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Title: N-terminal nesprin-2 variants regulate β-catenin signalling

Abstract

The spatial compartmentalisation of biochemical signalling pathways is essential for cell function. Nesprins are a multi-isomeric family of proteins that have emerged as signalling scaffolds, herein, we investigate the localisation and function of novel nesprin-2 N-terminal variants. We show that these nesprin-2 variants display cell specific distribution and reside in both the cytoplasm and nucleus. Immunofluorescence microscopy revealed that nesprin-2 N-terminal variants colocalised with β-catenin at cell-cell junctions in U2OS cells. Calcium switch assays demonstrated that nesprin-2 and β-catenin are lost from cell-cell junctions in low calcium conditions whereas emerin localisation at the NE remained unaltered, furthermore, an N-terminal fragment of nesprin-2 was sufficient for cell-cell junction localisation and interacted with β-catenin. Disruption of these N-terminal nesprin-2 variants, using siRNA depletion resulted in loss of β-catenin from cell-cell junctions, nuclear accumulation of active β-catenin and augmented β-catenin transcriptional activity. Importantly, we show that U2OS cells lack nesprin-2 giant, suggesting that the N-terminal nesprin-2 variants regulate β-catenin signalling independently of the NE. Together, these data identify N-terminal nesprin-2 variants as novel regulators of β-catenin signalling that tether β-catenin to cell-cell contacts to inhibit β-catenin transcriptional activity. - Highlights: • N-terminal nesprin-2 variants display cell specific expression patterns. • N-terminal spectrin repeatsmore » of nesprin-2 interact with β-catenin. • N-terminal nesprin-2 variants scaffold β-catenin at cell-cell junctions.. • Nesprin-2 variants play multiple roles in β-catenin signalling.« less

Authors:
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Publication Date:
OSTI Identifier:
22648595
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 345; Journal Issue: 2; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACTIN; CALCIUM; CELL NUCLEI; CELL PROLIFERATION; CONNECTORS; CYTOPLASM; FIBROBLASTS; MEMBRANES; MICROSCOPY; MICROTUBULES; MUSCLES; STEM CELLS; SWITCHES; VEINS

Citation Formats

Zhang, Qiuping, Minaisah, Rose-Marie, Ferraro, Elisa, Li, Chen, Porter, Lauren J., Zhou, Can, Gao, Fang, Zhang, Junyi, Rajgor, Dipen, Autore, Flavia, Shanahan, Catherine M., and Warren, Derek T., E-mail: derek.warren@kcl.ac.uk. N-terminal nesprin-2 variants regulate β-catenin signalling. United States: N. p., 2016. Web. doi:10.1016/J.YEXCR.2016.06.008.
Zhang, Qiuping, Minaisah, Rose-Marie, Ferraro, Elisa, Li, Chen, Porter, Lauren J., Zhou, Can, Gao, Fang, Zhang, Junyi, Rajgor, Dipen, Autore, Flavia, Shanahan, Catherine M., & Warren, Derek T., E-mail: derek.warren@kcl.ac.uk. N-terminal nesprin-2 variants regulate β-catenin signalling. United States. doi:10.1016/J.YEXCR.2016.06.008.
Zhang, Qiuping, Minaisah, Rose-Marie, Ferraro, Elisa, Li, Chen, Porter, Lauren J., Zhou, Can, Gao, Fang, Zhang, Junyi, Rajgor, Dipen, Autore, Flavia, Shanahan, Catherine M., and Warren, Derek T., E-mail: derek.warren@kcl.ac.uk. Fri . "N-terminal nesprin-2 variants regulate β-catenin signalling". United States. doi:10.1016/J.YEXCR.2016.06.008.
@article{osti_22648595,
title = {N-terminal nesprin-2 variants regulate β-catenin signalling},
author = {Zhang, Qiuping and Minaisah, Rose-Marie and Ferraro, Elisa and Li, Chen and Porter, Lauren J. and Zhou, Can and Gao, Fang and Zhang, Junyi and Rajgor, Dipen and Autore, Flavia and Shanahan, Catherine M. and Warren, Derek T., E-mail: derek.warren@kcl.ac.uk},
abstractNote = {The spatial compartmentalisation of biochemical signalling pathways is essential for cell function. Nesprins are a multi-isomeric family of proteins that have emerged as signalling scaffolds, herein, we investigate the localisation and function of novel nesprin-2 N-terminal variants. We show that these nesprin-2 variants display cell specific distribution and reside in both the cytoplasm and nucleus. Immunofluorescence microscopy revealed that nesprin-2 N-terminal variants colocalised with β-catenin at cell-cell junctions in U2OS cells. Calcium switch assays demonstrated that nesprin-2 and β-catenin are lost from cell-cell junctions in low calcium conditions whereas emerin localisation at the NE remained unaltered, furthermore, an N-terminal fragment of nesprin-2 was sufficient for cell-cell junction localisation and interacted with β-catenin. Disruption of these N-terminal nesprin-2 variants, using siRNA depletion resulted in loss of β-catenin from cell-cell junctions, nuclear accumulation of active β-catenin and augmented β-catenin transcriptional activity. Importantly, we show that U2OS cells lack nesprin-2 giant, suggesting that the N-terminal nesprin-2 variants regulate β-catenin signalling independently of the NE. Together, these data identify N-terminal nesprin-2 variants as novel regulators of β-catenin signalling that tether β-catenin to cell-cell contacts to inhibit β-catenin transcriptional activity. - Highlights: • N-terminal nesprin-2 variants display cell specific expression patterns. • N-terminal spectrin repeats of nesprin-2 interact with β-catenin. • N-terminal nesprin-2 variants scaffold β-catenin at cell-cell junctions.. • Nesprin-2 variants play multiple roles in β-catenin signalling.},
doi = {10.1016/J.YEXCR.2016.06.008},
journal = {Experimental Cell Research},
number = 2,
volume = 345,
place = {United States},
year = {Fri Jul 15 00:00:00 EDT 2016},
month = {Fri Jul 15 00:00:00 EDT 2016}
}