Publications by authors named "Jan B Parys"

151 Publications

A non-canonical role for pyruvate kinase M2 as a functional modulator of Ca signalling through IP receptors.

Biochim Biophys Acta Mol Cell Res 2022 Jan 11;1869(4):119206. Epub 2022 Jan 11.

Division of Hematology/Oncology, Dept. Medicine, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA; Dept of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Electronic address:

Pyruvate kinase isoform M2 (PKM2) is a rate-limiting glycolytic enzyme that is widely expressed in embryonic tissues. The expression of PKM2 declines in some tissues following embryogenesis, while other pyruvate kinase isozymes are upregulated. However, PKM2 is highly expressed in cancer cells and is believed to play a role in supporting anabolic processes during tumour formation. In this study, PKM2 was identified as an inositol 1,4,5-trisphosphate receptor (IPR)-interacting protein by mass spectrometry. The PKM2:IPR interaction was further characterized by pull-down and co-immunoprecipitation assays, which showed that PKM2 interacted with all three IPR isoforms. Moreover, fluorescence microscopy indicated that both IPR and PKM2 localized at the endoplasmic reticulum. PKM2 binds to IPR at a highly conserved 21-amino acid site (corresponding to amino acids 2078-2098 in mouse type 1 IPR isoform). Synthetic peptides (denoted 'TAT-D5SD' and 'D5SD'), based on the amino acid sequence at this site, disrupted the PKM2:IPR interaction and potentiated IPR-mediated Ca release both in intact cells (TAT-D5SD peptide) and in a unidirectional Ca flux assay on permeabilized cells (D5SD peptide). The TAT-D5SD peptide did not affect the enzymatic activity of PKM2. Reducing PKM2 protein expression using siRNA increased IPR-mediated Ca signalling in intact cells without altering the ER Ca content. These data identify PKM2 as an IPR-interacting protein that inhibits intracellular Ca signalling. The elevated expression of PKM2 in cancer cells is therefore not solely connected to its canonical role in glycolytic metabolism, rather PKM2 also has a novel non-canonical role in regulating intracellular signalling.
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http://dx.doi.org/10.1016/j.bbamcr.2021.119206DOI Listing
January 2022

Preface to the Special Issue of the European Calcium Society in honor of Professor Sir Michael J. Berridge.

Biochim Biophys Acta Mol Cell Res 2022 Feb 11;1869(2):119172. Epub 2021 Nov 11.

KU Leuven, Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut, Campus Gasthuisberg O/N-1 B-802, Herestraat 49, BE-3000 Leuven, Belgium. Electronic address:

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http://dx.doi.org/10.1016/j.bbamcr.2021.119172DOI Listing
February 2022

Bcl-xL acts as an inhibitor of IPR channels, thereby antagonizing Ca-driven apoptosis.

Cell Death Differ 2021 Nov 8. Epub 2021 Nov 8.

KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, and Leuven Kanker Instituut, Campus Gasthuisberg O/N-1 Box 802, Herestraat 49, 3000, Leuven, Belgium.

Anti-apoptotic Bcl-2-family members not only act at mitochondria but also at the endoplasmic reticulum, where they impact Ca dynamics by controlling IP receptor (IPR) function. Current models propose distinct roles for Bcl-2 vs. Bcl-xL, with Bcl-2 inhibiting IPRs and preventing pro-apoptotic Ca release and Bcl-xL sensitizing IPRs to low [IP] and promoting pro-survival Ca oscillations. We here demonstrate that Bcl-xL too inhibits IPR-mediated Ca release by interacting with the same IPR regions as Bcl-2. Via in silico superposition, we previously found that the residue K87 of Bcl-xL spatially resembled K17 of Bcl-2, a residue critical for Bcl-2's IPR-inhibitory properties. Mutagenesis of K87 in Bcl-xL impaired its binding to IPR and abrogated Bcl-xL's inhibitory effect on IPRs. Single-channel recordings demonstrate that purified Bcl-xL, but not Bcl-xL, suppressed IPR single-channel openings stimulated by sub-maximal and threshold [IP]. Moreover, we demonstrate that Bcl-xL-mediated inhibition of IPRs contributes to its anti-apoptotic properties against Ca-driven apoptosis. Staurosporine (STS) elicits long-lasting Ca elevations in wild-type but not in IPR-knockout HeLa cells, sensitizing the former to STS treatment. Overexpression of Bcl-xL in wild-type HeLa cells suppressed STS-induced Ca signals and cell death, while Bcl-xL was much less effective in doing so. In the absence of IPRs, Bcl-xL and Bcl-xL were equally effective in suppressing STS-induced cell death. Finally, we demonstrate that endogenous Bcl-xL also suppress IPR activity in MDA-MB-231 breast cancer cells, whereby Bcl-xL knockdown augmented IPR-mediated Ca release and increased the sensitivity towards STS, without altering the ER Ca content. Hence, this study challenges the current paradigm of divergent functions for Bcl-2 and Bcl-xL in Ca-signaling modulation and reveals that, similarly to Bcl-2, Bcl-xL inhibits IPR-mediated Ca release and IPR-driven cell death. Our work further underpins that IPR inhibition is an integral part of Bcl-xL's anti-apoptotic function.
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http://dx.doi.org/10.1038/s41418-021-00894-wDOI Listing
November 2021

Uniting the divergent Wolfram syndrome-linked proteins WFS1 and CISD2 as modulators of Ca signaling.

Sci Signal 2021 09 28;14(702):eabc6165. Epub 2021 Sep 28.

