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Dive into the research topics where Jan B. Parys is active.

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Featured researches published by Jan B. Parys.


Journal of Cell Biology | 2001

Functional specialization of calreticulin domains

Kimitoshi Nakamura; Anna Zuppini; Serge Arnaudeau; Jeffery Lynch; Irfan Ahsan; Ryoko Krause; Sylvia Papp; Humbert De Smedt; Jan B. Parys; Werner Müller-Esterl; Daniel Pablo Lew; Karl-Heinz Krause; Nicolas Demaurex; Michal Opas; Marek Michalak

Calreticulin is a Ca2+-binding chaperone in the endoplasmic reticulum (ER), and calreticulin gene knockout is embryonic lethal. Here, we used calreticulin-deficient mouse embryonic fibroblasts to examine the function of calreticulin as a regulator of Ca2+ homeostasis. In cells without calreticulin, the ER has a lower capacity for Ca2+ storage, although the free ER luminal Ca2+ concentration is unchanged. Calreticulin-deficient cells show inhibited Ca2+ release in response to bradykinin, yet they release Ca2+ upon direct activation with the inositol 1,4,5-trisphosphate (InsP3). These cells fail to produce a measurable level of InsP3 upon stimulation with bradykinin, likely because the binding of bradykinin to its cell surface receptor is impaired. Bradykinin binding and bradykinin-induced Ca2+ release are both restored by expression of full-length calreticulin and the N + P domain of the protein. Expression of the P + C domain of calreticulin does not affect bradykinin-induced Ca2+ release but restores the ER Ca2+ storage capacity. Our results indicate that calreticulin may play a role in folding of the bradykinin receptor, which affects its ability to initiate InsP3-dependent Ca2+ release in calreticulin-deficient cells. We concluded that the C domain of calreticulin plays a role in Ca2+ storage and that the N domain may participate in its chaperone functions.


Cold Spring Harbor Perspectives in Biology | 2011

Endoplasmic-Reticulum Calcium Depletion and Disease

Djalila Mekahli; Geert Bultynck; Jan B. Parys; Humbert De Smedt; Ludwig Missiaen

The endoplasmic reticulum (ER) as an intracellular Ca(2+) store not only sets up cytosolic Ca(2+) signals, but, among other functions, also assembles and folds newly synthesized proteins. Alterations in ER homeostasis, including severe Ca(2+) depletion, are an upstream event in the pathophysiology of many diseases. On the one hand, insufficient release of activator Ca(2+) may no longer sustain essential cell functions. On the other hand, loss of luminal Ca(2+) causes ER stress and activates an unfolded protein response, which, depending on the duration and severity of the stress, can reestablish normal ER function or lead to cell death. We will review these various diseases by mainly focusing on the mechanisms that cause ER Ca(2+) depletion.


Proceedings of the National Academy of Sciences of the United States of America | 2009

The BH4 domain of Bcl-2 inhibits ER calcium release and apoptosis by binding the regulatory and coupling domain of the IP3 receptor

Yi Ping Rong; Geert Bultynck; Ademuyiwa S. Aromolaran; Fei Zhong; Jan B. Parys; Humbert De Smedt; Gregory A. Mignery; H. Llewelyn Roderick; Martin D. Bootman; Clark W. Distelhorst

Although the presence of a BH4 domain distinguishes the antiapoptotic protein Bcl-2 from its proapoptotic relatives, little is known about its function. BH4 deletion converts Bcl-2 into a proapoptotic protein, whereas a TAT-BH4 fusion peptide inhibits apoptosis and improves survival in models of disease due to accelerated apoptosis. Thus, the BH4 domain has antiapoptotic activity independent of full-length Bcl-2. Here we report that the BH4 domain mediates interaction of Bcl-2 with the inositol 1,4,5-trisphosphate (IP3) receptor, an IP3-gated Ca2+ channel on the endoplasmic reticulum (ER). BH4 peptide binds to the regulatory and coupling domain of the IP3 receptor and inhibits IP3-dependent channel opening, Ca2+ release from the ER, and Ca2+-mediated apoptosis. A peptide inhibitor of Bcl-2-IP3 receptor interaction prevents these BH4-mediated effects. By inhibiting proapoptotic Ca2+ signals at their point of origin, the Bcl-2 BH4 domain has the facility to block diverse pathways through which Ca2+ induces apoptosis.


Proceedings of the National Academy of Sciences of the United States of America | 2008

Phosphorylation of inositol 1,4,5-trisphosphate receptors by protein kinase B/Akt inhibits Ca2+ release and apoptosis

Tania Szado; Veerle Vanderheyden; Jan B. Parys; Humbert De Smedt; Katja Rietdorf; Larissa Kotelevets; Eric Chastre; Farid Khan; Ulf Landegren; Ola Söderberg; Martin D. Bootman; H. Llewelyn Roderick

