polarity. Each of these potential mechanisms provides insights into the complexity that is likely responsible for the tumor-suppressive action of E-cadherin.
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Affiliation(s)
- A Jeanes
- 1Division of Molecular Cell Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
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32
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Abstract
It has long been recognized that the cell-cell adhesion receptor, E-cadherin, is an important determinant of tumor progression, serving as a suppressor of invasion and metastasis in many contexts. Yet how the loss of E-cadherin function promotes tumor progression is poorly understood. In this review, we focus on three potential underlying mechanisms: the capacity of E-cadherin to regulate beta-catenin signaling in the canonical Wnt pathway; its potential to inhibit mitogenic signaling through growth factor receptors and the possible links between cadherins and the molecular determinants of epithelial polarity. Each of these potential mechanisms provides insights into the complexity that is likely responsible for the tumor-suppressive action of E-cadherin.
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33
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Lynch AM, Hardin J. The assembly and maintenance of epithelial junctions in C. elegans. Front Biosci (Landmark Ed) 2009; 14:1414-32. [PMID: 19273138 DOI: 10.2741/3316] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The epithelial tissues of the C. elegans embryo provide a "minimalist" system for examining phylogenetically conserved proteins that function in epithelial polarity and cell-cell adhesion in a multicellular organism. In this review, we provide an overview of three major molecular complexes at the apical surface of epithelial cells in the C. elegans embryo: the cadherin-catenin complex, the more basal DLG-1/AJM-1 complex, and the apical membrane domain, which shares similarities with the subapical complex in Drosophila and the PAR/aPKC complex in vertebrates. We discuss how the assembly of these complexes contributes to epithelial polarity and adhesion, proteins that act as effectors and/or regulators of each subdomain, and how these complexes functionally interact during embryonic morphogenesis. Although much remains to be clarified, significant progress has been made in recent years to clarify the role of these protein complexes in epithelial morphogenesis, and suggests that C. elegans will continue to be a fruitful system in which to elucidate functional roles for these proteins in a living embryo.
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Affiliation(s)
- Allison M Lynch
- Program in Genetics, University of Wisconsin-Madison, University of Wisconsin-Madison, Department of Zoology, University of Wisconsin-Madison, USA
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34
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Feng Y, Sun X, Yang H, Teitelbaum DH. Dissociation of E-cadherin and beta-catenin in a mouse model of total parenteral nutrition: a mechanism for the loss of epithelial cell proliferation and villus atrophy. J Physiol 2008; 587:641-54. [PMID: 19064618 DOI: 10.1113/jphysiol.2008.162719] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Total parenteral nutrition (TPN) leads a loss of epithelial barrier function, decline in epithelial cell (EC) proliferation, and decreased expression of E-cadherin. As a large portion of intracellular beta-catenin is tightly associated with E-cadherin, we hypothesized that the loss of E-cadherin would result in a redistribution of intracellular beta-catenin, and could be a contributing mechanism for this TPN-associated loss of EC proliferation. An assessment of small bowel epithelium was performed in mice given either enteral nutrition (Control) or intravenous nutrition (TPN). TPN significantly down-regulated E-cadherin and beta-catenin expression, and resulted in a loss of a colocalization of these factors. TPN also up-regulated phosphorylated (p)-beta-catenin (Ser31/33,Thr41) and down-regulated (p)-beta-catenin(Ser552) expression. To further address mechanisms driving this, we observed a significant decrease in the abundance of p-AKT and p-GSK3beta expression, and an associated decline in tcf-4 transcription factors (cyclin D1, c-myc and Axin2), as well as a loss of EC proliferation by 7 days. To address whether the mechanism driving these changes was the absence of nutritional factors, glutamine was added to the TPN solution. This resulted in a partial restoration of beta-catenin expression and EC proliferation, suggesting that an alteration in nutrient delivery may affect many of these changes. Based on these findings, the loss of EC proliferation with TPN may well be due to a loss of total beta-catenin, as well as a concomitant change in the differential expression of beta-catenin phosphorylation sites, and a reduction in beta-catenin mediated tcf-4 transcription. This potential pathway may well explain many of the findings of mucosal atrophy associated with TPN.
