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Store Operated Calcium Entry in Cell Migration and Cancer Metastasis

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Store Operated Calcium Entry in Cell Migration and Cancer Metastasis cells Review Store Operated Calcium Entry in Cell Migration and Cancer Metastasis Ayat S. Hammad 1,2 and Khaled Machaca 1,3,* 1 Calcium Signaling Group, Weill Cornell Medicine Qatar, Doha 24144, Qatar; [email protected] 2 College of Health and Life Science, Hamad bin Khalifa University, Doha 24144, Qatar 3 Department of Physiology and Biophysics, Weill Cornell Medicine Qatar, Education City, Qatar Foundation, Doha 24144, Qatar * Correspondence: [email protected]; Tel.: +974-5535-6504; Fax: +974-4492-8422 Abstract: Ca2+ signaling is ubiquitous in eukaryotic cells and modulates many cellular events including cell migration. Directional cell migration requires the polarization of both signaling and structural elements. This polarization is reflected in various Ca2+ signaling pathways that impinge on cell movement. In particular, store-operated Ca2+ entry (SOCE) plays important roles in regulating cell movement at both the front and rear of migrating cells. SOCE represents a predominant Ca2+ influx pathway in non-excitable cells, which are the primary migrating cells in multicellular organisms. In this review, we summarize the role of Ca2+ signaling in cell migration with a focus on SOCE and its diverse functions in migrating cells and cancer metastasis. SOCE has been implicated in regulating focal adhesion turnover in a polarized fashion and the mechanisms involved are beginning to be elucidated. However, SOCE is also involved is other aspects of cell migration with a less well- defined mechanistic understanding. Therefore, much remains to be learned regarding the role and regulation of SOCE in migrating cells. Keywords: cell migration; STIM1; orai1; store-operated Ca2+ entry; Ca2+ signaling; focal adhesions; Citation: Hammad, A.S.; Machaca, K. polarization; cancer; metastasis Store Operated Calcium Entry in Cell Migration and Cancer Metastasis. Cells 2021, 10, 1246. https://doi.org/ 10.3390/cells10051246 1. Introduction Cell migration is essential for the development of multicellular organisms and is Academic Editor: Isabella Derler critical for many physiological processes, including organ development, morphogenesis, tissue repair and homeostasis, immune response and wound healing [1]. It is also essential Received: 27 April 2021 for tumor metastasis to colonize remote sites, which is the main cause of death from can- Accepted: 18 May 2021 cers [2]. For adherent cells to move in a directional fashion multiple coordinated processes Published: 19 May 2021 need to occur, including extension of lamellipodia at the front of the cell, disassembly of focal adhesions at the rear of the migrating cell and force generation through cytoskele- Publisher’s Note: MDPI stays neutral ton attachments to the extracellular matrix (ECM) to pull the cell forward. These events with regard to jurisdictional claims in published maps and institutional affil- require a complex coordinated machinery that involves environmental cues, signaling and iations. cytoskeleton components, as well as focal adhesion remodeling among other mechanisms. Interestingly, many of these aspects are Ca2+ dependent, highlighting the critical role of Ca2+ signaling in regulating cell movement. In this review, we briefly outline the involve- ment of Ca2+ signaling in cell migration while focusing on the role of store-operated Ca2+ entry (SOCE). Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. 2. Cell Migration This article is an open access article distributed under the terms and Cell migration is a complex coordinated process that incorporates many cellular com- conditions of the Creative Commons ponents and responds to a plethora of environmental cues. Typically, those environmental Attribution (CC BY) license (https:// signals guide the directional migration of cells [1]. For a cell to move in a directional fashion creativecommons.org/licenses/by/ it needs to polarize, with membrane extensions (lamellipodia) at the front end that are later 4.0/). stabilized by nascent focal adhesions. Lamellipodia are driven by actin polymerization Cells 2021, 10, 1246. https://doi.org/10.3390/cells10051246 https://www.mdpi.com/journal/cells Cells 2021, 10, x FOR PEER REVIEW 2 of 20 Cells 2021, 10, 1246 2 of 19 fashion it needs to polarize, with membrane extensions (lamellipodia) at the front end that are later stabilized by nascent focal adhesions. Lamellipodia are driven by actin polymer- izationfollowed followed by attachment by attachment to the to extracellular the extracellular matrix matrix (ECM) (ECM) to allow to allow for force for force generation. gener- ation.Attachment Attachment is mediated is mediated by nascent by nascent adhesions, adhesions, which