title: A ternary complex comprising FAK, PTPα and IP3 receptor 1 functionally engages focal adhesions and the endoplasmic reticulum to mediate IL-1-induced Ca2+ signalling in fibroblasts.
abstract: Ca(2+) release is tightly sequestered in eukaryotic cells to enable fine spatio-temporal control of signalling but how Ca(2+) release from the endoplasmic reticulum (ER) is linked to cell adhesions is not defined. We examined the spatial restriction of Ca(2+) release through the inositol 1,4,5-triphosphate receptor 1 (IP3R1) in response to interleukin-1 (IL-1) and the functions of the adhesion-associated proteins, focal adhesion kinase (FAK) and protein tyrosine phosphatase-α (PTPα). In cultured fibroblasts IL-1 treatment promoted co-localization of PTPα and FAK with the ER and increased association of IP3R1 with PTPα and FAK at focal adhesions (FAs). GST pull-down assays of purified proteins demonstrated that PTPα and FAK directly interacted with IP3R1. These interactions depended on the focal adhesion-targeting (FAT) and band4.1-ezrin-radixin-moesin (FERM) domains of FAK. PTPα was required for the association of IP3R1 with Src, which mediated IP3R1 phosphorylation and consequently ER Ca(2+) release. Collectively, these data indicate that PTPα and FAK, which are enriched in FAs, interact with IP3R1 at adjacent ER sites to spatially sequester IL-1-induced Ca(2+) signalling.
authors.affiliation: Matrix Dynamics Group, University of Toronto, Ontario, Canada, M5S 3E2.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Matrix Dynamics Group, University of Toronto, Ontario, Canada, M5S 3E2.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Departments of Medicine and Pediatrics, Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, CO 80206, U.S.A. Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, CO 80045, U.S.A.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Downey
authors.affiliation: Department of Cell and Systems Biology, Faculty of Arts and Science, University of Toronto, Toronto, Ontario, Canada, M5S 3G5.
authors.forename: Sergey
authors.initials: S
authors.lastname: Plotnikov
authors.affiliation: Matrix Dynamics Group, University of Toronto, Ontario, Canada, M5S 3E2 christopher.mcculloch@utoronto.ca.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: McCulloch
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects*; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D022001:Focal Adhesions; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4 / Q000378:metabolism*
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D007375:Interleukin-1; C025389:Itpr1 protein, mouse; D051416:Focal Adhesion Protein-Tyrosine Kinases; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4
keywords: Src-family kinases; calcium signalling; cell adhesion; endoplasmic reticulum; fibroblast; inositol triphosphate receptor