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Emerging Roles of the Single EF-Hand Ca2+ Sensor Tescalcin in the Regulation of Gene Expression, Cell Growth and Differentiation Ksenia G

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Emerging Roles of the Single EF-Hand Ca2+ Sensor Tescalcin in the Regulation of Gene Expression, Cell Growth and Differentiation Ksenia G © 2017. Published by The Company of Biologists Ltd | Journal of Cell Science (2017) 130, 521 doi:10.1242/jcs.200378 CORRECTION Correction: Emerging roles of the single EF-hand Ca2+ sensor tescalcin in the regulation of gene expression, cell growth and differentiation Ksenia G. Kolobynina, Valeria V. Solovyova, Konstantin Levay, Albert A. Rizvanov and Vladlen Z. Slepak There was an error published in J. Cell Sci. 129, 3533–3540. Incorrect language was used in the Commentary that concerns the apparent controversy between the results of tescalcin knockdown in hematopoietic precursor cell lines and its gene knockout in mice reported by Ukarapong et al. (2012). In the Commentary, the wording is as follows: “To explain the conflicting data, the authors [Ukarapong et al.] speculate that CHP1 and/or CHP2 could compensate for the lack of tescalcin, or that their genetic knockout was incomplete and allowed for the expression of a partial protein (Ukarapong et al., 2012)”. This gives the impression that Ukarapong et al. themselves argued about the incomplete knockout. The wording should read: “To explain the conflicting data, the authors [Ukarapong et al.] speculate that CHP1 and/or CHP2 could compensate for the lack of tescalcin (Ukarapong et al., 2012). Another possibility can be associated with the presence of a transcript corresponding to exons 1, 2, 7 and 8 of the TESC gene in the knockout mouse tissues detected by Ukarapong et al. Although unlikely, this finding leaves a formal possibility for this mRNA to be translated into a product with residual functional activity”. The authors of the Commentary apologize to Ukarapong et al. and to the readers of Journal of Cell Science for any confusion that this error may have caused. Reference Ukarapong, S., Bao, Y., Perera, E. M. and Berkovitz, G. D. (2012). Megakaryocyte development is normal in mice with targeted disruption of Tescalcin. Exp. Cell Res. 318, 662-669. Journal of Cell Science 521 © 2016. Published by The Company of Biologists Ltd | Journal of Cell Science (2016) 129, 3533-3540 doi:10.1242/jcs.191486 COMMENTARY Emerging roles of the single EF-hand Ca2+ sensor tescalcin in the regulation of gene expression, cell growth and differentiation Ksenia G. Kolobynina1, Valeria V. Solovyova1, Konstantin Levay2, Albert A. Rizvanov1 and Vladlen Z. Slepak2,* ABSTRACT tescalcin extends the duration of transient Ca2+ signals are expected Tescalcin (TESC, also known as calcineurin-homologous protein 3, to provide new insights into the graded signaling mechanisms that CHP3) is a 24-kDa EF-hand Ca2+-binding protein that has recently underlie development. Са2+ emerged as a regulator of cell differentiation and growth. The TESC Tescalcin belongs to a large family of -binding proteins that gene has also been linked to human brain abnormalities, and high contain the EF-hand, a structural motif annotated for the first time in expression of tescalcin has been found in several cancers. The 1973 in parvalbumin (Kretsinger and Nockolds, 1973; Mikhaylova expression level of tescalcin changes dramatically during development et al., 2011; Zhou et al., 2013). The canonical EF-hand consists of a Са2+ and upon signal-induced cell differentiation. Recent studies have -binding loop that contains 12 highly conserved residues shown that tescalcin is not only subjected to up- or down-regulation, but flanked by two helices, named as E and F, respectively. There are also has an active role in pathways that drive cell growth and also four types of non-canonical EF-hands that have insertions, differentiation programs. At the molecular level, there is compelling deletions or substitutions that fine-tune divalent cation coordination experimental evidence showing that tescalcin can directly interact with (Gifford et al., 2007; Lewit-Bentley and Réty, 2000). The and regulate the activities of the Na+/H+ exchanger NHE1, subunit 4 of superfamily of EF-hand proteins is divided into two groups. The Са2+ the COP9 signalosome (CSN4) and protein kinase glycogen-synthase first group has a -binding affinity of below 100 nM and does Са2+ kinase 3 (GSK3). In hematopoetic precursor cells, tescalcin has been not undergo major -induced conformational changes; these Са2+ Са2+ Са2+ shown to couple activation of the extracellular signal-regulated kinase -binding proteins are referred to as buffers or (ERK) cascade to the expression of transcription factors that control cell modulators (e.g. parvalbumin and calbindin). The second group is Са2+ Са2+ differentiation. The purpose of this Commentary is to summarize recent known as -sensors. These -sensing proteins have evolved Са2+ −5– −6 М efforts that have served to characterize the biochemical, genetic and to bind within the 10 10 range and typically exhibit Са2+ physiological attributes of tescalcin, and its unique role in the regulation -induced conformational changes that influence their of various cellular functions. interaction with target proteins (da Silva and Reinach, 1991; Bhattacharya et al., 2004). An archetypal Са2+ sensor is calmodulin, KEY WORDS: CHP3, COP9, GSK3, NHE1, Differentiation, Tescalcin which has four EF-hands and regulates a plethora of effectors (Clapham, 2007). Although Са2+ sensors regulate the activities of Introduction ion channels and enzymes, Са2+ buffers modulate the amplitude The role of Са2+ as a universal second messenger often depends on and kinetics of free Са2+ transients and maintain Са2+ homeostasis. Ca2+-binding proteins, which regulate the activities of enzymes, ion For example, Са2+ buffers keep the concentration of free Са2+ below channels and other proteins that allow cells to respond to the levels that would induce cell death (Christakos and Liu, 2004; fluctuations in the concentration of free intracellular Ca2+. The D’Orlando et al., 2001; Kook et al., 2014). Because the affinity of literature on Ca2+ sensing and signaling is rich, with many excellent tescalcin for Ca2+ is in the micromolar range (Gutierrez-Ford et al., reviews on the physiological role of Ca2+ and information on 2003), it is thought to be a Са2+-sensor. hundreds of Ca2+-binding proteins (see e.g. Clapham, 2007; Zhou In this article, we summarize the current insights into cellular et al., 2013). This Commentary draws attention to the relatively functions of tescalcin, focusing on its unique biochemical properties unknown Ca2+-sensor tescalcin, which was discovered as a gene and binding partners identified to date, namely, the Na+/H+ (TESC) that is differentially expressed in the development of exchanger NHE1, glycogen synthase kinase 3 (GSK3) and the embryonic mouse testis (Perera et al., 2001). Subsequent COP9 signalosome. We also discuss its potential physiological role investigations revealed broader expression patterns of TESC, and and the potential association of TESC gene mutations with human have illuminated its crucial role in several important cellular pathologies. pathways. Tescalcin is an unusual Ca2+-sensor in that it regulates relatively slow physiological processes such as cell differentiation. Structural features and metal-binding properties of tescalcin In contrast, most other Ca2+-sensors are associated with rapid Tescalcin contains only one canonical EF-hand motif in its events, such as muscle contraction or neurotransmitter release C-terminal half (amino acids 113–142) (Fig. 1). It also has three (Clapham, 2007; Zhou et al., 2013). Thus, efforts to understand how additional putative helix-loop-helix motifs that have likely evolved from EF-hands, but because of substitutions of crucial residues 1Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, and insertions, their similarity to the canonical EF-hand is too low Republic of Tatarstan, 420000, Russian Federation. 2Department of Molecular and to support chelation of Ca2+ (Gutierrez-Ford et al., 2003). Single Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. EF-hand proteins are very rare (Day et al., 2002; Huang et al., 2009; Mochizuki et al., 1996), and in most proteins these domains *Author for correspondence ([email protected]) are paired, which allows them to bind Ca2+ with higher affinity. K.G.K., 0000-0002-8035-8867; V.V.S., 0000-0002-8776-3662; K.L., 0000-0001- Proteins with an odd number of EF-hand domains are known to 9809-8891; A.A.R., 0000-0002-9427-5739; V.Z.S., 0000-0001-5397-7155 dimerize, so that the non-paired EF-hands of the two subunits Journal of Cell Science 3533 COMMENTARY Journal of Cell Science (2016) 129, 3533-3540 doi:10.1242/jcs.191486 N-myristoylation Fig. 1. Sequences of tescalcin and its close homologs. EF-hand 1 Shown here are the amino acid sequences human tescalcin CnB 1 MGNEASYPLEMCS--------HFDADEIKRLGKRFKKLDLDNSGSLSVEEFM (Genbank Accession Number AAL35615.1) with CHP1 CHP1 1 MGSRASTLLRDEELEEIKKETGFSHSQITRLYSRFTSLDKGENGTLSREDFQ (NP_009167), CHP2 (NP_071380.1) and calcineurin B (CnB, CHP2 1 MGSRSSHAAVIPDGDSIRRETGFSQASLLRLHHRFRALDRNKKGYLSRMDLQ AAB08721.1). Sequence alignment was performed using TESC 1 MGAAHSASEEVRELEG---KTGFSSDQIEQLHRRFKQLS-GDQPTIRKENFN ClustalW, with BoxShage 3.21 for presentation. Identical amino acids are shown in dark green; homologous residues EF-hand 2 are in teal. The four active EF-hand domains in CnB are denoted by blue brackets and are numbered. The solid CnB 45 SLPELQQNPLVQRVIDIFDTDG---------NGEVDFKEFIEGVSQFSVKGD bracket surrounding the canonical EF-hand 3 indicates that it CHP1 53 RIPELAINPLGDRIINAFFPEG---------EDQVNFRGFMRTLAHFRPIED is active in tescalcin. The red arrow
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