Calreticulin regulates TGF-β1-induced epithelial mesenchymal transition through modulating Smad signaling and calcium signaling

Wu, Yanjiao; Xu, Xiaoli; Ma, Lunkun; Qian, Yi; Sun, Weichao; Tang, Liling

doi:10.1016/j.biocel.2017.07.023

Cited by 28 publications

(27 citation statements)

References 30 publications

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“…Recent evidence from our group suggests a link between TRPV4 activation and TGFβ1 signals that mediate fibroblast differentiation . Previous reports have documented that calcium signalling is involved in EMT in many cell types . However, the identity of a plasma membrane calcium channel and the mechanism by which calcium signals are transduced/propagated in cells to drive EMT, are not well understood.…”

Section: Resultsmentioning

confidence: 97%

“…[24][25][26][27][28]74,75 Calcium signalling and the expression of specific Ca 2+ -permeable ion channels are involved in induction of proteins associated with EMT. [24][25][26][27][28] The identification of the role of specific Ca 2+ -permeable ion channels in the induction of EMT in the context of fibrosis and oncogenesis suggests that these channels may be appropriate therapeutic targets for control of EMT-mediated disease progression. Our recently published reports suggested that TRPV4-dependent Ca 2+ influx potentiates TGFβ1induced lung and dermal myofibroblast differentiation in response to matrix stiffness, and showed that TRPV4 KO mice were protected from bleomycin-induced fibrosis in skin and lungs.…”

Section: Discussionmentioning

confidence: 99%

“…[29][30][31] Previous reports have documented that calcium signalling is involved in EMT in many cell types. [24][25][26][27][28] However, the identity of a plasma membrane calcium channel and the mechanism by which calcium signals are transduced/propagated in cells to drive EMT, are not well understood. To test our hypothesis that TRPV4 activation might regulate EMT, NMEKs from WT and TRPV4 KO mice were treated with TGFβ1, and compared for acquisition of EMT-like phenotypic properties or EMT-related biochemical changes.…”

Section: Trpv4 Mediates Tgfβ1-induced Emt-like Changes In Normal Momentioning

confidence: 99%

“…Zarkoob et al have demonstrated specific effect of matrix stiffness on keratinocyte colony formation. Furthermore, it has been reported that calcium signalling and expression of specific Ca 2+ ‐permeable ion channels are involved in induction of EMT . However, role of matrix stiffness and/or calcium signalling‐induced EMT in skin keratinocytes has not been reported.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, it has been reported that calcium signalling and expression of specific Ca 2+ -permeable ion channels are involved in induction of EMT. [24][25][26][27][28] However, role of matrix stiffness and/or calcium signalling-induced EMT in skin keratinocytes has not been reported. Although the signalling mechanisms underlying EMT have been well studied, the identity of a matrix stiffness-sensing plasma membrane receptor/channel and the molecular mechanisms by which matrix stiffness signals are transmitted and propagated to drive EMT remain to be determined.…”

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confidence: 99%

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TRPV4 regulates matrix stiffness and TGFβ1‐induced epithelial‐mesenchymal transition

Sharma

Goswami

Zhang

et al. 2018

J Cellular Molecular Medi

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Substrate stiffness (or rigidity) of the extracellular matrix has important functions in numerous pathophysiological processes including fibrosis. Emerging data support a role for both a mechanical signal, for example, matrix stiffness, and a biochemical signal, for example, transforming growth factor β1 (TGFβ1), in epithelial‐mesenchymal transition (EMT), a process critically involved in fibrosis. Here, we report evidence showing that transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive channel, is the likely mediator of EMT in response to both TGFβ1 and matrix stiffness. Specifically, we found that: (a) genetic ablation or pharmacological inhibition of TRPV4 blocked matrix stiffness and TGFβ1‐induced EMT in normal mouse primary epidermal keratinocytes (NMEKs) as determined by changes in morphology, adhesion, migration and alterations of expression of EMT markers including E‐cadherin, N‐cadherin (NCAD) and α‐smooth muscle actin (α‐SMA), and (b) TRPV4 deficiency prevented matrix stiffness‐induced EMT in NMEKs over a pathophysiological range. Intriguingly, TRPV4 deletion in mice suppressed expression of mesenchymal markers, NCAD and α‐SMA, in a bleomycin‐induced murine skin fibrosis model. Mechanistically, we found that: (a) TRPV4 was essential for the nuclear translocation of YAP/TAZ (yes‐associated protein/transcriptional coactivator with PDZ‐binding motif) in response to matrix stiffness and TGFβ1, (b) TRPV4 deletion inhibited both matrix stiffness‐ and TGFβ1‐induced expression of YAP/TAZ proteins and (c) TRPV4 deletion abrogated both matrix stiffness‐ and TGFβ1‐induced activation of AKT, but not Smad2/3, suggesting a mechanism by which TRPV4 activity regulates EMT in NMEKs. Altogether, these data identify a novel role for TRPV4 in regulating EMT.

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Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Trpv4 Mediates Tgfβ1-induced Emt-like Changes In Normal Momentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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TRPV4 regulates matrix stiffness and TGFβ1‐induced epithelial‐mesenchymal transition

Sharma

Goswami

Zhang

et al. 2018

J Cellular Molecular Medi

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Calreticulin as a marker and therapeutic target for cancer

Zhang

Liu²,

Bai³

et al. 2022

Clin Exp Med

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

Owusu

Zimmerman

Murphy-Ullrich

2017

J. Cell Commun. Signal.

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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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Calreticulin regulates TGF-β1-induced epithelial mesenchymal transition through modulating Smad signaling and calcium signaling

Cited by 28 publications

References 30 publications

TRPV4 regulates matrix stiffness and TGFβ1‐induced epithelial‐mesenchymal transition

TRPV4 regulates matrix stiffness and TGFβ1‐induced epithelial‐mesenchymal transition

Calreticulin as a marker and therapeutic target for cancer

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

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