Imbalance of signals that control cell survival and death results in pathologies, including cancer and neurodegeneration. Two pathways that are integral to setting the balance between cell survival and cell death are controlled by lipid-activated protein kinase B (PKB)/Akt and Ca2+. PKB elicits its effects through the phosphorylation and inactivation of proapoptotic factors. Ca2+ stimulates many prodeath pathways, among which is mitochondrial permeability transition. We identified Ca2+ release through inositol 1,4,5-trisphosphate receptor (InsP3R) intracellular channels as a prosurvival target of PKB. We demonstrated that in response to survival signals, PKB interacts with and phosphorylates InsP3Rs, significantly reducing their Ca2+ release activity. Moreover, phosphorylation of InsP3Rs by PKB reduced cellular sensitivity to apoptotic stimuli through a mechanism that involved diminished Ca2+ flux from the endoplasmic reticulum to the mitochondria. In glioblastoma cells that exhibit hyperactive PKB, the same prosurvival effect of PKB on InsP3R was found to be responsible for the insensitivity of these cells to apoptotic stimuli. We propose that PKB-mediated abolition of InsP3-induced Ca2+ release may afford tumor cells a survival advantage.


Biology of the Cell | 2004

Subcellular distribution of the inositol 1,4,5-trisphosphate receptors: functional relevance and molecular determinants.

Elke Vermassen; Jan B. Parys; Jean-Pierre Mauger

Abstract The inositol 1,4,5‐trisphosphate receptor (IP3R) is an intracellular Ca2+ channel that is for the largest part expressed in the endoplasmic reticulum. Its precise subcellular localization is an important factor for the correct initiation and propagation of Ca2+ signals. The relative position of the IP3Rs, and thus of the IP3‐sensitive Ca2+ stores, to mitochondria, nucleus or plasma membrane determines in many cases the physiological consequences of IP3‐induced Ca2+ release. Most cell types express more than one IP3R isoform and their subcellular distribution is cell‐type dependent. Moreover, it was recently demonstrated that depending on the physiological status of the cell redistribution of IP3Rs and/or of IP3‐sensitive Ca2+ stores could occur. This indicates that the cell must be able to regulate not only IP3R expression but also its distribution. The various proteins potentially determining IP3R localization and redistribution will therefore be discussed.


Cell Calcium | 2011

A dual role for Ca(2+) in autophagy regulation.

Jean-Paul Decuypere; Geert Bultynck; Jan B. Parys

Autophagy is a cellular process responsible for delivery of proteins or organelles to lysosomes. It participates not only in maintaining cellular homeostasis, but also in promoting survival during cellular stress situations. It is now well established that intracellular Ca(2+) is one of the regulators of autophagy. However, this control of autophagy by intracellular Ca(2+) signaling is the subject of two opposite views. On the one hand, the available evidence indicates that intracellular Ca(2+) signals, and mainly inositol 1,4,5-trisphosphate receptors (IP(3)Rs), suppress autophagy. On the other hand, elevated cytosolic Ca(2+) concentrations ([Ca(2+)](cyt)) were also shown to promote the autophagic process. Here, we will provide a critical overview of the literature and discuss both hypotheses. Moreover, we will suggest a model explaining how changes in intracellular Ca(2+) signaling can lead to opposite outcomes, depending on the cellular state.


The EMBO Journal | 2004

Regulation of InsP3 receptor activity by neuronal Ca2+‐binding proteins

Nael Nadif Kasri; Anthony M. Holmes; Geert Bultynck; Jan B. Parys; Martin D. Bootman; Katja Rietdorf; Ludwig Missiaen; Fraser McDonald; Humbert De Smedt; Stuart J. Conway; Andrew B. Holmes; Michael J. Berridge; H. Llewelyn Roderick

Inositol 1,4,5‐trisphosphate receptors (InsP3Rs) were recently demonstrated to be activated independently of InsP3 by a family of calmodulin (CaM)‐like neuronal Ca2+‐binding proteins (CaBPs). We investigated the interaction of both naturally occurring long and short CaBP1 isoforms with InsP3Rs, and their functional effects on InsP3R‐evoked Ca2+ signals. Using several experimental paradigms, including transient expression in COS cells, acute injection of recombinant protein into Xenopus oocytes and 45Ca2+ flux from permeabilised COS cells, we demonstrated that CaBPs decrease the sensitivity of InsP3‐induced Ca2+ release (IICR). In addition, we found a Ca2+‐independent interaction between CaBP1 and the NH2‐terminal 159 amino acids of the type 1 InsP3R. This interaction resulted in decreased InsP3 binding to the receptor reminiscent of that observed for CaM. Unlike CaM, however, CaBPs do not inhibit ryanodine receptors, have a higher affinity for InsP3Rs and more potently inhibited IICR. We also show that phosphorylation of CaBP1 at a casein kinase 2 consensus site regulates its inhibition of IICR. Our data suggest that CaBPs are endogenous regulators of InsP3Rs tuning the sensitivity of cells to InsP3.


