Calreticulin Regulates Transforming Growth Factor-β-stimulated Extracellular Matrix Production

Zimmerman, Kurt A.; Graham, Lauren V.; Pallero, Manuel A.; Murphy-Ullrich, Joanne E.

doi:10.1074/jbc.m112.447243

Cited by 50 publications

(85 citation statements)

References 88 publications

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“…The direct profibrotic role of UPR mediators in activation of TGF-β signaling in lung fibroblasts could also be proven by a study from Zimmerman and coworkers who showed that the ER chaperone calreticulin is required for TGF-β induced expression of Col1a1 and Fn, whereas knockout of Calr resulted in abrogation of cellular responsiveness to TGF-β even in the presence of active Smad 2/3 signaling [233]. Importantly, calreticulin was required for TGF-β induced ECM synthesis under conditions of ER stress, as tunicamycin-induced ER stress was insufficient to induce ECM production in TGF-β stimulated Calr (-/-) MEFs (but induced ECM production in TGF-β stimulated Calr (+/+) wt-MEFs, due to upregulation of Calr in response to ER stress) [233]. Taken together, all these results point out that selected protective UPR pathways are involved in fibroproliferative remodeling that are independent of severe ER stress and apoptosis [232,233,238].…”

Section: Adaptive Er Stress In Mesenchymal Cells Of Ipf Lungsmentioning

confidence: 89%

“…Taken together, the results by Semren et al suggest that myofibroblasts use increased ERAD function as shown by elevated 26S proteasomal activity in order to maintain ER homeostasis and cell survival in response to TGF-β-mediated elevation of ECM protein-production [238]. The direct profibrotic role of UPR mediators in activation of TGF-β signaling in lung fibroblasts could also be proven by a study from Zimmerman and coworkers who showed that the ER chaperone calreticulin is required for TGF-β induced expression of Col1a1 and Fn, whereas knockout of Calr resulted in abrogation of cellular responsiveness to TGF-β even in the presence of active Smad 2/3 signaling [233]. Importantly, calreticulin was required for TGF-β induced ECM synthesis under conditions of ER stress, as tunicamycin-induced ER stress was insufficient to induce ECM production in TGF-β stimulated Calr (-/-) MEFs (but induced ECM production in TGF-β stimulated Calr (+/+) wt-MEFs, due to upregulation of Calr in response to ER stress) [233].…”

Section: Adaptive Er Stress In Mesenchymal Cells Of Ipf Lungsmentioning

confidence: 95%

“…Importantly, calreticulin was required for TGF-β induced ECM synthesis under conditions of ER stress, as tunicamycin-induced ER stress was insufficient to induce ECM production in TGF-β stimulated Calr (-/-) MEFs (but induced ECM production in TGF-β stimulated Calr (+/+) wt-MEFs, due to upregulation of Calr in response to ER stress) [233]. Taken together, all these results point out that selected protective UPR pathways are involved in fibroproliferative remodeling that are independent of severe ER stress and apoptosis [232,233,238].…”

Section: Adaptive Er Stress In Mesenchymal Cells Of Ipf Lungsmentioning

confidence: 98%

“…Various studies document that selected (prosurvivalacting) ER stress pathways may contribute directly to fibrogenesis and ECM production in IPF [232,233]. The activation and differentiation of fibroblasts into apoptosisresistant, ECM-producing myofibroblasts is a critical factor towards the development of IPF.…”

Section: Adaptive Er Stress In Mesenchymal Cells Of Ipf Lungsmentioning

confidence: 98%

“…Calreticulin is a ATF6-and XBP1-target gene [1,242] and acts in ECM producing cells as a collagen chaperone to mediate ER-to-Golgi trafficking, processing, and incorporation into the ECM [243]. In addition to its chaperone function, calreticulin has a role as a crucial regulator of ER-Ca 2+ signaling [233]. Regarding this, Zimmerman et al also showed that calreticulin mediates Ca 2+ release into the cytosol in response to TGF-β in MEF cells in vitro, thereby inducing calcineurin activation and consequent nuclear translocation of factor of activated T cells (NFAT) which directly stimulates transcription of ECM components COL1A1 and FN together with other known matrix-inducing transcription factors such as AP-1 and SP-1.…”

Section: Adaptive Er Stress In Mesenchymal Cells Of Ipf Lungsmentioning

confidence: 99%

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The role of Endoplasmic Reticulum (ER) stress in pulmonary fibrosis

