Affinage

ATP2C1

Calcium-transporting ATPase type 2C member 1 · UniProt P98194

Length
919 aa
Mass
100.6 kDa
Annotated
2026-06-09
100 papers in source corpus 32 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATP2C1 encodes SPCA1, a thapsigargin-insensitive P-type ATPase that pumps cytosolic Ca2+ and Mn2+ into the Golgi lumen to govern intra-Golgi and cytosolic ion homeostasis and secretory pathway function (PMID:15336968, PMID:14632183). In keratinocytes SPCA1 is the dominant Golgi Ca2+ pump, and heterozygous loss-of-function mutations cause Hailey-Hailey disease through impaired Golgi Ca2+ refill and reduced maximal luminal Ca2+ (PMID:10615129, PMID:10767338, PMID:14632183); many disease alleles preferentially cripple Mn2+ over Ca2+ transport and can trigger UPR and mis-localization in complementation assays (PMID:31455819). Luminal Ca2+ delivered by SPCA1 is functionally coupled to secretory sorting: sphingomyelin in the TGN membrane promotes SPCA1 Ca2+ flux that drives Ca2+-dependent oligomerization of Cab45 to package secretory cargo, and cofilin-1 recruits F-actin to the SPCA1 phosphorylation domain to support TGN Ca2+ import and cargo sorting (PMID:30393074, PMID:25179631). SPCA1-supplied luminal Ca2+ also activates TGN proprotein convertases required to process glycoproteins and receptors such as IGF1R and viral envelope proteins, the latter making SPCA1 essential for maturation and spread of multiple enveloped virus families (PMID:20837466, PMID:29024641). Through its Mn2+ pumping activity SPCA1 maintains Golgi Mn2+ homeostasis, stabilizing the Mn2+-handling protein TMEM165 against lysosomal degradation, and by controlling cytosolic Ca2+ it modulates surface trafficking of ZIP8/ZIP14 Mn2+ importers (PMID:31652305, PMID:35787370). SPCA1 is required for Golgi ribbon integrity and intra-Golgi transport, and at the organism level its loss is embryonic-lethal with Golgi stress, while it drives neuronal differentiation and neuroepithelial apical constriction via myosin II and cofilin-1-dependent actin dynamics (PMID:20604898, PMID:17597066, PMID:19793975, PMID:30228103). Cryo-EM structures spanning the catalytic cycle define a distinct Ca2+ release mechanism involving separation of transmembrane helices 4L and 6, and an N-terminal EF-hand-like motif binds Ca2+ to regulate autophosphorylation and ion turnover (PMID:37258749, PMID:30923126).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2000 High

    Establishing the disease gene: positional cloning linked ATP2C1 mutations to Hailey-Hailey disease and tied the phenotype to disrupted keratinocyte calcium handling, defining SPCA1 as a Golgi Ca2+ pump with physiological importance in epidermis.

    Evidence Positional cloning in HHD kindreds with keratinocyte Ca2+ measurements and in vivo epidermal calcium gradient analysis

    PMID:10615129 PMID:10767338

    Open questions at the time
    • Molecular transport mechanism and ion selectivity not resolved
    • Why haploinsufficiency manifests specifically in keratinocytes unexplained
  2. 2003 High

    Localizing the function: direct organelle Ca2+ measurements established SPCA1 as a Golgi-resident pump maintaining luminal Ca2+ stores and shaping cytosolic Ca2+ signals, with reduced refill in HHD cells.

    Evidence Immunofluorescence and Golgi-targeted aequorin in keratinocytes and HeLa cells with RNAi knockdown

    PMID:12804581 PMID:12810057 PMID:14632183

    Open questions at the time
    • Relative contribution of SPCA1 vs SERCA is cell-type dependent and not generalized
    • Mn2+ transport not yet assayed in these systems
  3. 2004 High

    Defining substrate scope and downstream consequences: SPCA1 transports both Ca2+ and Mn2+, contributes to beta-cell Ca2+ homeostasis/insulin secretion, supports glycoprotein processing and ERAD, and maintains basal keratinocyte state via Mn2+ sequestration.

    Evidence Transport assays, siRNA in beta cells and keratinocytes, pulse-chase glycoprotein processing, ionophore pharmacology

    PMID:14747290 PMID:15336968 PMID:15623514 PMID:16621454

    Open questions at the time
    • Mechanistic coupling between luminal ion levels and glycoprotein processing not yet defined
    • Distinction between Ca2+- and Mn2+-dependent effects incompletely separated
  4. 2005 Medium

    Transcriptional control: Sp1 and YY1 directly transactivate the ATP2C1 promoter and Ca2+ induces Sp1/ATP2C1 upregulation in normal but not HHD keratinocytes, adding a regulatory layer to disease pathogenesis.