KU Leuven, Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, Leuven Kanker Instituut, Campus Gasthuisberg O/N-1 B-802, Herestraat 49, BE-3000 Leuven, Belgium.

[Figure: see text].
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http://dx.doi.org/10.1126/scisignal.abc6165DOI Listing
September 2021

IP Receptor Biology and Endoplasmic Reticulum Calcium Dynamics in Cancer.

Prog Mol Subcell Biol 2021 ;59:215-237

Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Cancer Institute, KU Leuven, Leuven, Belgium.

Intracellular Ca signaling regulates a plethora of cellular functions. A central role in these processes is reserved for the inositol 1,4,5-trisphosphate receptor (IPR), a ubiquitously expressed Ca-release channel, mainly located in the endoplasmic reticulum (ER). Three IPR isoforms (IPR1, IPR2 and IPR3) exist, encoded respectively by ITPR1, ITPR2 and ITPR3. The proteins encoded by these genes are each about 2700 amino acids long and assemble into large tetrameric channels, which form the target of many regulatory proteins, including several tumor suppressors and oncogenes. Due to the important role of the IPRs in cell function, their dysregulation is linked to multiple pathologies. In this review, we highlight the complex role of the IPR in cancer, as it participates in most of the so-called "hallmarks of cancer". In particular, the IPR directly controls cell death and cell survival decisions via regulation of autophagy and apoptosis. Moreover, the IPR impacts cellular proliferation, migration and invasion. Typical examples of the role of the IPRs in these various processes are discussed. The relative levels of the IPR isoforms expressed and their subcellular localization, e.g. at the ER-mitochondrial interface, is hereby important. Finally, evidence is provided about how the knowledge of the regulation of the IPR by tumor suppressors and oncogenes can be exploited to develop novel therapeutic approaches to fight cancer.
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http://dx.doi.org/10.1007/978-3-030-67696-4_11DOI Listing
August 2021

A comprehensive overview of the complex world of the endo- and sarcoplasmic reticulum Ca-leak channels.

Biochim Biophys Acta Mol Cell Res 2021 06 30;1868(7):119020. Epub 2021 Mar 30.

KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine and Leuven Kanker Instituut, Campus Gasthuisberg O/N-1 B-802, Herestraat 49, B-3000 Leuven, Belgium. Electronic address:

Inside cells, the endoplasmic reticulum (ER) forms the largest Ca store. Ca is actively pumped by the SERCA pumps in the ER, where intraluminal Ca-binding proteins enable the accumulation of large amount of Ca. IP receptors and the ryanodine receptors mediate the release of Ca in a controlled way, thereby evoking complex spatio-temporal signals in the cell. The steady state Ca concentration in the ER of about 500 μM results from the balance between SERCA-mediated Ca uptake and the passive leakage of Ca. The passive Ca leak from the ER is often ignored, but can play an important physiological role, depending on the cellular context. Moreover, excessive Ca leakage significantly lowers the amount of Ca stored in the ER compared to normal conditions, thereby limiting the possibility to evoke Ca signals and/or causing ER stress, leading to pathological consequences. The so-called Ca-leak channels responsible for Ca leakage from the ER are however still not well understood, despite over 20 different proteins have been proposed to contribute to it. This review has the aim to critically evaluate the available evidence about the various channels potentially involved and to draw conclusions about their relative importance.
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http://dx.doi.org/10.1016/j.bbamcr.2021.119020DOI Listing
June 2021

Balancing ER-Mitochondrial Ca Fluxes in Health and Disease.

Trends Cell Biol 2021 07 4;31(7):598-612. Epub 2021 Mar 4.

Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, Leuven Kanker Instituut, KU Leuven, Campus Gasthuisberg O/N-1 B-802, Herestraat 49, BE-3000 Leuven, Belgium. Electronic address:

Organelles cooperate with each other to control cellular homeostasis and cell functions by forming close connections through membrane contact sites. Important contacts are present between the endoplasmic reticulum (ER), the main intracellular Ca-storage organelle, and the mitochondria, the organelle responsible not only for the majority of cellular ATP production but also for switching on cell death processes. Several Ca-transport systems focalize at these contact sites, thereby enabling the efficient transmission of Ca signals from the ER toward mitochondria. This provides tight control of mitochondrial functions at the microdomain level. Here, we discuss how ER-mitochondrial Ca transfers support cell function and how their dysregulation underlies, drives, or contributes to pathogenesis and pathophysiology, with a major focus on cancer and neurodegeneration but also with attention to other diseases such as diabetes and rare genetic diseases.
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http://dx.doi.org/10.1016/j.tcb.2021.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195822PMC
July 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

BIRD-2, a BH4-domain-targeting peptide of Bcl-2, provokes Bax/Bak-independent cell death in B-cell cancers through mitochondrial Ca-dependent mPTP opening.

Cell Calcium 2021 03 12;94:102333. Epub 2021 Jan 12.

Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, Leuven Cancer Institute (LKI), KU Leuven, Campus Gasthuisberg O/N-1 Bus 802, Herestraat 49, 3000, Leuven, Belgium. Electronic address:

Anti-apoptotic Bcl-2 critically controls cell death by neutralizing pro-apoptotic Bcl-2-family members at the mitochondria. Bcl-2 proteins also act at the endoplasmic reticulum, the main intracellular Ca-storage organelle, where they inhibit IP receptors (IPR) and prevent pro-apoptotic Ca-signaling events. IPR channels are targeted by the BH4 domain of Bcl-2. Some cancer types rely on the IPR-Bcl-2 interaction for survival. We previously developed a cell-permeable, BH4-domain-targeting peptide that can abrogate Bcl-2's inhibitory action on IPRs, named Bcl-2 IP receptor disrupter-2 (BIRD-2). This peptide kills several Bcl-2-dependent cancer cell types, including diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukaemia (CLL) cells, by eliciting intracellular Ca signalling. However, the exact mechanisms by which these excessive Ca signals triggered by BIRD-2 provoke cancer cell death remain elusive. Here, we demonstrate in DLBCL that although BIRD-2 activates caspase 3/7 and provokes cell death in a caspase-dependent manner, the cell death is independent of pro-apoptotic Bcl-2-family members, Bim, Bax and Bak. Instead, BIRD-2 provokes mitochondrial Ca overload that is rapidly followed by opening of the mitochondrial permeability transition pore (mPTP). Inhibiting mitochondrial Ca overload using Ru265, an inhibitor of the mitochondrial Ca uniporter complex counteracts BIRD-2-induced cancer cell death. Finally, we validated our findings in primary CLL patient samples where BIRD-2 provoked mitochondrial Ca overload and Ru265 counteracted BIRD-2-induced cell death. Overall, this work reveals the mechanisms by which BIRD-2 provokes cell death, which occurs via mitochondrial Ca overload but acts independently of pro-apoptotic Bcl-2-family members.
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http://dx.doi.org/10.1016/j.ceca.2020.102333DOI Listing
March 2021

Synthesis and Characterization of Store-Operated Calcium Entry Inhibitors Active in the Submicromolar Range.

Int J Mol Sci 2020 Dec 21;21(24). Epub 2020 Dec 21.

Physiopathogénèse et Traitements des Maladies du Foie, Université Paris-Saclay, Rue des Adeles, 91405 Orsay, France.

The store-operated calcium entry, better known as SOCE, forms the main Ca influx pathway in non-excitable cells, especially in leukocytes, where it is required for cell activation and the immune response. During the past decades, several inhibitors were developed, but they lack specificity or efficacy. From the non-specific SOCE inhibitor 2-aminoethyl diphenylborinate (2-APB), we synthetized 16 new analogues by replacing/modifying the phenyl groups. Among them, our compound P11 showed the best inhibitory capacity with a ≈ 75 nM. Furthermore, below 1 µM, P11 was devoid of any inhibitory activity on the two other main cellular targets of 2-APB, the IP receptors, and the SERCA pumps. Interestingly, Jurkat T cells secrete interleukin-2 under phytohemagglutinin stimulation but undergo cell death and stop IL-2 synthesis when stimulated in the presence of increasing P11 concentrations. Thus, P11 could represent the first member of a new and potent family of immunosuppressors.
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http://dx.doi.org/10.3390/ijms21249777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767506PMC
December 2020

EPIC3, a novel Ca indicator located at the cell cortex and in microridges, detects high Ca subdomains during Ca influx and phagocytosis.

Cell Calcium 2020 12 9;92:102291. Epub 2020 Oct 9.

Neutrophil Signalling Group, Cardiff University Medical School, Cardiff, CF14 4XN, UK. Electronic address:

The construction of a low affinity Ca-probe that locates to the cell cortex and cell surface wrinkles, is described called. EPIC3 (ezrin-protein indicator of Ca). The novel probe is a fusion of CEPIA3 with ezrin, and is used in combination with a Ca-insensitive probe, ezrin-mCherry, both of which locate at the cell cortex. EPIC3 was used to monitor the effect of Ca influx on intra-wrinkle Ca in the macrophage cell line, RAW 264.7. During experimentally-induced Cainflux, EPIC3 reported Ca concentrations at the cell cortex in the region of 30-50 μM, with peak locations towards the tips of wrinkles reaching 80 μM. These concentrations were associated with cleavage of ezrin (a substrate for the Ca activated protease calpain-1) and released the C-terminal fluors. The cortical Ca levels, restricted to near the site of phagocytic cup formation and pseudopodia extension during phagocytosis also reached high levels (50-80 μM) during phagocytosis. As phagocytosis was completed, hotspots of Ca near the phagosome were also observed.
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http://dx.doi.org/10.1016/j.ceca.2020.102291DOI Listing
December 2020

Transmembrane BAX Inhibitor-1 Motif Containing Protein 5 (TMBIM5) Sustains Mitochondrial Structure, Shape, and Function by Impacting the Mitochondrial Protein Synthesis Machinery.

Cells 2020 09 23;9(10). Epub 2020 Sep 23.

Institute for Molecular Medicine, Johannes Gutenberg University Medical Center Mainz, D-55131 Mainz, Germany.

The Transmembrane Bax Inhibitor-1 motif (TMBIM)-containing protein family is evolutionarily conserved and has been implicated in cell death susceptibility. The only member with a mitochondrial localization is TMBIM5 (also known as GHITM or MICS1), which affects cristae organization and associates with the Parkinson's disease-associated protein CHCHD2 in the inner mitochondrial membrane. We here used CRISPR-Cas9-mediated knockout HAP1 cells to shed further light on the function of TMBIM5 in physiology and cell death susceptibility. We found that compared to wild type, -knockout cells were smaller and had a slower proliferation rate. In these cells, mitochondria were more fragmented with a vacuolar cristae structure. In addition, the mitochondrial membrane potential was reduced and respiration was attenuated, leading to a reduced mitochondrial ATP generation. TMBIM5 did not associate with Mic10 and Mic60, which are proteins of the mitochondrial contact site and cristae organizing system (MICOS), nor did knockout affect their expression levels. -knockout cells were more sensitive to apoptosis elicited by staurosporine and BH3 mimetic inhibitors of Bcl-2 and Bcl-XL. An unbiased proteomic comparison identified a dramatic downregulation of proteins involved in the mitochondrial protein synthesis machinery in TMBIM5-knockout cells. We conclude that TMBIM5 is important to maintain the mitochondrial structure and function possibly through the control of mitochondrial biogenesis.
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http://dx.doi.org/10.3390/cells9102147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598220PMC
September 2020

STIM1 Deficiency Leads to Specific Down-Regulation of ITPR3 in SH-SY5Y Cells.

