T-cadherin attenuates the PERK branch of the unfolded protein response and protects vascular endothelial cells from endoplasmic reticulum stress-induced apoptosis

Emmanouil Kyriakakis, Maria Philippova, Manjunath B. Joshi, Dennis Pfaff, Valery Bochkov, Taras Afonyushkin, Paul Erne, Therese J. Resink

    Research output: Contribution to journalArticle

    25 Citations (Scopus)

    Abstract

    Endoplasmic reticulum (ER) stress activated by perturbations in ER homeostasis induces the unfolded protein response (UPR) with chaperon Grp78 as the key activator of UPR signalling. The aim of UPR is to restore normal ER function; however prolonged or severe ER stress triggers apoptosis of damaged cells to ensure protection of the whole organism. Recent findings support an association of ER stress-induced apoptosis of vascular cells with cardiovascular pathologies. T-cadherin (T-cad), an atypical glycosylphosphatidylinositol-anchored member of the cadherin superfamily is upregulated in atherosclerotic lesions. Here we investigate the ability of T-cad to influence UPR signalling and endothelial cell (EC) survival during ER stress. EC were treated with a variety of ER stress-inducing compounds (thapsigargin, dithiothereitol, brefeldin A, tunicamycin, A23187 or homocysteine) and induction of ER stress validated by increases in levels of UPR signalling molecules Grp78 (glucose-regulated protein of 78. kDa), phospho-eIF2α (phosphorylated eukaryotic initiation factor 2 α) and CHOP (C/EBP homologous protein). All compounds also increased T-cad mRNA and protein levels. Overexpression or silencing of T-cad in EC respectively attenuated or amplified the ER stress-induced increase in phospho-eIF2α, Grp78, CHOP and active caspases. Effects of T-cad-overexpression or T-cad-silencing on ER stress responses in EC were not affected by inclusion of either N-acetylcysteine (reactive oxygen species scavenger), LY294002 (phosphatidylinositol-3-kinase inhibitor) or SP6000125 (Jun N-terminal kinase inhibitor). The data suggest that upregulation of T-cad on EC during ER stress attenuates the activation of the proapoptotic PERK (PKR (double-stranded RNA-activated protein kinase)-like ER kinase) branch of the UPR cascade and thereby protects EC from ER stress-induced apoptosis.

    Original languageEnglish
    Pages (from-to)1308-1316
    Number of pages9
    JournalCellular Signalling
    Volume22
    Issue number9
    DOIs
    Publication statusPublished - 09-2010

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    Unfolded Protein Response
    Endoplasmic Reticulum Stress
    Endothelial Cells
    Apoptosis
    Transcription Factor CHOP
    Endoplasmic Reticulum
    Phosphotransferases
    Eukaryotic Initiation Factor-2
    H-cadherin
    Phosphatidylinositol 3-Kinase
    eIF-2 Kinase
    Brefeldin A
    Tunicamycin
    Glycosylphosphatidylinositols
    2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
    Thapsigargin
    Double-Stranded RNA
    Calcimycin
    Acetylcysteine
    Homocysteine

    All Science Journal Classification (ASJC) codes

    • Cell Biology

    Cite this

    Kyriakakis, Emmanouil ; Philippova, Maria ; Joshi, Manjunath B. ; Pfaff, Dennis ; Bochkov, Valery ; Afonyushkin, Taras ; Erne, Paul ; Resink, Therese J. / T-cadherin attenuates the PERK branch of the unfolded protein response and protects vascular endothelial cells from endoplasmic reticulum stress-induced apoptosis. In: Cellular Signalling. 2010 ; Vol. 22, No. 9. pp. 1308-1316.
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    T-cadherin attenuates the PERK branch of the unfolded protein response and protects vascular endothelial cells from endoplasmic reticulum stress-induced apoptosis. / Kyriakakis, Emmanouil; Philippova, Maria; Joshi, Manjunath B.; Pfaff, Dennis; Bochkov, Valery; Afonyushkin, Taras; Erne, Paul; Resink, Therese J.

    In: Cellular Signalling, Vol. 22, No. 9, 09.2010, p. 1308-1316.

    Research output: Contribution to journalArticle

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    AU - Kyriakakis, Emmanouil

    AU - Philippova, Maria

    AU - Joshi, Manjunath B.

    AU - Pfaff, Dennis

    AU - Bochkov, Valery

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    AU - Erne, Paul

    AU - Resink, Therese J.

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