STIM1 Controls Endothelial Barrier Function Independently of Orai1 and Ca
            <sup>2+</sup>
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Shinde, Arti V.; Motiani, Rajender K.; Zhang, Xuexin; Abdullaev, Iskandar F.; Adam, Alejandro P.; González-Cobos, José C.; Zhang, Wei; Matrougui, Khalid; Vincent, Peter; Trebak, Mohamed

doi:10.1126/scisignal.2003425

Cited by 78 publications

(76 citation statements)

References 71 publications

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“…Functional studies demonstrated that these mutations cause hyperactivation of the CRAC channel (24). However, it remains unknown whether myopathy with tubular aggregates is caused by the increased activity of the CRAC channel, increased activity of another Ca 2+ channel using STIM1 as a sensor (25), or a function of STIM1 that is unrelated to Ca 2+ signaling, as STIM1 can function independently of ORAI1 (26)(27)(28).Stormorken syndrome [Mendelian Inheritance in Man (MIM) 185070] is a rare autosomal-dominant condition with Significance Stormorken syndrome is a rare autosomal-dominant genetic condition characterized by congenital miosis, bleeding diathesis, thrombocytopenia, and proximal muscle weakness. Other manifestations include functional or anatomical asplenia, ichthyosis, headaches, and dyslexia.…”

mentioning

confidence: 99%

Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis

Nesin

Wiley

Kousi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

221

345

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Signaling through the store-operated Ca 2+ release-activated Ca 2+ (CRAC) channel regulates critical cellular functions, including gene expression, cell growth and differentiation, and Ca 2+ homeostasis. Loss-of-function mutations in the CRAC channel pore-forming protein ORAI1 or the Ca 2+ sensing protein stromal interaction molecule 1 (STIM1) result in severe immune dysfunction and nonprogressive myopathy. Here, we identify gain-of-function mutations in the cytoplasmic domain of STIM1 (p.R304W) associated with thrombocytopenia, bleeding diathesis, miosis, and tubular myopathy in patients with Stormorken syndrome, and in ORAI1 (p.P245L), associated with a Stormorken-like syndrome of congenital miosis and tubular aggregate myopathy but without hematological abnormalities. Heterologous expression of STIM1 p.R304W results in constitutive activation of the CRAC channel in vitro, and spontaneous bleeding accompanied by reduced numbers of thrombocytes in zebrafish embryos, recapitulating key aspects of Stormorken syndrome. p.P245L in ORAI1 does not make a constitutively active CRAC channel, but suppresses the slow Ca 2+ -dependent inactivation of the CRAC channel, thus also functioning as a gain-of-function mutation. These data expand our understanding of the phenotypic spectrum of dysregulated CRAC channel signaling, advance our knowledge of the molecular function of the CRAC channel, and suggest new therapies aiming at attenuating store-operated Ca 2+ entry in the treatment of patients with Stormorken syndrome and related pathologic conditions. human genetics | calcium signaling C a 2+ influx in response to the depletion of intracellular Ca 2+ stores, or store-operated Ca 2+ entry, constitutes one of the major routes of Ca 2+ entry in all animal cells (1). Under physiological conditions, Ca 2+ influx is activated in response to numerous G protein-coupled receptors and receptor tyrosine kinases signaling via inositol-1,4,5-trisphosphate as a second messenger (2). Store-operated Ca 2+ entry is mediated primarily by the Ca 2+ release-activated Ca 2+ (CRAC) channel (3), which consists of the pore-forming subunits ORAI1-3 (or CRAC modulators 1-3) and Ca 2+ sensors, STIM1 and STIM2 (4-7). STIM proteins reside in the membrane of endoplasmic reticulum (ER), whereas ORAI proteins reside in the plasma membrane. STIM1 is a single transmembrane-spanning protein (8-12) that, in resting cells, exists as a dimer that binds Ca 2+ through two EF hand-containing domains located in the ER lumen (13). Depletion of Ca 2+ in the ER induces a series of molecular events in the conformation and localization of STIM1, initiated by the formation of higher-order oligomers, protein unfolding, and accumulation at discrete sites in the cell where the ER membrane is in close proximity to the plasma membrane (11,(13)(14)(15)(16). In these sites, STIM1 binds to the cytosolic C and N termini of ORAI1 (17, 18), resulting in channel activation and generation of a highly Ca 2+ -selective CRAC current, or I CRAC (3,19,20). I CRAC is responsible not only ...

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mentioning

confidence: 99%

Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis

Nesin

Wiley

Kousi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

221

345

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“…In this context, the recent interest in human 'transportome' involvement in tumour vascularization is a promising field, because several members are activated downstream of the recruitment of VEGF receptors. For example, whereas the interference with the bulk VEGF signalling alters the activity of a multitude of different cells and functions, targeting TRPC6 or Orai1 may affect only EC migration and proliferation [31,34,44,53,92], whereas TRPC1 and STIM1 may selectively influence vascular permeability [56][57][58]61].…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, knockdown of Orai1 inhibits VEGF-mediated HUVEC migration, proliferation and tubulogenesis [33][34][35]. On the other hand, thrombin-induced decrease in EC permeability requires STIM1, but is unrelated to Orai1 and Ca 2þ entry [61] (table 1 and figure 2).…”