Int J Mol Sci 2020 Sep 9;21(18). Epub 2020 Sep 9.

Department of Biochemistry and Molecular Biology, School of Life Sciences and Institute of Molecular Pathology and Biomarkers, University of Extremadura, 06006 Badajoz, Spain.

STIM1 is an endoplasmic reticulum (ER) protein that modulates the activity of a number of Ca transport systems. By direct physical interaction with ORAI1, a plasma membrane Ca channel, STIM1 activates the current, whereas the binding with the voltage-operated Ca channel Ca1.2 inhibits the current through this latter channel. In this way, STIM1 is a key regulator of Ca signaling in excitable and non-excitable cells, and altered STIM1 levels have been reported to underlie several pathologies, including immunodeficiency, neurodegenerative diseases, and cancer. In both sporadic and familial Alzheimer's disease, a decrease of STIM1 protein levels accounts for the alteration of Ca handling that compromises neuronal cell viability. Using SH-SY5Y cells edited by CRISPR/Cas9 to knockout gene expression, this work evaluated the molecular mechanisms underlying the cell death triggered by the deficiency of STIM1, demonstrating that STIM1 is a positive regulator of gene expression. ITPR3 (or IP3R3) is a Ca channel enriched at ER-mitochondria contact sites where it provides Ca for transport into the mitochondria. Thus, STIM1 deficiency leads to a strong reduction of transcript and ITPR3 protein levels, a consequent decrease of the mitochondria free Ca concentration ([Ca]), reduction of mitochondrial oxygen consumption rate, and decrease in ATP synthesis rate. All these values were normalized by ectopic expression of ITPR3 in STIM1-KO cells, providing strong evidence for a new mode of regulation of [Ca] mediated by the STIM1-ITPR3 axis.
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http://dx.doi.org/10.3390/ijms21186598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555297PMC
September 2020

Necroptosis in Immuno-Oncology and Cancer Immunotherapy.

Cells 2020 08 1;9(8). Epub 2020 Aug 1.

Department of Cellular and Molecular Medicine, Laboratory of Cell Stress & Immunity (CSI), KU Leuven, 3000 Leuven, Belgium.

Immune-checkpoint blockers (ICBs) have revolutionized oncology and firmly established the subfield of immuno-oncology. Despite this renaissance, a subset of cancer patients remain unresponsive to ICBs due to widespread immuno-resistance. To "break" cancer cell-driven immuno-resistance, researchers have long floated the idea of therapeutically facilitating the immunogenicity of cancer cells by disrupting tumor-associated immuno-tolerance via conventional anticancer therapies. It is well appreciated that anticancer therapies causing immunogenic or inflammatory cell death are best positioned to productively activate anticancer immunity. A large proportion of studies have emphasized the importance of immunogenic apoptosis (i.e., immunogenic cell death or ICD); yet, it has also emerged that necroptosis, a programmed necrotic cell death pathway, can also be immunogenic. Emergence of a proficient immune profile for necroptosis has important implications for cancer because resistance to apoptosis is one of the major hallmarks of tumors. Putative immunogenic or inflammatory characteristics driven by necroptosis can be of great impact in immuno-oncology. However, as is typical for a highly complex and multi-factorial disease like cancer, a clear cause versus consensus relationship on the immunobiology of necroptosis in cancer cells has been tough to establish. In this review, we discuss the various aspects of necroptosis immunobiology with specific focus on immuno-oncology and cancer immunotherapy.
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http://dx.doi.org/10.3390/cells9081823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464343PMC
August 2020

Type 3 IP receptors: The chameleon in cancer.

Int Rev Cell Mol Biol 2020 11;351:101-148. Epub 2020 Mar 11.

KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine and Leuven Kanker Instituut (LKI), Leuven, Belgium. Electronic address:

Inositol 1,4,5-trisphosphate (IP) receptors (IPRs), intracellular calcium (Ca) release channels, fulfill key functions in cell death and survival processes, whose dysregulation contributes to oncogenesis. This is essentially due to the presence of IPRs in microdomains of the endoplasmic reticulum (ER) in close proximity to the mitochondria. As such, IPRs enable efficient Ca transfers from the ER to the mitochondria, thus regulating metabolism and cell fate. This review focuses on one of the three IPR isoforms, the type 3 IPR (IPR3), which is linked to proapoptotic ER-mitochondrial Ca transfers. Alterations in IPR3 expression have been highlighted in numerous cancer types, leading to dysregulations of Ca signaling and cellular functions. However, the outcome of IPR3-mediated Ca transfers for mitochondrial function is complex with opposing effects on oncogenesis. IPR3 can either suppress cancer by promoting cell death and cellular senescence or support cancer by driving metabolism, anabolic processes, cell cycle progression, proliferation and invasion. The aim of this review is to provide an overview of IPR3 dysregulations in cancer and describe how such dysregulations alter critical cellular processes such as proliferation or cell death and survival. Here, we pose that the IPR3 isoform is not only linked to proapoptotic ER-mitochondrial Ca transfers but might also be involved in prosurvival signaling.
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http://dx.doi.org/10.1016/bs.ircmb.2020.02.003DOI Listing
October 2020

The Eighth ECS Workshop on "Calcium Signaling in Aging and Neurodegenerative Diseases".