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Affiliation(s)
- Yongjia Feng
- Section of Pediatric Surgery, University of Michigan, Mott Children's Hospital F3970, Ann Arbor, MI 48109-5245, USA
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35
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Fuchs E, Nowak JA. Building epithelial tissues from skin stem cells. COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY 2008; 73:333-50. [PMID: 19022769 DOI: 10.1101/sqb.2008.73.032] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The skin epidermis and its appendages provide a protective barrier that guards against loss of fluids, physical trauma, and invasion by harmful microbes. To perform these functions while confronting the harsh environs of the outside world, our body surface undergoes constant rejuvenation through homeostasis. In addition, it must be primed to repair wounds in response to injury. The adult skin maintains epidermal homeostasis, hair regeneration, and wound repair through the use of its stem cells. What are the properties of skin stem cells, when do they become established during embryogenesis, and how are they able to build tissues with such remarkably distinct architectures? How do stem cells maintain tissue homeostasis and repair wounds and how do they regulate the delicate balance between proliferation and differentiation? What is the relationship between skin cancer and mutations that perturbs the regulation of stem cells? In the past 5 years, the field of skin stem cells has bloomed as we and others have been able to purify and dissect the molecular properties of these tiny reservoirs of goliath potential. We report here progress on these fronts, with emphasis on our laboratory's contributions to the fascinating world of skin stem cells.
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Affiliation(s)
- E Fuchs
- Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, New York 10065, USA
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Waldow T, Witt W, Janke A, Ulmer A, Buzin A, Matschke K. Cell-cell junctions and vascular endothelial growth factor in rat lung as affected by ischemia/reperfusion and preconditioning with inhaled nitric oxide. J Surg Res 2008; 157:30-42. [PMID: 19500802 DOI: 10.1016/j.jss.2008.07.042] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2008] [Revised: 07/29/2008] [Accepted: 07/31/2008] [Indexed: 02/06/2023]
Abstract
BACKGROUND Previous investigations have shown that short term inhalation of nitric oxide (NO) before ischemia and reperfusion (I/R) prevents I/R-related consequences on lung function. Here we correlate effects of NO-induced preconditioning, especially on the lung permeability barrier, with analysis of cell junction proteins and the level of vascular endothelial growth factor (VEGF). METHODS A rat model of left lung in situ I/R was used. After left lateral thoracotomy, left lung ischemia was maintained for 60 min, followed by 30 min or 4 h (h) reperfusion (I/R groups). In the NO groups, inhalation of NO (10 min, 15 ppm) preceded I/R. Animals in control groups underwent sham surgery without NO inhalation and ischemia. The extent of I/R injury was assessed in terms of oxygenation (arterial PO(2)) and lung permeability (Evans blue extravasation). Expression of junctional proteins and phosphorylation was determined in complete protein extracts from lung tissue, whereas the adherens junction (AJ) core complex was analyzed in Triton extracts by co-immunoprecipitation using antibodies against E-cadherin and VE-cadherin. RESULTS The inhalation of NO prevented the I/R-induced increase of permeability at 30 min reperfusion, and the PO(2) increased from 27% of controls in the I/R group to 77% in the NO group. Left lung I/R correlated with a progressive loss of cadherins (VE-cadherin, E-cadherin, desmoglein 1) during reperfusion, whereas AJ catenins were largely preserved. Preconditioning with NO resulted in an increased ratio of catenins (alpha- and beta-catenin) to E-cadherin in immunoprecipitates and in reduced phosphorylation of beta-catenin. A reduction of VEGF in left lung lavage fluid was observed at 4 h but not at 30 min reperfusion. CONCLUSIONS The NO-induced changes of the AJ complex may have contributed to the stabilization of the lung permeability barrier during reperfusion.
