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The role of the endoplasmic reticulum protein calreticulin in mediating TGF-β-stimulated extracellular matrix production in fibrotic disease

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Journal of Cell Communication and Signaling Aims and scope

Abstract

Endoplasmic reticulum (ER) stress is a key factor contributing to fibrotic disease. Although ER stress is a short-term adaptive response, with chronic stimulation, it can activate pathways leading to fibrosis. ER stress can induce TGF-β signaling, a central driver of extracellular matrix production in fibrosis. This review will discuss the role of an ER protein, calreticulin (CRT), which has both chaperone and calcium regulatory functions, in fibrosis. CRT expression is upregulated in multiple different fibrotic diseases. The roles of CRT in regulation of fibronectin extracellular matrix assembly, extracellular matrix transcription, and collagen secretion and processing into the extracellular matrix will be discussed. Evidence for the importance of CRT in ER calcium release and NFAT activation downstream of TGF-β signaling will be presented. Finally, we will summarize evidence from animal models in which CRT expression is genetically reduced or experimentally downregulated in targeted tissues of adult animals and discuss how these models define a key role for CRT in fibrotic diseases.

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Abbreviations

ATF4:

Activating transcription factor 4

ATF6:

Activating transcription factor 6

CHOP:

C/EBP homologous protein

CRT:

Calreticulin

ECM:

Extracellular matrix

EMT:

Epithelial to mesenchymal transition

ER:

Endoplasmic reticulum

ERp57:

Endoplasmic reticulum protein of 57 kDa

GADD34:

Growth arrest and DNA damage-inducible 34

GRP78:

Glucose regulated protein 78 kD

HSP47:

Heat shock protein 47 kD

IRE1:

Inositol-requiring protein 1

JNK:

c-jun N-terminal kinase

LRP1:

Low-density lipoprotein receptor-related protein 1

MAPK:

Mitogen-activated protein kinase

MDCK:

Madin-Darby canine kidney

MEFs:

Mouse embryonic fibroblasts

MEKK1:

Mitogen-activated protein kinase kinase kinase 1

NFAT:

Nuclear factor of activated T cells

ORP150:

150-kDa oxygen-regulated protein

4-PBA:

4-phenylbutyrate

PERK:

Protein kinase RNA (PKR)-like ER kinase

PI3K:

Phosphoinositide-3 kinase

Smad 2/3:

Mothers against decapentaplegic homologs 2/3

TGF-β:

Transforming growth factor beta

TSP-1:

Thrombospondin 1

TUDCA:

Tauroursodeoxycholic acid

UPR:

Unfolded protein response

UUO:

Unilateral ureteric obstruction

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Acknowledgements

Original research presented in this review was supported by grants from the American Heart Association (12IRG9160008) and from the Department of Defense (W81XWH-14-1-0203) to JEMU and by NIH T32 HL007918 and T32 AI007051 to KAZ.

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Authors and Affiliations

  1. Department of Pathology, University of Alabama at Birmingham, G001A Volker Hall, Birmingham, AL, 35294, USA

    Benjamin Y. Owusu & Joanne E. Murphy-Ullrich

  2. Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Kurt A. Zimmerman & Joanne E. Murphy-Ullrich

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  1. Benjamin Y. Owusu
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  2. Kurt A. Zimmerman
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  3. Joanne E. Murphy-Ullrich
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Correspondence to Joanne E. Murphy-Ullrich.

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Owusu, B.Y., Zimmerman, K.A. & Murphy-Ullrich, J.E. The role of the endoplasmic reticulum protein calreticulin in mediating TGF-β-stimulated extracellular matrix production in fibrotic disease. J. Cell Commun. Signal. 12, 289–299 (2018). https://doi.org/10.1007/s12079-017-0426-2

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  • DOI: https://doi.org/10.1007/s12079-017-0426-2

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