Int J Mol Sci 2019 Dec 12;20(24). Epub 2019 Dec 12.

Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid y Consejo Superior de Investigaciones Científicas (CSIC), 47003 Valladolid, Spain.

The European Calcium Society (ECS) is very glad to present the realization of a special issue of the International Journal of Molecular Sciences (IJMS) related to the eighth ECS workshop organized this year around the theme of "Calcium Signaling in Aging and Neurodegenerative Diseases" [...].
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http://dx.doi.org/10.3390/ijms20246263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941050PMC
December 2019

New Insights in the IP Receptor and Its Regulation.

Adv Exp Med Biol 2020 ;1131:243-270

KU Leuven, Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut, Leuven, Belgium.

The inositol 1,4,5-trisphosphate (IP) receptor (IPR) is a Ca-release channel mainly located in the endoplasmic reticulum (ER). Three IPR isoforms are responsible for the generation of intracellular Ca signals that may spread across the entire cell or occur locally in so-called microdomains. Because of their ubiquitous expression, these channels are involved in the regulation of a plethora of cellular processes, including cell survival and cell death. To exert their proper function a fine regulation of their activity is of paramount importance. In this review, we will highlight the recent advances in the structural analysis of the IPR and try to link these data with the newest information concerning IPR activation and regulation. A special focus of this review will be directed towards the regulation of the IPR by protein-protein interaction. Especially the protein family formed by calmodulin and related Ca-binding proteins and the pro- and anti-apoptotic/autophagic Bcl-2-family members will be highlighted. Finally, recently identified and novel IPR regulatory proteins will be discussed. A number of these interactions are involved in cancer development, illustrating the potential importance of modulating IPR-mediated Ca signaling in cancer treatment.
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http://dx.doi.org/10.1007/978-3-030-12457-1_10DOI Listing
October 2019

Full focus on calcium.

Sci Signal 2019 09 17;12(599). Epub 2019 Sep 17.

Calcium Signalling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.

Intracellular calcium (Ca) signals are of prime importance for cellular function and behavior and are underpinned by a plethora of Ca channels, pumps, transporters, and binding proteins that are regulated in complex ways. A series of biennial meetings, the International Meetings of the European Calcium Society (ECS), focuses on a better understanding of these complex mechanisms in the framework of cellular and organismal (patho)physiology.
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http://dx.doi.org/10.1126/scisignal.aaz0961DOI Listing
September 2019

Bcl-2-Protein Family as Modulators of IP Receptors and Other Organellar Ca Channels.

Cold Spring Harb Perspect Biol 2020 04 1;12(4). Epub 2020 Apr 1.

Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, B-3000 Leuven, Belgium.

The pro- and antiapoptotic proteins belonging to the B-cell lymphoma-2 (Bcl-2) family exert a critical control over cell-death processes by enabling or counteracting mitochondrial outer membrane permeabilization. Beyond this mitochondrial function, several Bcl-2 family members have emerged as critical modulators of intracellular Ca homeostasis and dynamics, showing proapoptotic and antiapoptotic functions. Bcl-2 family proteins specifically target several intracellular Ca-transport systems, including organellar Ca channels: inositol 1,4,5-trisphosphate receptors (IPRs) and ryanodine receptors (RyRs), Ca-release channels mediating Ca flux from the endoplasmic reticulum, as well as voltage-dependent anion channels (VDACs), which mediate Ca flux across the mitochondrial outer membrane into the mitochondria. Although the formation of protein complexes between Bcl-2 proteins and these channels has been extensively studied, a major advance during recent years has been elucidating the complex interaction of Bcl-2 proteins with IPRs. Distinct interaction sites for different Bcl-2 family members were identified in the primary structure of IPRs. The unique molecular profiles of these Bcl-2 proteins may account for their distinct functional outcomes when bound to IPRs. Furthermore, Bcl-2 inhibitors used in cancer therapy may affect IPR function as part of their proapoptotic effect and/or as an adverse effect in healthy cells.
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http://dx.doi.org/10.1101/cshperspect.a035089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7111250PMC
April 2020

L-asparaginase-induced apoptosis in ALL cells involves IP receptor signaling.

Cell Calcium 2019 11 28;83:102076. Epub 2019 Aug 28.

KU Leuven, Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut, Campus Gasthuisberg O/N-1 B-802, Herestraat 49, BE-3000 Leuven, Belgium. Electronic address:

L-asparaginase treatment is used in the clinic to treat acute lymphoblastic leukemia (ALL) patients. Lee et al. (2019, Blood 133:2222-2232) demonstrated that L-asparaginase induces apoptosis by activating inositol 1,4,5-trisphosphate (IP)-induced Ca signaling in a Huntingin-associated protein 1 (HAP1)-dependent manner. Moreover, HAP1 levels inversely correlate with the sensitivity of the ALL cells to L-asparaginase. HAP1 can therefore be used as biomarker for evaluating L-asparaginase resistance.
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http://dx.doi.org/10.1016/j.ceca.2019.102076DOI Listing
November 2019

Bcl-2 and IP compete for the ligand-binding domain of IPRs modulating Ca signaling output.

Cell Mol Life Sci 2019 Oct 16;76(19):3843-3859. Epub 2019 Apr 16.

Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, Leuven Cancer Institute (LKI), KU Leuven, Campus Gasthuisberg O/N-1 Bus 802, Herestraat 49, 3000, Leuven, Belgium.

Bcl-2 proteins have emerged as critical regulators of intracellular Ca dynamics by directly targeting and inhibiting the IP receptor (IPR), a major intracellular Ca-release channel. Here, we demonstrate that such inhibition occurs under conditions of basal, but not high IPR activity, since overexpressed and purified Bcl-2 (or its BH4 domain) can inhibit IPR function provoked by low concentration of agonist or IP, while fails to attenuate against high concentration of agonist or IP. Surprisingly, Bcl-2 remained capable of inhibiting IPR1 channels lacking the residues encompassing the previously identified Bcl-2-binding site (a.a. 1380-1408) located in the ARM2 domain, part of the modulatory region. Using a plethora of computational, biochemical and biophysical methods, we demonstrate that Bcl-2 and more particularly its BH4 domain bind to the ligand-binding domain (LBD) of IPR1. In line with this finding, the interaction between the LBD and Bcl-2 (or its BH4 domain) was sensitive to IP and adenophostin A, ligands of the IPR. Vice versa, the BH4 domain of Bcl-2 counteracted the binding of IP to the LBD. Collectively, our work reveals a novel mechanism by which Bcl-2 influences IPR activity at the level of the LBD. This allows for exquisite modulation of Bcl-2's inhibitory properties on IPRs that is tunable to the level of IP signaling in cells.
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http://dx.doi.org/10.1007/s00018-019-03091-8DOI Listing
October 2019

Calcium signaling in health, disease and therapy.

Biochim Biophys Acta Mol Cell Res 2018 11 30;1865(11 Pt B):1657-1659. Epub 2018 Aug 30.

KU Leuven, Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut, Campus Gasthuisberg O/N-1 B-802, Herestraat 49, BE-3000 Leuven, Belgium. Electronic address:

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http://dx.doi.org/10.1016/j.bbamcr.2018.08.019DOI Listing
November 2018

The emerging interrelation between ROCO and related kinases, intracellular Ca signaling, and autophagy.

Biochim Biophys Acta Mol Cell Res 2019 07 21;1866(7):1054-1067. Epub 2018 Dec 21.

KU Leuven, Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut, Campus Gasthuisberg O/N-1 B-802, Herestraat 49, BE-3000 Leuven, Belgium. Electronic address:

ROCO kinases form a family of proteins characterized by kinase activity in addition to the presence of the so-called ROC (Ras of complex proteins)/COR (C-terminal of ROC) domains having a role in their GTPase activity. These are the death-associated protein kinase (DAPK) 1 and the leucine-rich repeat kinases (LRRK) 1 and 2. These kinases all play roles in cellular life and death decisions and in autophagy in particular. Related to the ROCO kinases is DAPK 2 that however cannot be classified as a ROCO protein due to the absence of the ROC/COR domains. This review aims to bring together what is known about the relation between these proteins and intracellular Ca signals in the induction and regulation of autophagy. Interestingly, DAPK 1 and 2 and LRRK2 are all linked to Ca signaling in their effects on autophagy, though in various ways. Present evidence supports an upstream role for LRRK2 that via lysosomal and endoplasmic reticulum Ca release can trigger autophagy induction. In contrast herewith, DAPK1 and 2 react on existing Ca signals to stimulate the autophagic pathway. Further research will be needed for obtaining a full understanding of the role of these various kinases in autophagy and to assess their exact relation with intracellular Ca signaling as this would be helpful in the development of novel therapeutic strategies against neurodegenerative disorders, cancer and auto-immune diseases. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech.
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http://dx.doi.org/10.1016/j.bbamcr.2018.12.008DOI Listing
July 2019

The ER Stress Inducer l-Azetidine-2-Carboxylic Acid Elevates the Levels of Phospho-eIF2α and of LC3-II in a Ca-Dependent Manner.

Cells 2018 Nov 30;7(12). Epub 2018 Nov 30.

Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut, KU Leuven, Campus Gasthuisberg O/N-1 B-802, Herestraat 49, BE-3000 Leuven, Belgium.

Accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to reduce protein load and restore homeostasis, including via induction of autophagy. We used the proline analogue l-azetidine-2-carboxylic acid (AZC) to induce ER stress, and assessed its effect on autophagy and Ca homeostasis. Treatment with 5 mM AZC did not induce poly adenosine diphosphate ribose polymerase (PARP) cleavage while levels of binding immunoglobulin protein (BiP) and phosphorylated eukaryotic translation initiation factor 2α (eIF2α) increased and those of activating transcription factor 6 (ATF6) decreased, indicating activation of the protein kinase RNA-like ER kinase (PERK) and the ATF6 arms of the UPR but not of apoptosis. AZC treatment in combination with bafilomycin A1 (Baf A1) led to elevated levels of the lipidated form of the autophagy marker microtubule-associated protein light chain 3 (LC3), pointing to activation of autophagy. Using the specific PERK inhibitor AMG PERK 44, we could deduce that activation of the PERK branch is required for the AZC-induced lipidation of LC3. Moreover, both the levels of phospho-eIF2α and of lipidated LC3 were strongly reduced when cells were co-treated with the intracellular Ca chelator 1,2-bis(-aminophenoxy)ethane-,,,-tetraaceticacid tetra(acetoxy-methyl) ester (BAPTA-AM) but not when co-treated with the Na⁺/K⁺ ATPase inhibitor ouabain, suggesting an essential role of Ca in AZC-induced activation of the PERK arm of the UPR and LC3 lipidation. Finally, AZC did not trigger Ca release from the ER though appeared to decrease the cytosolic Ca rise induced by thapsigargin while also decreasing the time constant for Ca clearance. The ER Ca store content and mitochondrial Ca uptake however remained unaffected.
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http://dx.doi.org/10.3390/cells7120239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316609PMC
November 2018

Extracellular and ER-stored Ca contribute to BIRD-2-induced cell death in diffuse large B-cell lymphoma cells.