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Affiliation(s)
- Thomas Waldow
- Clinic for Cardiac Surgery, University Hospital Dresden, Germany
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Finamore A, Massimi M, Conti Devirgiliis L, Mengheri E. Zinc deficiency induces membrane barrier damage and increases neutrophil transmigration in Caco-2 cells. J Nutr 2008; 138:1664-70. [PMID: 18716167 DOI: 10.1093/jn/138.9.1664] [Citation(s) in RCA: 136] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Zinc may contribute to the host defense by maintaining the membrane barrier. In this study, we questioned whether zinc deficiency affects the membrane function and junctional structure of intestinal epithelial cells, causing increased neutrophil migration. We used the Caco-2 cell line grown in control (C), zinc-deficient, or zinc-replete medium until differentiation. Zinc deprivation induced a decrease of transepithelial electrical resistance and alterations to tight and adherens junctions, with delocalization of zonula occludens (ZO-1), occludin, beta-catenin, and E-cadherin. Disorganization of F-actin and beta-tubulin was also found in zinc deficiency. These changes were associated with a loss of the amounts of ZO-1, occluding, and beta-tubulin. In addition, zinc deficiency caused a dephosphorylation of occludin and hyperphosphorylation of beta-catenin and ZO-1. Disruption of membrane barrier integrity led to increased migration of neutrophils. In addition, zinc deficiency induced an increase in the secretion of interleukin-8, epithelial neutrophil activating peptide-78, and growth-regulated oncogene-alpha, alterations that were not found when culture medium was replete with zinc. These results provide new information on the critical role played by dietary zinc in the maintenance of membrane barrier integrity and in controlling inflammatory cell infiltration.
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Affiliation(s)
- Alberto Finamore
- Istituto Nazionale di Ricerca per gli Alimenti e la Nutrizione, 00178 Rome, Italy and 4Dipartimento Biologia di Base ed Applicata, Università de L'Aquila, 67100 Italy
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Inge LJ, Rajasekaran SA, Wolle D, Barwe SP, Ryazantsev S, Ewing CM, Isaacs WB, Rajasekaran AK. alpha-Catenin overrides Src-dependent activation of beta-catenin oncogenic signaling. Mol Cancer Ther 2008; 7:1386-97. [PMID: 18566211 DOI: 10.1158/1535-7163.mct-07-2029] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Loss of alpha-catenin is one of the characteristics of prostate cancer. The catenins (alpha and beta) associated with E-cadherin play a critical role in the regulation of cell-cell adhesion. Tyrosine phosphorylation of beta-catenin dissociates it from E-cadherin and facilitates its entry into the nucleus, where beta-catenin acts as a transcriptional activator inducing genes involved in cell proliferation. Thus, beta-catenin regulates cell-cell adhesion and cell proliferation. Mechanisms controlling the balance between these functions of beta-catenin invariably are altered in cancer. Although a wealth of information is available about beta-catenin deregulation during oncogenesis, much less is known about how or whether alpha-catenin regulates beta-catenin functions. In this study, we show that alpha-catenin acts as a switch regulating the cell-cell adhesion and proliferation functions of beta-catenin. In alpha-catenin-null prostate cancer cells, reexpression of alpha-catenin increased cell-cell adhesion and decreased beta-catenin transcriptional activity, cyclin D1 levels, and cell proliferation. Further, Src-mediated tyrosine phosphorylation of beta-catenin is a major mechanism for decreased beta-catenin interaction with E-cadherin in alpha-catenin-null cells. alpha-Catenin attenuated the effect of Src phosphorylation by increasing beta-catenin association with E-cadherin. We also show that alpha-catenin increases the sensitivity of prostate cancer cells to a Src inhibitor in suppressing cell proliferation. This study reveals for the first time that alpha-catenin is a key regulator of beta-catenin transcriptional activity and that the status of alpha-catenin expression in tumor tissues might have prognostic value for Src targeted therapy.