Korfei

Ruppert

Loeh

et al. 2016

Endoplasmic Reticulum Stress in Diseases

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The activation of Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) was first observed in patients with familial interstitial pneumonia (FIP) carrying mutations in the C-terminal BRICHOS domain of surfactant protein C (SFTPC). Here, aggresome formation and severe ER stress was demonstrated in type-II alveolar epithelial cells (AECII), which specifically express this very hydrophobic surfactant protein. In subsequent studies, FIP-patients with mutations in the gene encoding surfactant protein A2 (SFTPA2) were discovered, whose overexpression in epithelial cells in vitro also resulted in significant induction of ER stress. Moreover, prominent ER stress in AECII was also observed in FIP-patients not carrying the SFTPC/SFTPA2 mutations, as well as in patients with the more common sporadic forms of IP. Additionally, cases of adult-onset FIP with mutations in Telomerase genes and other telomereassociated components were reported. These mutations were associated with telomere shortening, which is a potential cause for triggering a persistent DNA damage response and replicative senescence in affected cells. Moreover, shortened telomeres were observed directly in the AECII of FIP-patients, and even sporadic IP cases, in the absence of any gene mutations. Here, we try to figure out the possible origins of ER stress in sporadic IP cases and non-SFTPC/SFTPA2-associated FIP.

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Section: Adaptive Er Stress In Mesenchymal Cells Of Ipf Lungsmentioning

confidence: 89%

Section: Adaptive Er Stress In Mesenchymal Cells Of Ipf Lungsmentioning

confidence: 95%

Section: Adaptive Er Stress In Mesenchymal Cells Of Ipf Lungsmentioning

confidence: 98%

Section: Adaptive Er Stress In Mesenchymal Cells Of Ipf Lungsmentioning

confidence: 98%

Section: Adaptive Er Stress In Mesenchymal Cells Of Ipf Lungsmentioning

confidence: 99%

See 3 more Smart Citations

The role of Endoplasmic Reticulum (ER) stress in pulmonary fibrosis

Korfei

Ruppert

Loeh

et al. 2016

Endoplasmic Reticulum Stress in Diseases

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show abstract

Immunomodulation of wound healing leading to efferocytosis

Zhao,

Li,

Mao

et al. 2024

Smart Medicine

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Effectively eliminating apoptotic cells is precisely controlled by a variety of signaling molecules and a phagocytic effect known as efferocytosis. Abnormalities in efferocytosis may bring about the development of chronic conditions, including angiocardiopathy, chronic inflammatory diseases and autoimmune diseases. During wound healing, failure of efferocytosis leads to the collection of apoptosis, the release of necrotic material and chronic wounds that are difficult to heal. In addition to the traditional phagocytes‐macrophages, other important cell species including dendritic cells, neutrophils, vascular endothelial cells, fibroblasts and keratinocytes contribute to wounding healing. This review summarizes how efferocytosis‐mediated immunomodulation plays a repair‐promoting role in wound healing, providing new insights for patients suffering from various cutaneous wounds.

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Intracellular signaling dynamics and their role in coordinating tissue repair

Ghilardi

O'Reilly

Sgro

2020

WIREs Mechanisms of Disease

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Tissue repair is a complex process that requires effective communication and coordination between cells across multiple tissues and organ systems. Two of the initial intracellular signals that encode injury signals and initiate tissue repair responses are calcium and extracellular signal-regulated kinase (ERK). However, calcium and ERK signaling control a variety of cellular behaviors important for injury repair including cellular motility, contractility, and proliferation, as well as the activity of several different transcription factors, making it challenging to relate specific injury signals to their respective repair programs. This knowledge gap ultimately hinders the development of new wound healing therapies that could take advantage of native cellular signaling programs to more effectively repair tissue damage. The objective of this review is to highlight the roles of calcium and ERK signaling dynamics as mechanisms that link specific injury signals to specific cellular repair programs during epithelial and stromal injury repair. We detail how the signaling networks controlling calcium and ERK can now also be dissected using classical signal processing techniques with the advent of new biosensors and optogenetic signal controllers. Finally, we advocate the importance of recognizing calcium and ERK dynamics as key links between injury detection and injury repair programs that both organize and execute a coordinated tissue repair response between cells across different tissues and organs.

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Calreticulin Regulates Transforming Growth Factor-β-stimulated Extracellular Matrix Production

Cited by 50 publications

References 88 publications

The role of Endoplasmic Reticulum (ER) stress in pulmonary fibrosis

The role of Endoplasmic Reticulum (ER) stress in pulmonary fibrosis

Immunomodulation of wound healing leading to efferocytosis

Intracellular signaling dynamics and their role in coordinating tissue repair

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