Cell Death Discov 2018 2;4:101. Epub 2018 Nov 2.

1Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven and Leuven Kanker Instituut, Leuven, 3000 Belgium.

The anti-apoptotic protein Bcl-2 is upregulated in several cancers, including diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). In a subset of these cancer cells, Bcl-2 blocks Ca-mediated apoptosis by suppressing the function of inositol 1,4,5-trisphosphate (IP) receptors (IPRs) located at the endoplasmic reticulum (ER). A peptide tool, called Bcl-2/IP receptor disruptor-2 (BIRD-2), was developed to disrupt Bcl-2/IPR complexes, triggering pro-apoptotic Ca signals and killing Bcl-2-dependent cancer cells. In DLBCL cells, BIRD-2 sensitivity depended on the expression level of IPR2 channels and constitutive IP signaling downstream of the B-cell receptor. However, other cellular pathways probably also contribute to BIRD-2-provoked cell death. Here, we examined whether BIRD-2-induced apoptosis depended on extracellular Ca and more particularly on store-operated Ca entry (SOCE), a Ca-influx pathway activated upon ER-store depletion. Excitingly, DPB162-AE, a SOCE inhibitor, suppressed BIRD-2-induced cell death in DLBCL cells. However, DPB162-AE not only inhibits SOCE but also depletes the ER Ca store. Treatment of the cells with YM-58483 and GSK-7975A, two selective SOCE inhibitors, did not protect against BIRD-2-induced apoptosis. Similar data were obtained by knocking down STIM1 using small interfering RNA. Yet, extracellular Ca contributed to BIRD-2 sensitivity in DLBCL, since the extracellular Ca buffer ethylene glycol tetraacetic acid (EGTA) blunted BIRD-2-triggered apoptosis. The protective effects observed with DPB162-AE are likely due to ER Ca-store depletion, since a similar protective effect could be obtained using the sarco/endoplasmic reticulum Ca-ATPase inhibitor thapsigargin. Thus, both the ER Ca-store content and extracellular Ca, but not SOCE, are critical factors underlying BIRD-2-provoked cell death.
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http://dx.doi.org/10.1038/s41420-018-0118-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214954PMC
November 2018

The multifaceted STAT3: How a transcription factor regulates Ca signaling via a degradative pathway.

Authors:
Jan B Parys

Cell Calcium 2018 12 12;76:137-139. Epub 2018 Oct 12.

KU Leuven, Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut, Campus Gasthuisberg O/N-1 B-802, Herestraat 49, BE-3000 Leuven, Belgium. Electronic address:

STAT3 is a pleiotropic prosurvival transcription factor with functions in nucleus and mitochondria. Avalle et al. (Cell Death Diff., 2018) now present evidence that STAT3 also promotes IPR3 degradation at the endoplasmic reticulum, thereby limiting Ca transfer to the mitochondria and thus supporting cellular survival via an alternate pathway.
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http://dx.doi.org/10.1016/j.ceca.2018.10.002DOI Listing
December 2018

Nonlinear relationship between ER Ca depletion versus induction of the unfolded protein response, autophagy inhibition, and cell death.

Cell Calcium 2018 12 17;76:48-61. Epub 2018 Sep 17.

Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership for Molecular Medicine, University of Oslo, Norway. Electronic address:

Endoplasmic reticulum (ER) Ca depletion activates the unfolded protein response (UPR), inhibits bulk autophagy and eventually induces cell death in mammalian cells. However, the extent and duration of ER Ca depletion required is unknown. We instigated a detailed study in two different cell lines, using sarco/endoplasmic reticulum Ca-ATPase (SERCA) inhibitors to gradually reduce ER Ca levels in a controlled manner. Remarkably, UPR induction (as assessed by expression analyses of UPR-regulated proteins) and autophagy inhibition (as assessed by analyses of effects on starvation-induced bulk autophagy) required substantially higher drug concentrations than those needed to strongly decrease total ER Ca levels. In fact, even when ER Ca levels were so low that we could hardly detect any release of Ca upon challenge with ER Ca purging agents, UPR was not induced, and starvation-induced bulk autophagy was still fully supported. Moreover, although we observed reduced cell proliferation at this very low level of ER Ca, cells could tolerate prolonged periods (days) without succumbing to cell death. Addition of increasing concentrations of extracellular EGTA also gradually depleted the ER of Ca, and, as with the SERCA inhibitors, EGTA-induced activation of UPR and cell death required higher EGTA concentrations than those needed to strongly reduce ER Ca levels. We conclude that ER Ca depletion-induced effects on UPR, autophagy and cell death require either an extreme general depletion of ER Ca levels, or Ca depletion in areas of the ER that have a higher resistance to Ca drainage than the bulk of the ER.
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http://dx.doi.org/10.1016/j.ceca.2018.09.005DOI Listing
December 2018

Pathophysiological consequences of isoform-specific IP receptor mutations.

Biochim Biophys Acta Mol Cell Res 2018 11 12;1865(11 Pt B):1707-1717. Epub 2018 Jun 12.

