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

Qiuping Zhang, Rose-Marie Minaisah, Elisa Ferraro, Chen Li, Lauren J. Porter, Can Zhou, Fang Gao, Junyi Zhang, Dipen Rajgor, Flavia Autore, Catherine M. Shanahan, Derek T. Warren

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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.

Original languageEnglish
Pages (from-to)168-179
Number of pages12
JournalExperimental Cell Research
Volume345
Issue number2
Early online date16 Jun 2016
DOIs
Publication statusPublished - 15 Jul 2016

Keywords

  • Cell-cell junctions
  • Nesprin-2
  • Scaffold protein
  • Β-catenin

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