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Affiliation(s)
- Landon J Inge
- Nemours Center for Childhood Cancer Research, Alfred I. DuPont Hospital for Children, 1701 Rockland Road, Wilmington, DE 19803, USA
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Mruk DD, Silvestrini B, Cheng CY. Anchoring junctions as drug targets: role in contraceptive development. Pharmacol Rev 2008; 60:146-80. [PMID: 18483144 PMCID: PMC3023124 DOI: 10.1124/pr.107.07105] [Citation(s) in RCA: 118] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
In multicellular organisms, cell-cell interactions are mediated in part by cell junctions, which underlie tissue architecture. Throughout spermatogenesis, for instance, preleptotene leptotene spermatocytes residing in the basal compartment of the seminiferous epithelium must traverse the blood-testis barrier to enter the adluminal compartment for continued development. At the same time, germ cells must also remain attached to Sertoli cells, and numerous studies have reported extensive restructuring at the Sertoli-Sertoli and Sertoli-germ cell interface during germ cell movement across the seminiferous epithelium. Furthermore, the proteins and signaling cascades that regulate adhesion between testicular cells have been largely delineated. These findings have unveiled a number of potential "druggable" targets that can be used to induce premature release of germ cells from the seminiferous epithelium, resulting in transient infertility. Herein, we discuss a novel approach with the aim of developing a nonhormonal male contraceptive for future human use, one that involves perturbing adhesion between Sertoli and germ cells in the testis.
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Affiliation(s)
- Dolores D Mruk
- Population Council, Center for Biomedical Research, The Mary M Wohlford Laboratory for Male Contraceptive Research, 1230 York Avenue, New York, NY 10065, USA.
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40
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Shtutman M, Chausovsky A, Prager-Khoutorsky M, Schiefermeier N, Boguslavsky S, Kam Z, Fuchs E, Geiger B, Borisy GG, Bershadsky AD. Signaling function of alpha-catenin in microtubule regulation. Cell Cycle 2008; 7:2377-83. [PMID: 18677116 DOI: 10.4161/cc.6362] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Centrosomes control microtubule dynamics in many cell types, and their removal from the cytoplasm leads to a shift from dynamic instability to treadmilling behavior and to a dramatic decrease of microtubule mass (Rodionov et al., 1999; PNAS 96:115). In cadherin-expressing cells, these effects can be reversed:non-centrosomal cytoplasts that form cadherin-mediated adherens junctions display dense arrays of microtubules (Chausovsky et al., 2000; Nature Cell Biol 2:797). In adherens junctions, cadherin's cytoplasmic domain binds p120 catenin and beta-catenin, which in turn binds alpha-catenin. To elucidate the roles of the cadherin-associated proteins in regulating microtubule dynamics, we prepared GFP-tagged, plasma membrane targeted or untargeted p120 catenin, alpha-catenin and beta-catenin and tested their ability to rescue the loss of microtubule mass caused by centrosomal removal in the poorly adhesive cell line CHO-K1. Only membrane targeting of alpha-catenin led to a significant increase in microtubule length and density in centrosome-free cytoplasts. Expression of non-membrane-targeted alpha-catenin produced only a slight effect, while both membrane-targeted and non-targeted p120 and beta-catenin were ineffective in this assay. Together, these findings suggest that alpha-catenin is able to regulate microtubule dynamics in a centrosome-independent manner.
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Affiliation(s)
- Michael Shtutman
- Cancer Center, Ordway Research Institute, Albany, New York, USA.
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Abstract
The skin epidermis and its appendages provide a protective barrier that is impermeable to harmful microbes and also prevents dehydration. To perform their functions while being confronted with the physicochemical traumas of the environment, these tissues undergo continual rejuvenation through homeostasis, and, in addition, they must be primed to undergo wound repair in response to injury. The skin's elixir for maintaining tissue homeostasis, regenerating hair, and repairing the epidermis after injury is its stem cells, which reside in the adult hair follicle, sebaceous gland, and epidermis. Stem cells have the remarkable capacity to both self-perpetuate and also give rise to the differentiating cells that constitute one or more tissues. In recent years, scientists have begun to uncover the properties of skin stem cells and unravel the mysteries underlying their remarkable capacity to perform these feats. In this paper, I outline the basic lineages of the skin epithelia and review some of the major findings about mammalian skin epithelial stem cells that have emerged in the past five years.
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Affiliation(s)
- Elaine Fuchs
- Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065, USA.