KU Leuven, Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, Leuven Kanker Instituut, Campus Gasthuisberg O/N-1 B-802, Herestraat 49, BE-3000 Leuven, Belgium. Electronic address:

Ca signaling governs a diverse range of cellular processes and, as such, is subject to tight regulation. A main component of the complex intracellular Ca-signaling network is the inositol 1,4,5-trisphosphate (IP) receptor (IPR), a tetrameric channel that mediates Ca release from the endoplasmic reticulum (ER) in response to IP. IPR function is controlled by a myriad of factors, such as Ca, ATP, kinases and phosphatases and a plethora of accessory and regulatory proteins. Further complexity in IPR-mediated Ca signaling is the result of the existence of three main isoforms (IPR1, IPR2 and IPR3) that display distinct functional characteristics and properties. Despite their abundant and overlapping expression profiles, IPR1 is highly expressed in neurons, IPR2 in cardiomyocytes and hepatocytes and IPR3 in rapidly proliferating cells as e.g. epithelial cells. As a consequence, dysfunction and/or dysregulation of IPR isoforms will have distinct pathophysiological outcomes, ranging from neurological disorders for IPR1 to dysfunctional exocrine tissues and autoimmune diseases for IPR2 and -3. Over the past years, several IPR mutations have surfaced in the sequence analysis of patient-derived samples. Here, we aimed to provide an integrative overview of the clinically most relevant mutations for each IPR isoform and the subsequent molecular mechanisms underlying the etiology of the disease.
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http://dx.doi.org/10.1016/j.bbamcr.2018.06.004DOI Listing
November 2018

Constitutive IP signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP receptor disruptor BIRD-2.

Cell Death Differ 2019 03 13;26(3):531-547. Epub 2018 Jun 13.

Lab. Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine and Leuven Kanker Instituut, KU Leuven, Leuven, Belgium.

Anti-apoptotic Bcl-2 proteins are upregulated in different cancers, including diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL), enabling survival by inhibiting pro-apoptotic Bcl-2-family members and inositol 1,4,5-trisphosphate (IP) receptor (IPR)-mediated Ca-signaling. A peptide tool (Bcl-2/IPR Disruptor-2; BIRD-2) was developed to abrogate the interaction of Bcl-2 with IPRs by targeting Bcl-2's BH4 domain. BIRD-2 triggers cell death in primary CLL cells and in DLBCL cell lines. Particularly, DLBCL cells with high levels of IPR2 were sensitive to BIRD-2. Here, we report that BIRD-2-induced cell death in DLBCL cells does not only depend on high IPR2-expression levels, but also on constitutive IP signaling, downstream of the tonically active B-cell receptor. The basal Ca level in SU-DHL-4 DLBCL cells was significantly elevated due to the constitutive IP production. This constitutive IP signaling fulfilled a pro-survival role, since inhibition of phospholipase C (PLC) using U73122 (2.5 µM) caused cell death in SU-DHL-4 cells. Milder inhibition of IP signaling using a lower U73122 concentration (1 µM) or expression of an IP sponge suppressed both BIRD-2-induced Ca elevation and apoptosis in SU-DHL-4 cells. Basal PLC/IP signaling also fulfilled a pro-survival role in other DLBCL cell lines, including Karpas 422, RI-1 and SU-DHL-6 cells, whereas PLC inhibition protected these cells against BIRD-2-evoked apoptosis. Finally, U73122 treatment also suppressed BIRD-2-induced cell death in primary CLL, both in unsupported systems and in co-cultures with CD40L-expressing fibroblasts. Thus, constitutive IP signaling in lymphoma and leukemia cells is not only important for cancer cell survival, but also represents a vulnerability, rendering cancer cells dependent on Bcl-2 to limit IPR activity. BIRD-2 seems to switch constitutive IP signaling from pro-survival into pro-death, presenting a plausible therapeutic strategy.
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http://dx.doi.org/10.1038/s41418-018-0142-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370760PMC
March 2019

A critical appraisal of the role of intracellular Ca-signaling pathways in Kawasaki disease.

Cell Calcium 2018 05 3;71:95-103. Epub 2018 Feb 3.

KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, B-3000 Leuven, Belgium. Electronic address:

Kawasaki disease is a multi-systemic vasculitis that generally occurs in children and that can lead to coronary artery lesions. Recent studies showed that Kawasaki disease has an important genetic component. In this review, we discuss the single-nucleotide polymorphisms in the genes encoding proteins with a role in intracellular Ca signaling: inositol 1,4,5-trisphosphate 3-kinase C, caspase-3, the store-operated Ca-entry channel ORAI1, the type-3 inositol 1,4,5-trisphosphate receptor, the Na/Ca exchanger 1, and phospholipase Cß4 and Cß1. An increase of the free cytosolic Ca concentration is proposed to be a major factor in susceptibility to Kawasaki disease and disease outcome, but only for polymorphisms in the genes encoding the inositol 1,4,5-trisphosphate 3-kinase C and the Na/Ca exchanger 1, the free cytosolic Ca concentration was actually measured and shown to be increased. Excessive cytosolic Ca signaling can result in hyperactive calcineurin in T cells with an overstimulated nuclear factor of activated T cells pathway, in hypersecretion of interleukin-1ß and tumor necrosis factor-α by monocytes/macrophages, in increased urotensin-2 signaling, and in an overactivation of vascular endothelial cells.
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http://dx.doi.org/10.1016/j.ceca.2018.01.002DOI Listing
May 2018
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