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

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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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