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Daugherty RL, Gottardi CJ. Phospho-regulation of Beta-catenin adhesion and signaling functions. Physiology (Bethesda) 2008; 22:303-9. [PMID: 17928543 DOI: 10.1152/physiol.00020.2007] [Citation(s) in RCA: 186] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Beta-catenin plays a critical structural role in cadherin-based adhesions and is also an essential co-activator of Wnt-mediated gene expression. The degree to which beta-catenin participates in these two functions is dictated by the availability of beta-catenin binding partners, and an emerging theme is that these binding interactions are regulated by phosphorylation. Inputs from various cell-signaling events can therefore impact beta-catenin function, which may be necessary for the finely tuned adhesive and signaling responses required for tissue morphogenesis.
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Affiliation(s)
- Rebecca Leadem Daugherty
- The Integrated Graduate Program in the Life Sciences, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
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Niessen CM, Gottardi CJ. Molecular components of the adherens junction. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2008; 1778:562-71. [PMID: 18206110 DOI: 10.1016/j.bbamem.2007.12.015] [Citation(s) in RCA: 186] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2007] [Revised: 12/13/2007] [Accepted: 12/17/2007] [Indexed: 12/24/2022]
Abstract
Adherens junctions serve to couple individual cells into various arrangements required for tissue structure and function. The central structural components of adherens junctions are transmembrane adhesion receptors, and their associated actin-binding/regulatory proteins. The molecular machineries that organize these adhesion receptor complexes into higher order junction structures, and the functional consequences of this junctional organization will be discussed.
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Affiliation(s)
- Carien M Niessen
- Center for Molecular Medicine, University of Cologne, LFI, 05, Room 59, Joseph Stelzmannstrasse 9, D-50931 Cologne, Germany.
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Abstract
Adherens and tight junctions are intercellular junctions crucial for epithelial adhesion and barrier function in a wide variety of tissues and organisms. In stratifying epithelia, such as the epidermis, the role of adherens and tight junctions was considered less important owing to the abundance of desmosomes, mediating firm mechanical stability between the cells, and to the barrier function of the stratum corneum, respectively. This view has changed in recent years because of different studies that showed the importance of these structures for proper skin physiology and barrier function. The current review provides an overview of the crucial molecular constituents of these structures and highlights some recent results on their regulation. In particular, I will discuss their importance in skin biology.
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Affiliation(s)
- Carien M Niessen
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
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Weydig C, Starzinski-Powitz A, Carra G, Löwer J, Wessler S. CagA-independent disruption of adherence junction complexes involves E-cadherin shedding and implies multiple steps in Helicobacter pylori pathogenicity. Exp Cell Res 2007; 313:3459-71. [PMID: 17692843 DOI: 10.1016/j.yexcr.2007.07.015] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2007] [Revised: 07/13/2007] [Accepted: 07/13/2007] [Indexed: 12/17/2022]
Abstract
Infection with Helicobacter pylori (H. pylori) leads to depolarization and migration of polarized epithelial cells, both strongly enhanced by injection of the pathogenic factor CagA (cytotoxin-associated gene A) into the host cytoplasm. Depolarization and migration of epithelial cells imply the disruption of cell adhesion junctions (AJs) comprising a protein complex of E-cadherin, beta-catenin, p120(ctn), and alpha-catenin. Here, we analyzed the disintegration of E-cadherin-mediated AJs and demonstrated that loss of E-cadherin-dependent cell-cell contacts is entirely independent of CagA. Upon infection with H. pylori, either wild-type (wt) or a cagA mutant (DeltacagA), interaction between E-cadherin and alpha-catenin dissociated rapidly, while binding of E-cadherin to beta-catenin and p120(ctn) was hardly affected. Simultaneously, loss of cell adhesion involved E-cadherin cleavage induced by a bacterial factor secreted by H. pylori. Finally, beta-catenin-mediated transcription, a hallmark of many carcinomas, was not activated in H. pylori-infected epithelial cells at this stage of infection. Altogether, our data indicate that H. pylori-induced pathogenesis is a multi-step process initiated by CagA-independent mechanisms. These include proteolytical cleavage of E-cadherin and dissociation of the E-cadherin/beta-catenin/p120(ctn) complex from the actin cytoskeleton by disrupting binding to alpha-catenin.