which further further mature mature through through interaction inter- actionwith thewith actin the cytoskeleton actin cytoskeleton and myosin and myosin mediated mediated force generation force generation (Figure1). (Figure At the rear1). At of thethe rear cell, of mature the cell focal, mature adhesions focal adhesions disassemble disassemble to allow theto allow cell body the cell to bebody pulled to be forward pulled forwardthus mediating thus mediating directional directional cell movement cell movement [3]. Focal [3] adhesions. Focal adhesions are large are dynamic large dynamic plasma plasmamembrane-associated membrane-associated macromolecular macromolecular assemblies assemblies that are rich that in are integrins, rich in andintegrins, connect and the connectactin cytoskeleton the actin cytoskeleton to the extracellular to the extracellular matrix [4]. The matrix dynamic [4]. regulationThe dynamic of focal regulation adhesions of focalis essential adhesions for successfulis essential cell for migration successful and cell is migration mediated and by Ca is 2+mediateddependent by Ca assembly2+ depend- and entdisassembly assembly and cycles disassembly [5,6], as will cycles be further [5,6], as discussed will be further below. discussed below. FigureFigure 1. Model 1. Model summarizing summarizing the polarization the polarization of various of various cytoskeletal cytoskeletal and Ca2+ and signaling Ca2+ signaling components components in a migrating in a migrating cell. Mature cell. focal adhesionsMature focal (FA), adhesions L-type voltage (FA), L-type-gated Ca2+ voltage-gated channels Ca2+(VGCC), channels ERM (Ezrin, (VGCC), Radixin ERM (Ezrin,and Moesin) Radixin proteins, and Moesin) as well proteins, as cortical as actin (Membranewell as cortical Proximal actin Actin (Membrane (MPA) Proximalare enriched Actin at the (MPA) rear areend enriched of the cell. at TRPM7 the rear and end the of theplasma cell. membrane TRPM7 and Ca the2+-ATPase plasma 2+ (PMCA)membrane are enriched Ca2+ at-ATPase the leading (PMCA) edge are of enriched the migrating at the cell. leading Store edge-operated of the migratingCa entry cell.(SOCE) Store-operated, which is mediated Ca2+ entry by (SOCE),STIM1 2+ and Orai1which have is mediated been functionally by STIM1 implicated and Orai1 in have disassembly been functionally of FA at implicatedthe rear end, in as disassembly well as in refilling of FA at Ca the rearstores end, at asthe well leading as in edge. See text for further details. The figure was created using BioRender.com. refilling Ca2+ stores at the leading edge. See text for further details. The figure was created using BioRender.com. TheThe actin actin cytoskeleton isis vital vital in in the the regulation regulation of focalof focal adhesions adhesions as well as well as in as generating in gen- eratingthe forces the requiredforces required for cell for migration. cell migration. In that context,In that context, actin dynamics actin dynamics are regulated are regulated by small byGTPases, small GTPases, including including Rac1, Cdc42 Rac1, and Cdc42 RhoA and [7]. RhoA Rac regulates [7]. Rac protrusive regulates forcesprotrusive in lamellipodia forces in lamellipodiathrough modulating through actinmodulating formation actin via formati actin nucleationon via actin complexes nucleation such complexes as SCAR/WAVE such as SCAR/WAVEand Arp2/3 [7 and,8]. Rho,Arp2/3 Rho-kinase [7,8]. Rho, and Rho Ca2+-kinase/calmodulin-activated and Ca2+/calmodulin myosin-light-activated chain myosin kinase- lightregulate chain actomyosin kinase regulate fibers contractionactomyosin that fibers cause contraction the retraction that ofcause the trailingthe retraction end of theof the cell trailingand its end netforward of the cell movement and its net [7,9 forwa]. Cdc42rd regulatesmovement cell [7,9] polarity. Cdc42 in migratingregulates cell cells polarity through ininteractions migrating withcells thethrough PAR complexinteractions and with the actin the cytoskeletonPAR complex [10 and,11 ].the actin cytoskeleton [10,11]Therefore,. the actin cytoskeleton through spatially controlled cycles of polymerization andTherefore, depolymerization the actin supportscytoskeleton membrane through deformation spatially controlled and force cycles generation of polymeriza- that are tionrequired and depolymerization for cell movement. supports In addition membrane to the actin deformation fibers that and crisscross force generation the cell, cells that form are requireda shell of for cortical cell movement. actin bundles In addition around to theirthe actin periphery. fibers that Cortical crisscross actin the directly cell, cells interacts form awith shell the of PMcortical through actin thebundles ERM proteinsaround their (ezrin, periphery. radixin andCortical moesin), actin that directly associate interacts with withPtdIns
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