    Evidence Reporter assays, EMSA, and Ca2+ stimulation in normal vs HHD keratinocytes

    PMID:15955096

    Open questions at the time
    • Single lab; in vivo relevance of the transcriptional defect unconfirmed
    • Whether impaired upregulation is cause or consequence of HHD Ca2+ defect unclear
  5. 2007 High

    In vivo essentiality: complete Atp2c1 knockout causes Golgi stress and embryonic lethality while heterozygotes develop epithelial tumors, establishing SPCA1 as essential for Golgi homeostasis and a haploinsufficient tumor predisposition gene.

    Evidence Mouse targeted knockout with Golgi ultrastructure, apoptosis, and tumor incidence analysis

    PMID:17597066

    Open questions at the time
    • Molecular trigger of Golgi stress not defined
    • Mechanism connecting haploinsufficiency to tumorigenesis unresolved
  6. 2010 High

    Defining the Golgi transport role: SPCA1 localizes to lateral rims and TGN tubules and is required for intra-Golgi transport, Golgi ribbon maintenance, and Ca2+-dependent proprotein convertase processing of receptors such as IGF1R.

    Evidence EM/IF localization, siRNA with VSV-G and brefeldin A transport assays, IGF1R processing in breast cancer cells

    PMID:20604898 PMID:20837466

    Open questions at the time
    • IGF1R study used pharmacological inhibition rather than genetic loss
    • How luminal Ca2+ directly activates convertases not mechanistically reconstituted
  7. 2014 High

    Linking the pump to the cytoskeleton: cofilin-1 recruits F-actin to the SPCA1 phosphorylation domain at the TGN, and disrupting this interface impairs TGN Ca2+ import and cargo sorting, connecting actin dynamics to pump function.

    Evidence In vitro binding with purified proteins, pulldown, mutagenesis, and TGN Ca2+/cargo sorting assays in HeLa

    PMID:25179631

    Open questions at the time
    • How actin/cofilin binding mechanistically enhances Ca2+ import unclear
    • Regulation of the interaction in vivo not addressed
  8. 2017 High

    Mechanism in viral pathogenesis: an unbiased genetic screen showed SPCA1 Ca2+ transport activates TGN proprotein convertases that cleave viral glycoproteins, making it required for maturation and spread of multiple enveloped virus families.

    Evidence Genome-wide haploid/CRISPR knockout screen with glycoprotein processing, protease activity, and viral spread assays

    PMID:29024641

    Open questions at the time
    • Whether SPCA1 is broadly required across all enveloped viruses unknown
    • Direct biochemical link between luminal Ca2+ and convertase catalysis not isolated
  9. 2018 High

    Coupling ion transport to secretion and morphogenesis: sphingomyelin-promoted SPCA1 Ca2+ flux drives Cab45 oligomerization for cargo sorting, and SPCA1 loss disrupts neural tube apical constriction via myosin II and cofilin-1, integrating pump activity with lipid signaling and tissue morphogenesis.

    Evidence SM manipulation with Cab45 oligomerization/vesicle assays; mouse Spca1 allele with apical constriction and cytoskeletal imaging; Orai1-coupled Ca2+ entry overexpression studies

    PMID:29555205 PMID:30228103 PMID:30393074

    Open questions at the time
    • Orai1 coupling shown only in overexpression and unconfirmed at endogenous levels
    • How cytoskeletal effects relate to luminal vs cytosolic Ca2+ not fully separated
  10. 2019 High

    Resolving Mn2+-specific functions and intrinsic regulation: SPCA1 Mn2+ pumping stabilizes TMEM165 against lysosomal degradation, an N-terminal EF-hand-like motif tunes autophosphorylation and ion turnover, and HHD alleles preferentially impair Mn2+ transport, refining the disease mechanism toward Mn2+ handling.

    Evidence Selective-mutant complementation in SPCA1-deficient cells, yeast reconstitution with purified pump and EF-hand mutagenesis, yeast complementation of HHD missense alleles

    PMID:28692648 PMID:30923126 PMID:31455819 PMID:31652305

    Open questions at the time
    • Yeast/heterologous systems may not fully model human pump behavior
    • Relative pathogenic weight of Ca2+ vs Mn2+ defects in HHD epidermis unresolved
  11. 2022 High

    Extending Mn2+ homeostasis control to the cell surface: SPCA1-set cytosolic Ca2+ regulates plasma membrane trafficking of ZIP8/ZIP14 Mn2+ importers, positioning SPCA1 within a broader Mn2+ buffering network alongside its TMEM165-stabilizing role in patient cells.

