Malfolded protein formation and perturbance of calcium homoeostasis results in the induction of the endoplasmic reticulum (ER) chaperone protein, namely the 78kDa glucose-regulated protein (GRP78)/immunoglobulin heavy-chain binding protein. Various ER stress inducers can activate grp78, but signal transduction mechanisms are not well understood. We report in the present study that the induction of endogenous grp78 mRNA by the amino acid analogue azetidine (AzC) requires the integrity of a signal transduction pathway mediated by p38 mitogen-activated protein kinase (p38 MAPK). In contrast, induction of grp78 by thapsigargin that depletes the ER calcium storage can occur even when the p38 MAPK pathway is blocked. Treatment of cells with AzC results in the sustained activation of p38 MAPK. We identified an ER transmembrane activating transcription factor 6 (ATF6) as a target of p38 MAPK phosphorylation in AzC-treated cells. ATF6 undergoes proteolytic cleavage on AzC treatment, releasing a nuclear form that is an activator of the grp78 promoter. We show here that constitutively active mitogen-activated protein kinase kinase 6, a selective p38 MAPK activator, enhances the ability of the nuclear form of ATF6 to transactivate the grp78 promoter. Our results provide direct evidence that different ER stress inducers use diverse pathways to activate grp78 and that in addition to activation by proteolytic cleavage, ATF6 undergoes specific ER stress-induced phosphorylation. We propose that phosphorylation of ATF6 is a novel mechanism for augmenting its potential as a transcription activator.
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September 2002
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Research Article|
September 15 2002
Requirement of the p38 mitogen-activated protein kinase signalling pathway for the induction of the 78 kDa glucose-regulated protein/immunoglobulin heavy-chain binding protein by azetidine stress: activating transcription factor 6 as a target for stress-induced phosphorylation
Shengzhan LUO;
Shengzhan LUO
Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, University of Southern California, Los Angeles, CA 90089-9176, U.S.A.
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Amy S. LEE
Amy S. LEE
1
Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, University of Southern California, Los Angeles, CA 90089-9176, U.S.A.
1To whom correspondence should be addressed (e-mail [email protected]).
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Publisher: Portland Press Ltd
Received:
December 07 2001
Revision Received:
May 31 2002
Accepted:
June 20 2002
Accepted Manuscript online:
June 20 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 366 (3): 787–795.
Article history
Received:
December 07 2001
Revision Received:
May 31 2002
Accepted:
June 20 2002
Accepted Manuscript online:
June 20 2002
Citation
Shengzhan LUO, Amy S. LEE; Requirement of the p38 mitogen-activated protein kinase signalling pathway for the induction of the 78 kDa glucose-regulated protein/immunoglobulin heavy-chain binding protein by azetidine stress: activating transcription factor 6 as a target for stress-induced phosphorylation. Biochem J 15 September 2002; 366 (3): 787–795. doi: https://doi.org/10.1042/bj20011802
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