title: Epithelial-mesenchymal transition, IP3 receptors and ER-PM junctions: translocation of Ca2+ signalling complexes and regulation of migration.
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 observed a dramatic redistribution of inositol trisphosphate receptors (IP3Rs) and stromal interaction molecule 1 (STIM1)-competent endoplasmic reticulum-plasma membrane junctions (ER-PM junctions) when pancreatic ductal adenocarcinoma (PDAC) cells disconnect from their neighbours and undergo individual migration. In cellular monolayers IP3Rs are juxtaposed with tight junctions. When individual cells migrate away from their neighbours IP3Rs preferentially accumulate at the leading edge where they surround focal adhesions. Uncaging of inositol trisphosphate (IP3) resulted in prominent accumulation of paxillin in focal adhesions, 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 Ca(2+) signalling complexes in this region. Importantly, migration of PDAC cells was strongly suppressed by selective inhibition of IP3Rs and store-operated Ca(2+) entry (SOCE), indicating that these mechanisms are functionally required for migration.
authors.affiliation: Department of Cellular and Molecular Physiology, University of Liverpool, Crown Street, Liverpool L69 3BX, U.K.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Okeke
authors.affiliation: Department of Cellular and Molecular Physiology, University of Liverpool, Crown Street, Liverpool L69 3BX, U.K.
authors.forename: Tony
authors.initials: T
authors.lastname: Parker
authors.affiliation: Department of Cellular and Molecular Physiology, University of Liverpool, Crown Street, Liverpool L69 3BX, U.K.
authors.forename: Hayley
authors.initials: H
authors.lastname: Dingsdale
authors.affiliation: Department of Cellular and Molecular Physiology, University of Liverpool, Crown Street, Liverpool L69 3BX, U.K.
authors.forename: Matthew
authors.initials: M
authors.lastname: Concannon
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Crown Street, Liverpool L69 3BX, U.K.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Awais
authors.affiliation: Department of Cellular and Molecular Physiology, University of Liverpool, Crown Street, Liverpool L69 3BX, U.K.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Voronina
authors.affiliation: CEA, Institut de Biologie et Technologies de Saclay (iBiTec-S), Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), bâtiment 152, 91191 Gif-sur-Yvette Cedex, France Institut des Neurosciences Paris-Saclay, UMR 9197, CNRS/Université Paris-Sud, CNRS, 91190-Gif sur Yvette Cedex, France.
authors.forename: Jordi
authors.initials: J
authors.lastname: Molgó
authors.affiliation: Respiratory Therapy Area Unit, Medicines Research Centre, GlaxoSmithKline, Stevenage SG1 2NY, England, U.K.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Begg
authors.affiliation: Biotechnology Group, National Physical Laboratory, Hampton Road, Teddington TW11 0LW, U.K.
authors.forename: Daniel
authors.initials: D
authors.lastname: Metcalf
authors.affiliation: Biotechnology Group, National Physical Laboratory, Hampton Road, Teddington TW11 0LW, U.K.
authors.forename: Alex E
authors.initials: AE
authors.lastname: Knight
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Crown Street, Liverpool L69 3BX, U.K.
authors.forename: Robert
authors.initials: R
authors.lastname: Sutton
authors.affiliation: Department of Cellular and Molecular Physiology, University of Liverpool, Crown Street, Liverpool L69 3BX, U.K.
authors.forename: Lee
authors.initials: L
authors.lastname: Haynes
authors.affiliation: Department of Cellular and Molecular Physiology, University of Liverpool, Crown Street, Liverpool L69 3BX, U.K. a.tepikin@liv.ac.uk.
authors.forename: Alexei V
authors.initials: AV
authors.lastname: Tepikin
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D055785:Gene Knockdown Techniques; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D021381:Protein Transport; D000071737:Stromal Interaction Molecule 1
chemical_list: D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1
keywords: ER–PM junctions; IP3 receptors; PANC-1 cells; epithelial–mesenchymal transition; focal adhesions; pancreatic ductal adenocarcinoma