    Evidence Gain/loss-of-function with surface biotinylation, imaging, and 54Mn2+ uptake in endothelial cells; patient fibroblast ICP-MS/GPP130 Mn2+ sensing

    PMID:32335229 PMID:35787370

    Open questions at the time
    • In vivo systemic Mn2+ handling role not established
    • Single-lab mechanism for ZIP trafficking control
  12. 2023 High

    Structural basis of transport: cryo-EM structures across the catalytic cycle reveal a distinct Ca2+ release mechanism via separation of transmembrane helices 4L and 6, explaining how SPCA1 differs from other P-type II ATPases.

    Evidence Six cryo-EM conformational states with molecular dynamics simulations

    PMID:37258749

    Open questions at the time
    • Structural basis for Mn2+ versus Ca2+ selectivity not resolved
    • Structures of disease mutants not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SPCA1 achieves and switches between Ca2+ and Mn2+ selectivity, and how this dictates tissue-specific disease manifestation, remains unresolved.
  • Structural/biochemical determinants of Ca2+ vs Mn2+ selectivity unknown
  • Why haploinsufficiency causes epidermis-restricted disease despite ubiquitous expression unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0140657 ATP-dependent activity 3 GO:0016787 hydrolase activity 2
Localization
GO:0005794 Golgi apparatus 2 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-382551 Transport of small molecules 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1643685 Disease 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
CAB45/SDF4CFL1ORAI1TMEM165

