Okeke, E*; Parker, T*; Dingsdale, H*; Concannon, M*; Awais, M*; Voronina, S*; Molgo, J*; Begg, M*; Metcalf, D; Knight, A E; Sutton, R*; Haynes, L*; Tapikin, A V* (2016) Epithelial-mesenchymal transition, IP3 receptors and ER-PM junctions: translocation of Ca2+ signalling complexes and regulation of migration. Biochem. J., 473. pp. 757-767.

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Abstract

Disconnection of a cell from its epithelial neighbours and the formation of a mesenchymal phenotype are associated with profound changes in the distribution of cellular components and the formation of new cellular polarity. We investigated the redistribution of proteins involved in Ca2+ signalling ¿ inositol trisphosphate receptors (IP3Rs) and stromal interaction molecule 1 (STIM1) ¿ during this transition. IP3Rs are Ca2+ -releasing channels in the endoplasmic reticulum (ER). Restoring the ER Ca2+ concentration ([Ca2+]ER) after release involves store operated Ca2+ entry (SOCE) mediated by STIM1, which activates specific plasma membrane (PM) ion channels to permit influx of Ca2+; the process of activation takes place at unique ER-PM junctions.
We observed a dramatic redistribution of IP3Rs and ER-PM junctions when pancreatic ductal adenocarcinoma (PDAC) cells disconnect from their neighbours and undergo individual migration. In cellular monolayers IP3Rs are juxtaposed to cell-cell contacts and closely co-positioned with markers of tight junctions. When individual cells migrate away from their neighbours IP3Rs preferentially accumulate at the leading edge where they surround focal adhesions. Uncaging of IP3 resulted in prominent rearrangement of focal adhesion, highlighting important functional implications of the observed novel structural relationships. ER-PM junctions and STIM1 proteins also migrate to the leading edge and position closely behind the IP3Rs, creating a stratified distribution of Ca2+ signalling complexes in this region. Importantly, migration of PANC-1 cells was strongly suppressed by selective inhibition of IP3Rs and SOCE, indicating that these mechanisms are functionally required for migration.

Item Type:	Article
Keywords:	pancreatic cancer, super-resolution microscopy, dSTORM, ER-PM junctions
Subjects:	Biotechnology Biotechnology > Bio-Diagnostics
Identification number/DOI:	10.1042/BJ20150364
Last Modified:	02 Feb 2018 13:13
URI:	https://eprintspublications.npl.co.uk/id/eprint/7100