Cell Calcium | 2010

Intracellular Ca2+ storage in health and disease: A dynamic equilibrium

Eva Sammels; Jan B. Parys; Ludwig Missiaen; Humbert De Smedt; Geert Bultynck

Homeostatic control of the endoplasmic reticulum (ER) both as the site for protein handling (synthesis, folding, trafficking, disaggregation and degradation) and as a Ca2+ store is of crucial importance for correct functioning of the cell. Disturbance of the homeostatic control mechanisms leads to a vast array of severe pathologies. The Ca2+ content of the ER is a dynamic equilibrium between active uptake via Ca2+ pumps and Ca2+ release by a number of highly regulated Ca2+-release channels. Regulation of the Ca2+-release channels is very complex and several mechanisms are still poorly understood or controversial. There is increasing evidence that a number of unrelated proteins, either by themselves or in association with other Ca2+ channels, can provide additional Ca2+-leak pathways. The ER is a dynamic organelle and changes in its size and components have been described, either as a result of (de)differentiation processes affecting the secretory capacity of cells, or as a result of adaptation mechanisms to diverse stress conditions such as the unfolded protein response and autophagy. In this review we want to give an overview of the current knowledge of the (short-term) regulatory mechanisms that affect Ca2+-release and Ca2+-leak pathways and of the (long-term) adaptations in ER size and capacity. Understanding of the consequences of these mechanisms for cellular Ca2+ signaling could provide a huge therapeutic potential.


Biochimica et Biophysica Acta | 2009

Regulation of inositol 1,4,5-trisphosphate-induced Ca2+ release by reversible phosphorylation and dephosphorylation

Veerle Vanderheyden; Benoit Devogelaere; Ludwig Missiaen; Humbert De Smedt; Geert Bultynck; Jan B. Parys

The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) is a universal intracellular Ca2+-release channel. It is activated after cell stimulation and plays a crucial role in the initiation and propagation of the complex spatio-temporal Ca2+ signals that control cellular processes as different as fertilization, cell division, cell migration, differentiation, metabolism, muscle contraction, secretion, neuronal processing, and ultimately cell death. To achieve these various functions, often in a single cell, exquisite control of the Ca2+ release is needed. This review aims to highlight how protein kinases and protein phosphatases can interact with the IP3R or with associated proteins and so provide a large potential for fine tuning the Ca2+-release activity and for creating efficient Ca2+ signals in subcellular microdomains.


Journal of Biological Chemistry | 1997

Molecular and Functional Evidence for Multiple Ca2+-binding Domains in the Type 1 Inositol 1,4,5-Trisphosphate Receptor

Ilse Sienaert; Ludwig Missiaen; Humbert De Smedt; Jan B. Parys; Henk Sipma; Rik Casteels

Structural and functional analyses were used to investigate the regulation of the inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R) by Ca2+. To define the structural determinants for Ca2+ binding, cDNAs encoding GST fusion proteins that covered the complete linear cytosolic sequence of the InsP3R-1 were expressed in bacteria. The fusion proteins were screened for Ca2+ and ruthenium red binding through the use of 45Ca2+ and ruthenium red overlay procedures. Six new cytosolic Ca2+-binding regions were detected on the InsP3R in addition to the one described earlier (Sienaert, I., De Smedt, H., Parys, J. B., Missiaen, L., Vanlingen, S., Sipma, H., and Casteels, R. (1996)J. Biol. Chem. 271, 27005–27012). Strong45Ca2+ and ruthenium red binding domains were localized in the N-terminal region of the InsP3R as follows: two Ca2+-binding domains were located within the InsP3-binding domain, and three Ca2+ binding stretches were localized in a 500-amino acid region just downstream of the InsP3-binding domain. A sixth Ca2+-binding stretch was detected in the proximity of the calmodulin-binding domain. Evidence for the involvement of multiple Ca2+-binding sites in the regulation of the InsP3R was obtained from functional studies on permeabilized A7r5 cells, in which we characterized the effects of Ca2+ and Sr2+ on the EC50 and cooperativity of the InsP3-induced Ca2+ release. The activation by cytosolic Ca2+was due to a shift in EC50 toward lower InsP3concentrations, and this effect was mimicked by Sr2+. The inhibition by cytosolic Ca2+ was caused by a decrease in cooperativity and by a shift in EC50 toward higher InsP3 concentrations. The effect on the cooperativity occurred at lower Ca2+ concentrations than the inhibitory effect on the EC50. In addition, Sr2+ mimicked the effect of Ca2+ on the cooperativity but not the inhibitory effect on the EC50. The different [Ca2+] and [Sr2+] dependencies suggest that three different cytosolic interaction sites were involved. Luminal Ca2+ stimulated the release without affecting the Hill coefficient or the EC50, excluding the involvement of one of the cytosolic Ca2+-binding sites. We conclude that multiple Ca2+-binding sites are localized on the InsP3R-1 and that at least four different Ca2+-interaction sites may be involved in the complex feedback regulation of the release by Ca2+.

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Ludwig Missiaen

Katholieke Universiteit Leuven

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Humbert De Smedt

Katholieke Universiteit Leuven

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Geert Callewaert

Katholieke Universiteit Leuven

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H De Smedt

Katholieke Universiteit Leuven

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Ilse Sienaert

Katholieke Universiteit Leuven

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Rik Casteels

Katholieke Universiteit Leuven

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Tomas Luyten

Katholieke Universiteit Leuven

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Sara Vanlingen

Katholieke Universiteit Leuven

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Nael Nadif Kasri

Radboud University Nijmegen

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