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 ATP2C1 encodes a P-type Ca2+-transport ATPase that sequesters calcium into the Golgi apparatus; heterozygous loss-of-function mutations in ATP2C1 cause Hailey-Hailey disease, associated with impaired cytoplasmic calcium regulation in keratinocytes and attenuation of the normal epidermal calcium gradient in vivo. Positional cloning, mutation identification in 21 HHD kindreds, Ca2+ signaling measurements in cultured keratinocytes, in vivo calcium gradient analysis Nature genetics High 10615129 10767338
2003 Human ATP2C1 (SPCA1) protein (~115 kDa) localizes to the Golgi apparatus in keratinocytes and is responsible for maintaining Golgi Ca2+ stores; Hailey-Hailey disease keratinocytes show slower Golgi Ca2+ refill and a lower maximum Golgi Ca2+ concentration, demonstrating the physiological role of ATP2C1 in controlling intraorganelle Ca2+ levels. Immunofluorescence localization, Golgi-targeted aequorin Ca2+ measurements, comparison of HHD vs. normal keratinocytes in vitro and in vivo The Journal of investigative dermatology High 14632183
2003 SPCA1 mediates Ca2+ uptake into a subfraction of the Golgi apparatus in HeLa cells; RNAi-mediated knockdown of SPCA1 reduces Golgi Ca2+ accumulation and decreases frequency of baseline cytosolic Ca2+ oscillations in response to histamine, demonstrating SPCA1's contribution to cytosolic Ca2+ signal shaping. RNAi knockdown, Golgi-targeted aequorin Ca2+ measurements, cytosolic Ca2+ imaging Biochemical and biophysical research communications High 12804581
2003 Keratinocytes rely predominantly on SPCA1 (rather than SERCA) to load the Golgi with Ca2+, whereas in COS-1 cells SERCA is the predominant Golgi Ca2+ pump; SPCA1-overexpressing COS-1 cells recapitulate the Ca2+ signaling phenotype of keratinocytes including prolonged latency of cytosolic Ca2+ signals, reflecting extra Ca2+ buffering by the SPCA1-containing store. SPCA1 overexpression in COS-1 cells, ER- and Golgi-targeted aequorin measurements, cytosolic Ca2+ imaging with capacitative Ca2+ entry Cell calcium Medium 12810057
2004 SPCA1 (ATP2C1) transports both Ca2+ and Mn2+ into the Golgi lumen and plays a role in cytosolic and intra-Golgi Ca2+ and Mn2+ homeostasis; it is distinct from SERCA and is thapsigargin-insensitive. Review consolidating functional transport assays and mutant analysis Biochemical and biophysical research communications Medium 15336968
2004 ATP2C1 (PMR1 in beta cells) localizes to both microsomal and dense-core secretory vesicle fractions in pancreatic beta cells; siRNA-mediated depletion inhibits Ca2+ uptake into ER and secretory vesicles (~20%), markedly enhances L-type Ca2+ channel flux, augments glucose-stimulated insulin secretion, and alters cytosolic Ca2+ oscillation kinetics, demonstrating a role partially non-overlapping with SERCA in beta-cell Ca2+ homeostasis and insulin secretion. Subcellular fractionation, organelle-targeted aequorin Ca2+ measurements, siRNA knockdown, patch-clamp/Ca2+ imaging, insulin secretion assay Diabetes High 14747290
2004 ATP2C1 knockdown by siRNA impairs post-translational processing of thyroglobulin (a secretory glycoprotein) and ER-associated degradation of mutant thyroglobulin, while degradation of a nonglycosylated misfolded substrate is unaffected; ATP2C1 deficiency also renders cells hypersensitive to ER stress without basally elevating ER chaperones or activating the UPR (PERK, ATF6, or Ire1/XBP1). siRNA knockdown, pulse-chase protein processing assays, ER stress sensitivity assays, UPR marker analysis The Journal of biological chemistry High 15623514
2005 SPCA1, not SERCA, is the primary intracellular Ca2+ pump mediating progesterone-induced Ca2+ oscillations in human spermatozoa; SPCA1 protein localizes to the region behind the nucleus extending into the midpiece of sperm, whereas SERCA is undetectable in these cells. Pharmacological inhibition (thapsigargin, cyclopiazonic acid, bis-phenol), Western blotting, immunolocalization Journal of cell science Medium 15811949
2006 ATP2C1 is specifically expressed in the basal layer of normal epidermis; siRNA-mediated knockdown of ATP2C1 induces keratinocyte differentiation markers (K10 keratin and involucrin), while a manganese-selective ionophore (Br-A23187) but not a calcium ionophore (A23187) recapitulates this effect, suggesting ATP2C1 maintains basal keratinocytes in an undifferentiated state primarily through Mn2+ sequestration in the Golgi. Immunohistochemistry, siRNA knockdown, differentiation marker expression assays, ionophore treatment Journal of dermatological science Medium 16621454
2007 Complete loss of Atp2c1 (Spca1-/-) in mice causes lethal Golgi stress with dilated Golgi membranes, reduced Golgi stacking, increased Golgi-associated vesicles, increased apoptosis, and embryonic death by gestational day 10.5; heterozygous adult mice develop squamous cell tumors of keratinized epithelia, demonstrating that SPCA1 is essential for Golgi homeostasis and that haploinsufficiency predisposes to cancer. Targeted gene knockout in mice, electron microscopy of Golgi ultrastructure, apoptosis assays, tumor incidence in aged heterozygotes The Journal of biological chemistry High 17597066
2009 SPCA1 knockdown in N2a neuroblastoma cells and primary hippocampal neurons impairs Golgi Ca2+ homeostasis, disrupts trafficking of Golgi-resident and plasma membrane-targeted proteins, delays neuronal differentiation (fewer and shorter neurites), and causes cell death upon complete suppression, establishing SPCA1 as required for neural polarity and differentiation. siRNA knockdown in N2a and primary neurons, Ca2+ imaging, immunocytochemical trafficking assays, morphological differentiation analysis The Journal of neuroscience High 19793975