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Affiliation(s)
- Christiane Weydig
- Junior Research Group, Paul-Ehrlich Institute, Paul-Ehrlich Str 51-59, D-63225, Langen, Germany
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Wanner SJ, Miller JR. Regulation of otic vesicle and hair cell stereocilia morphogenesis by Ena/VASP-like (Evl) in Xenopus. J Cell Sci 2007; 120:2641-51. [PMID: 17635997 DOI: 10.1242/jcs.004556] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
The inner ear is derived from a thickening in the embryonic ectoderm, called the otic placode. This structure undergoes extensive morphogenetic movements throughout its development and gives rise to all components of the inner ear. Ena/VASP-like (Evl) is an actin binding protein involved in the regulation of cytoskeletal dynamics and organization. We have examined the role of Evl during the morphogenesis of the Xenopus inner ear. Evl (hereafter referred to as Xevl) is expressed throughout otic vesicle formation and is enriched in the neuroblasts that delaminate to form the vestibulocochlear ganglion and in hair cells that possess mechanosensory stereocilia. Knockdown of Xevl perturbs epithelial morphology and intercellular adhesion in the otic vesicle and disrupts formation of the vestibulocochlear ganglion, evidenced by reduction of ganglion size, disorganization of the ganglion, and defects in neurite outgrowth. Later in embryogenesis, Xevl is required for development of mechanosensory hair cells. In Xevl knockdown embryos, hair cells of the ventromedial sensory epithelium display multiple abnormalities including disruption of the cuticular plate at the base of stereocilia and disorganization of the normal staircase appearance of stereocilia. Based on these data, we propose that Xevl plays an integral role in regulating morphogenesis of the inner ear epithelium and the subsequent development of the vestibulocochlear ganglion and mechanosensory hair cells.
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Affiliation(s)
- Sarah J Wanner
- Department of Genetics, Cell Biology and Development and Developmental Biology Center, University of Minnesota, Minneapolis, MN 55455, USA
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Cohen D, Tian Y, Müsch A. Par1b promotes hepatic-type lumen polarity in Madin Darby canine kidney cells via myosin II- and E-cadherin-dependent signaling. Mol Biol Cell 2007; 18:2203-15. [PMID: 17409351 PMCID: PMC1877095 DOI: 10.1091/mbc.e07-02-0095] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Kidney-derived Madin Darby canine kidney (MDCK) cells form lumina at their apices, and target luminal proteins to an intracellular vacuolar apical compartment (VAC) when prevented from polarizing. Hepatocytes, by contrast, organize their luminal surfaces (the bile canaliculi; BC) between their lateral membranes, and, when nonpolarized, they display an intracellular luminal compartment that is distinct from the VACs of MDCK cells. Overexpression of the serine/threonine kinase Par1b/EMK1/MARK2 induces BC-like lateral lumina and a hepatic-type intracellular luminal compartment in MDCK cells, suggesting a role for Par1b in the branching decision between kidney- and hepatic-type epithelial phenotypes. Here, we report that Par1b promotes lateral lumen polarity in MDCK cells independently of Ca(2+)-mediated cell-cell adhesion by inhibiting myosin II in a rho kinase-dependent manner. Polarization was inhibited by E-cadherin depletion but promoted by an adhesion-defective E-cadherin mutant. By contrast, apical surface formation in control MDCK cells required Ca(2+)-dependent cell-cell adhesion, but it occurred in the absence of E-cadherin. We propose that E-cadherin, when in an adhesion-incompetent state at the lateral domain, serves as targeting patch for the establishment of lateral luminal surfaces. E-cadherin depletion also reverted the hepatic-type intracellular luminal compartment in Par1b-MDCK cells to VACs characteristic of control MDCK cells, indicating a novel link between E-cadherin and luminal protein targeting.
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Affiliation(s)
- David Cohen
- *The Margaret Dyson Institute of Vision Research and
| | - Yuan Tian
- Graduate Program in Physiology, Biophysics, and Systems Biology, Weill Medical College of Cornell University, New York, NY 10021
| | - Anne Müsch
- *The Margaret Dyson Institute of Vision Research and
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