Section: Transient Receptor Potential Proteins and Stim1-orai1 Complexmentioning

confidence: 99%

“…HMEC, human microvascular EC; HPAEC, human pulmonary artery EC; HUVEC, human umbilical vein EC; EA.hy926, EC line derived from HUVEC fused with human lung adenocarcinoma cell line A549; PAEC, porcine aortic endothelial cells; BTEC, tumour-derived EC from breast carcinoma; H5VEC, heart endothelioma (H5V) EC; MAEC, mouse aortic EC; EPC, endothelial progenitor cells; RCC-EPC, EPC isolated from renal carcinoma patients; Numbers in parenthesis indicate the respective reference number. EPC [30] HMEC [31] BTEC [32] RCC-EPC [29] HUVEC [33 -35] HUVEC [36] HUVEC [37] HUVEC [38] HUVEC [36,39] MAEC from KO mice [40] HMEC [41,42] EPC [43] survival and proliferation RCC-EPC [29] EPC [30] HMEC [31] HUVEC [44] PAEC [45] H5V EC [46] HUVEC [40] HUVEC, HMEC [41,55] EPC [43] permeability HMEC,HUVEC [56 -58] HPAEC [59] Frog mesenteric microvessels [60] H5V EC [46] HUVEC [61] in vivo angiogenesis zebrafish [62] CAM [44] collateral growth [45] HERG-1-Retinoblastoma [63] EAG1-Xenograft in SCID mice and human osteosarcoma [27,28] CAM [54] xenograft in nude mice [38] Rabbit cornea [64] human mammary carcinoma, glioblastoma [65,66] AQP1 KO mice and C57BL/ 6 mice …”

Section: Transient Receptor Potential Proteins and Stim1-orai1 Complexmentioning

confidence: 99%

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Functional properties of ion channels and transporters in tumour vascularization

Fiorio

Munaron

2014

Phil. Trans. R. Soc. B

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Vascularization is crucial for solid tumour growth and invasion, providing metabolic support and sustaining metastatic dissemination. It is now accepted that ion channels and transporters play a significant role in driving the cancer growth at all stages. They may represent novel therapeutic, diagnostic and prognostic targets for anti-cancer therapies. On the other hand, although the expression and role of ion channels and transporters in the vascular endothelium is well recognized and subject of recent reviews, only recently has their involvement in tumour vascularization been recognized. Here, we review the current literature on ion channels and transporters directly involved in the angiogenic process. Particular interest will be focused on tumour angiogenesis in vivo as well as in the different steps that drive this process in vitro , such as endothelial cell proliferation, migration, adhesion and tubulogenesis. Moreover, we compare the ‘transportome’ system of tumour vascular network with the physiological one.

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“…STIM1 has also been shown to control several cellular processes independently of Orai1-mediated Ca 2+ entry [85]. Therefore, it is possible that STIM1 may regulate neurogenesis of mouse ESCs via TRPCs and LTCCs rather than via Orai1.…”

Section: Plasma Membrane Ca 2+ Channelsmentioning

confidence: 99%

The role of Ca2+ signaling on the self-renewal and neural differentiation of embryonic stem cells (ESCs)

et al. 2016

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Embryonic stem cells (ESCs) are promising resources for both scientific research and clinical regenerative medicine. With regards to the latter, ESCs are especially useful for treating several neurodegenerative disorders. Two significant characteristics of ESCs, which make them so valuable, are their capacity for self-renewal and their pluripotency, both of which are regulated by the integration of various signaling pathways. Intracellular Ca 2+ signaling is involved in several of these pathways. It is known to be precisely controlled by different Ca 2+ channels and pumps, which play an important role in a variety of cellular activities, including proliferation, differentiation and apoptosis. Here, we provide a review of the recent work conducted to investigate the function of Ca 2+ signaling in the self-renewal and the neural differentiation of ESCs. Specifically, we describe the role of intracellular Ca 2+ mobilization mediated by RyRs (ryanodine receptors); by cADPR (cyclic adenosine 5'-diphosphate ribose) and CD38 (cluster of differentiation 38/cADPR hydrolase); and by NAADP (nicotinic acid adenine dinucleotide phosphate) and TPC2 (two pore channel 2). We also discuss the Ca 2+ influx mediated by SOCs (store-operated Ca 2+ channels), TRPCs (transient receptor potential cation channels) and LTCC (L-type Ca 2+ channels) in the pluripotent ESCs as well as in neural differentiation of ESCs. Moreover, we describe the integration of Ca 2+ signaling in the other signaling pathways that are known to regulate the fate of ESCs.

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STIM1 Controls Endothelial Barrier Function Independently of Orai1 and Ca ²⁺ Entry

Cited by 78 publications

References 71 publications

Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis

Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis

Functional properties of ion channels and transporters in tumour vascularization

The role of Ca2+ signaling on the self-renewal and neural differentiation of embryonic stem cells (ESCs)

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STIM1 Controls Endothelial Barrier Function Independently of Orai1 and Ca 2+ Entry

Cited by 78 publications

References 71 publications

Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis

Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis

Functional properties of ion channels and transporters in tumour vascularization

The role of Ca2+ signaling on the self-renewal and neural differentiation of embryonic stem cells (ESCs)

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Product

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STIM1 Controls Endothelial Barrier Function Independently of Orai1 and Ca ²⁺ Entry