2010 SPCA1 localizes predominantly to the lateral rims of Golgi cisternae, tubular non-compact zones connecting Golgi stacks, and tubular trans-Golgi network regions; SPCA1 knockdown causes Golgi fragmentation (loss of cis-most and trans-most cisternae), inhibits exit of VSV-G protein from the Golgi, and delays retrograde redistribution of Golgi glycosylation enzymes to the ER induced by brefeldin A, demonstrating SPCA1 is required for intra-Golgi transport and Golgi ribbon maintenance. Immunofluorescence/electron microscopy localization, siRNA knockdown, VSV-G trafficking assay, brefeldin A retrograde transport assay Traffic High 20604898
2010 SPCA1 inhibition in MDA-MB-231 basal-like breast cancer cells alters processing of IGF1R by proprotein convertases in the secretory pathway (accumulation of inactive pro-IGF1R in the TGN, reduced functional IGF1Rβ), without altering global cytosolic Ca2+ signaling or ER stress, demonstrating SPCA1 controls Ca2+-dependent enzyme activity in the Golgi lumen to regulate proprotein processing. SPCA1 inhibition, Western blot for IGF1R processing, 3D proliferation/morphology assays, ER stress assays, Ca2+ imaging The Journal of biological chemistry Medium 20837466
2012 ATP2C1/SPCA1 knockdown in keratinocytes up-regulates tight junction proteins claudins 1 and 4 even at low extracellular Ca2+, and causes delayed translocation of desmoplakin and desmoglein 3 with increased intracellular accumulation, indicating SPCA1 specifically regulates claudin expression and desmosomal/tight junction protein trafficking. siRNA knockdown, qPCR, Western blot, indirect immunofluorescence in low and high Ca2+ conditions Experimental dermatology Medium 22639968
2012 Bis-phenol selectively inhibits human SPCA1d Ca2+-ATPase activity (IC50 ~0.13 µM) with 62-fold greater potency than hSERCA2b (IC50 ~8.1 µM), and can mobilize Ca2+ from thapsigargin-insensitive stores in intact cells, establishing bis-phenol as a selective SPCA1 inhibitor. Overexpression of SPCA1d and SERCA2b in COS-7 cells, Ca2+-dependent ATPase activity assays, Ca2+ mobilization assays in intact cells Biochemical and biophysical research communications High 22796571
2013 PMR-1 (C. elegans ortholog of SPCA1/ATP2C1) is required for embryonic cell migration; pmr-1 mutant embryos show reduced migration rates of ventral neuroblasts and other blastomeres, and genetic interaction experiments show that changing activity of IP3R (itr-1) or RyR (unc-68) modulates lethality, placing pmr-1 in a Ca2+ channel network regulating cell migration. Forward genetic screen, time-lapse imaging of cell migration, genetic epistasis with itr-1 and unc-68 PLoS genetics High 23696750
2014 Cofilin-1 (CFL-1) recruits F-actin to the phosphorylation domain (P-domain) of SPCA1 at the TGN; a 132-amino-acid portion of the SPCA1 P-domain interacts with actin in a CFL-1-dependent manner. Mutagenesis of four residues constituting the CFL-1 binding site in SPCA1 impairs Ca2+ import into the TGN and secretory cargo sorting. In vitro binding assay with purified proteins, Ni-NTA pulldown with P-domain fragment, mutagenesis, TGN Ca2+ imaging, cargo sorting assay in HeLa cells The Journal of cell biology High 25179631
2016 ATP2C1 inactivation in keratinocytes increases oxidative stress and activates Notch1; RNA-seq of HHD patient lesional keratinocytes shows consistent down-regulation of the DNA damage response (DDR); Notch1 activation downstream of oxidative stress induced by ATP2C1 loss drives keratinocyte differentiation and represses DDR gene expression, identifying an ATP2C1/NOTCH1 axis in epidermal homeostasis. siRNA knockdown, RNA-seq, oxidative stress assays, Notch1 activation assays in cultured keratinocytes and HHD patient lesions Scientific reports Medium 27528123
2017 Genome-wide haploid knockout screen identifies SPCA1 as required for maturation and spread of viruses from Paramyxoviridae, Flaviviridae, and Togaviridae families; SPCA1 Ca2+ transport activity is required because it activates proprotein convertases in the TGN that cleave viral glycoproteins; SPCA1-deficient cells accumulate uncleaved, non-functional viral glycoproteins and fail to support viral spread. Genome-wide CRISPR/haploid cell knockout screen, glycoprotein processing assays, protease activity assays, viral spread assays in SPCA1-KO cells Cell host & microbe High 29024641
2017 In zebrafish, ATP2C1 expression provides compensatory Mn2+ transport protection in embryos lacking the Mn efflux transporter Slc30a10; wild-type or mutant SLC30A10 expression can inhibit the protective effect of ATP2C1 in response to Mn challenge in both zebrafish and HeLa cells, indicating ATP2C1 functions as a Mn2+ transport buffer that can substitute for SLC30A10. CRISPR/Cas9 zebrafish knockout, rescue experiments with ATP2C1 expression constructs, HeLa cell Mn challenge assays PLoS genetics Medium 28692648
2018 SPCA1 activity couples secretory protein sorting to sphingomyelin synthesis in the TGN: sphingomyelin in the TGN membrane promotes SPCA1-mediated Ca2+ flux into the TGN lumen, which drives Ca2+-dependent oligomerization of the secreted Ca2+-binding protein Cab45, enabling Cab45 to package client secreted proteins into sphingomyelin-enriched vesicular carriers for export to the cell surface. SPCA1 activity assays, sphingomyelin manipulation, Cab45 oligomerization assays, Ca2+ flux measurements, vesicle trafficking assays Developmental cell High 30393074
2018 Loss of Spca1 in mice impairs neuroepithelial cell apical constriction during neural tube closure, not primarily through apoptosis; SPCA1 promotes apical constriction by regulating myosin II localization and actin dynamics through cofilin-1, with cofilin-1 acting as a downstream effector of SPCA1 function. Novel Spca1 allele characterization in mice, apical constriction imaging, myosin II localization by immunofluorescence, actin dynamics assays, cofilin-1 localization analysis Development High 30228103
2018 SPCA1 overexpression induces STIM1-independent, Orai1-dependent cytosolic Ca2+ influx (store-independent Ca2+ entry, SICE) and co-localizes with Orai1 near the plasma membrane as shown by TIRF microscopy; this functional coupling elevates Ca2+ in non-ER stores and induces Golgi swelling with nuclear translocation of TFE3 (Golgi stress marker); HHD-associated SPCA1 mutations differentially impair Ca2+ transport, Orai1 activation, or both. SPCA1/SPCA2 overexpression, Orai1 knockdown, TIRF microscopy co-localization, cytosolic Ca2+ measurements, Golgi swelling assay, TFE3 nuclear translocation assay, HHD mutant functional analysis Biochimica et biophysica acta. Molecular cell research Medium 29555205
2019 SPCA1a has an N-terminal EF-hand-like motif that binds Ca2+ and regulates pump activity: Ca2+ binding to this motif promotes autophosphorylation and SPCA1a activity, modulates substrate ion affinity, and accounts for a biphasic activation curve and lower apparent Ca2+ affinity relative to SPCA2. SPCA1a has lower Ca2+ affinity and a ~2-fold higher Ca2+ turnover rate compared with Mn2+; mutation of the EF-hand-like motif lowers Ca2+ turnover rate and increases substrate affinity. Yeast recombinant expression and purification of SPCA1a and SPCA2, biochemical reconstitution, Ca2+/Mn2+ transport assays, autophosphorylation assays, EF-hand mutagenesis The Journal of biological chemistry High 30923126
2019 TMEM165 stability depends on SPCA1's Mn2+ pumping activity: TMEM165 is constitutively degraded in lysosomes in the absence of SPCA1; among SPCA1 mutants, only Q747A (which favors Mn2+ over Ca2+ transport) rescues TMEM165 abundance and Golgi localization; SERCA2b overexpression also rescues TMEM165, indicating Mn2+ homeostasis in the Golgi lumen governs TMEM165 stability. SPCA1-deficient Hap1 cells, SPCA1 complementation with transport-selective mutants, lysosomal inhibitors, Western blot, immunofluorescence The Biochemical journal High 31652305
2019 In yeast complementation assays, fourteen HHD-associated ATP2C1 missense mutations preferentially impair Mn2+ transport over Ca2+ transport (12/14 fail to complement Mn2+ sensitivity; 13/14 partially complement high-Ca2+ requirement); nine mutations show cold-sensitive complementation; twelve mutations induce the unfolded protein response (UPR) in the absence of wild-type ATP2C1, and four cause hSPCA1 mis-localization to the vacuolar membrane; co-expression of wild-type ATP2C1 or ATP2A2 prevents UPR induction and mis-localization. Yeast complementation system, Mn2+/Ca2+ sensitivity growth assays, UPR reporter assays, fluorescence localization of hSPCA1 variants Scientific reports Medium 31455819
2021 UVA irradiation increases SPCA1 expression in human dermal fibroblasts via MAPK/c-jun pathway; c-jun binds the SPCA1 promoter and transcriptionally up-regulates SPCA1; SPCA1 knockdown aggravates UVA-induced senescence by elevating intracellular Ca2+, increasing ROS, and increasing MAPK activity, while SPCA1 overexpression reduces Ca2+ overload, lowers ROS, and suppresses MAPK, establishing a negative feedback loop. Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), siRNA knockdown, SPCA1 overexpression, ROS/Ca2+/senescence assays Frontiers in cell and developmental biology Medium 34239867
2022 SPCA1 knockdown in brain microvascular endothelial cells increases cytoplasmic Ca2+, which in turn increases plasma membrane localization of ZIP8 and ZIP14 metal transporters (via surface biotinylation and immunofluorescence), resulting in enhanced Mn2+ uptake; conversely, SPCA1 overexpression or gain-of-function mutant decreases cytoplasmic Ca2+ and reduces Mn2+ accumulation, demonstrating that SPCA1 regulates ZIP-mediated Mn2+ uptake through cytoplasmic Ca2+ control of transporter membrane trafficking. siRNA knockdown, SPCA1 overexpression with gain-of-function mutant, surface protein biotinylation, indirect immunofluorescence, GFP-tagged transporter localization, 54Mn2+ uptake assay The Journal of biological chemistry High 35787370
2023 Six cryo-EM structures of human SPCA1 in a near-complete conformational cycle reveal unique conformational changes during ATP binding and phosphorylation compared to other P-type II ATPases; transmembrane helix 4L and 6 separation causes conformational distortion of the Ca2+-binding site constituting a distinct Ca2+ release mechanism; the CaE2P intermediate state is resolved, providing the structural basis for Ca2+ entry and release in hSPCA1. Cryo-electron microscopy structure determination (6 conformational states), molecular dynamics simulations Cell research High 37258749
2005 Transcription factors Sp1 and YY1 directly bind the region +21/+57 of the ATP2C1 promoter and transactivate it; Ca2+ stimulation increases nuclear Sp1 and ATP2C1 mRNA in normal keratinocytes, but both increases are suppressed in HHD patient keratinocytes, indicating impaired transcriptional upregulation contributes to keratinocyte-specific pathogenesis. Transient reporter assay, EMSA, Sp1/YY1 overexpression, Ca2+ stimulation experiments in normal vs. HHD keratinocytes The Journal of investigative dermatology Medium 15955096
2020 TMEM165 expression is more sensitive to MnCl2-induced degradation in HHD patient fibroblasts and keratinocytes (with partial SPCA1 deficiency) than in controls; ICP-MS and GPP130 Golgi Mn2+ sensor demonstrate cytosolic Mn2+ accumulation in MnCl2-supplemented HHD fibroblasts, linking SPCA1 Mn2+ pumping function to TMEM165 stability in a pathological context. HHD patient fibroblasts and keratinocytes, Western blot, ICP-MS, GPP130 as Golgi Mn2+ sensor, MnCl2 supplementation Biochimie Medium 32335229

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease. Nature genetics 417 10615129
2000 Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca(2+) pump. Human molecular genetics 248 10767338
2004 Gambogic acid inhibits proliferation of human lung carcinoma SPC-A1 cells in vivo and in vitro and represses telomerase activity and telomerase reverse transcriptase mRNA expression in the cells. Biological & pharmaceutical bulletin 148 15516720
2003 Human keratinocyte ATP2C1 localizes to the Golgi and controls Golgi Ca2+ stores. The Journal of investigative dermatology 120 14632183
2007 Loss of the Atp2c1 secretory pathway Ca(2+)-ATPase (SPCA1) in mice causes Golgi stress, apoptosis, and midgestational death in homozygous embryos and squamous cell tumors in adult heterozygotes. The Journal of biological chemistry 103 17597066
2004 SPCA1 pumps and Hailey-Hailey disease. Biochemical and biophysical research communications 82 15336968
2009 Identification of microRNA profiles in docetaxel-resistant human non-small cell lung carcinoma cells (SPC-A1). Journal of cellular and molecular medicine 77 19900214
2011 MiR-100 resensitizes docetaxel-resistant human lung adenocarcinoma cells (SPC-A1) to docetaxel by targeting Plk1. Cancer letters 76 22120675
2003 The contribution of the SPCA1 Ca2+ pump to the Ca2+ accumulation in the Golgi apparatus of HeLa cells assessed via RNA-mediated interference. Biochemical and biophysical research communications 75 12804581
2004 Role for plasma membrane-related Ca2+-ATPase-1 (ATP2C1) in pancreatic beta-cell Ca2+ homeostasis revealed by RNA silencing. Diabetes 71 14747290
2010 Golgi calcium pump secretory pathway calcium ATPase 1 (SPCA1) is a key regulator of insulin-like growth factor receptor (IGF1R) processing in the basal-like breast cancer cell line MDA-MB-231. The Journal of biological chemistry 68 20837466
2002 Hailey-Hailey disease: molecular and clinical characterization of novel mutations in the ATP2C1 gene. The Journal of investigative dermatology 68 11841554
2005 Secretory pathway Ca(2+)-ATPase (SPCA1) Ca(2)+ pumps, not SERCAs, regulate complex [Ca(2+)](i) signals in human spermatozoa. Journal of cell science 63 15811949
2018 Activity of the SPCA1 Calcium Pump Couples Sphingomyelin Synthesis to Sorting of Secretory Proteins in the Trans-Golgi Network. Developmental cell 58 30393074
2009 Silencing the SPCA1 (secretory pathway Ca2+-ATPase isoform 1) impairs Ca2+ homeostasis in the Golgi and disturbs neural polarity. The Journal of neuroscience : the official journal of the Society for Neuroscience 56 19793975
2010 The SPCA1 Ca2+ pump and intracellular membrane trafficking. Traffic (Copenhagen, Denmark) 54 20604898
2017 Mendelian Disorders of Cornification Caused by Defects in Intracellular Calcium Pumps: Mutation Update and Database for Variants in ATP2A2 and ATP2C1 Associated with Darier Disease and Hailey-Hailey Disease. Human mutation 53 28035777
2017 Diverse Viruses Require the Calcium Transporter SPCA1 for Maturation and Spread. Cell host & microbe 51 29024641
2004 The expression, activity and localisation of the secretory pathway Ca2+ -ATPase (SPCA1) in different mammalian tissues. Biochimica et biophysica acta 50 15328051
2017 The role of the ATP2C1 gene in Hailey-Hailey disease. Cellular and molecular life sciences : CMLS 49 28551824
2004 Deficiency of ATP2C1, a Golgi ion pump, induces secretory pathway defects in endoplasmic reticulum (ER)-associated degradation and sensitivity to ER stress. The Journal of biological chemistry 49 15623514
2003 Similar Ca(2+)-signaling properties in keratinocytes and in COS-1 cells overexpressing the secretory-pathway Ca(2+)-ATPase SPCA1. Cell calcium 45 12810057
2001 Mutations of ATP2C1 in Japanese patients with Hailey-Hailey disease: intrafamilial and interfamilial phenotype variations and lack of correlation with mutation patterns. The Journal of investigative dermatology 45 11886536
2016 ATP2C1 gene mutations in Hailey-Hailey disease and possible roles of SPCA1 isoforms in membrane trafficking. Cell death & disease 44 27277681
2005 Effects of ultraviolet B irradiation, proinflammatory cytokines and raised extracellular calcium concentration on the expression of ATP2A2 and ATP2C1. The British journal of dermatology 40 15840101
2017 Zebrafish slc30a10 deficiency revealed a novel compensatory mechanism of Atp2c1 in maintaining manganese homeostasis. PLoS genetics 38 28692648
2014 Cofilin recruits F-actin to SPCA1 and promotes Ca2+-mediated secretory cargo sorting. The Journal of cell biology 37 25179631
2005 Effects of drugs and anticytokine antibodies on expression of ATP2A2 and ATP2C1 in cultured normal human keratinocytes. The British journal of dermatology 37 15888147
2013 Enhancement of (-)-epigallocatechin-3-gallate and theaflavin-3-3'-digallate induced apoptosis by ascorbic acid in human lung adenocarcinoma SPC-A-1 cells and esophageal carcinoma Eca-109 cells via MAPK pathways. Biochemical and biophysical research communications 36 23892041
2002 Mutation analysis of ATP2C1 gene in Taiwanese patients with Hailey-Hailey disease. The British journal of dermatology 33 11966689
2011 Oleanolic acid from Prunella Vulgaris L. induces SPC-A-1 cell line apoptosis via regulation of Bax, Bad and Bcl-2 expression. Asian Pacific journal of cancer prevention : APJCP 32 21545203
2005 Transcriptional regulation of ATP2C1 gene by Sp1 and YY1 and reduced function of its promoter in Hailey-Hailey disease keratinocytes. The Journal of investigative dermatology 32 15955096
2020 FAS/FAS-L-mediated apoptosis and autophagy of SPC-A-1 cells induced by water-soluble polysaccharide from Polygala tenuifolia. International journal of biological macromolecules 30 32027895
2015 Wnt signaling regulates the stemness of lung cancer stem cells and its inhibitors exert anticancer effect on lung cancer SPC-A1 cells. Medical oncology (Northwood, London, England) 30 25731617
2012 Hailey-Hailey disease and tight junctions: Claudins 1 and 4 are regulated by ATP2C1 gene encoding Ca(2+) /Mn(2+) ATPase SPCA1 in cultured keratinocytes. Experimental dermatology 30 22639968
2007 Functional and immunocytochemical evidence for the expression and localization of the secretory pathway Ca2+-ATPase isoform 1 (SPCA1) in cerebellum relative to other Ca2+ pumps. Journal of neurochemistry 30 17680983
2004 Anti-proliferative effects of oridonin on SPC-A-1 cells and its mechanism of action. The Journal of international medical research 28 15587755
2011 Impaired migration and cell volume regulation in aquaporin 5-deficient SPC-A1 cells. Respiratory physiology & neurobiology 27 21315850
2018 Store-independent coupling between the Secretory Pathway Ca2+ transport ATPase SPCA1 and Orai1 in Golgi stress and Hailey-Hailey disease. Biochimica et biophysica acta. Molecular cell research 26 29555205
2016 siRNA-induced TRAF6 knockdown promotes the apoptosis and inhibits the invasion of human lung cancer SPC-A1 cells. Oncology reports 26 26847475
2008 Molecular and clinical characterization in Japanese and Korean patients with Hailey-Hailey disease: six new mutations in the ATP2C1 gene. Journal of dermatological science 25 18372165
2008 Activity and localization of the secretory pathway Ca2+-ATPase isoform 1 (SPCA1) in different areas of the mouse brain during postnatal development. Molecular and cellular neurosciences 25 18599310
2003 Four novel mutations in ATP2C1 found in Chinese patients with Hailey-Hailey disease. The British journal of dermatology 25 14510977
2015 Curcumol induces apoptosis in SPC-A-1 human lung adenocarcinoma cells and displays anti-neoplastic effects in tumor bearing mice. Asian Pacific journal of cancer prevention : APJCP 24 25824755
2010 Synergistic effects of tea polyphenols and ascorbic acid on human lung adenocarcinoma SPC-A-1 cells. Journal of Zhejiang University. Science. B 24 20506578
2007 Calcium and survivin are involved in the induction of apoptosis by dihydroartemisinin in human lung cancer SPC-A-1 cells. Methods and findings in experimental and clinical pharmacology 24 17344942
2006 Regulation of MUC5AC mucin secretion by depletion of AQP5 in SPC-A1 cells. Biochemical and biophysical research communications 24 16500622
2016 The loss of ATP2C1 impairs the DNA damage response and induces altered skin homeostasis: Consequences for epidermal biology in Hailey-Hailey disease. Scientific reports 23 27528123
2014 Loss of RhoA expression prevents proliferation and metastasis of SPCA1 lung cancer cells in vitro. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 23 25661383
2017 RhoA inhibits apoptosis and increases proliferation of cultured SPCA1 lung cancer cells. Molecular medicine reports 22 28487954
2008 Apoptotic activity of genistein on human lung adenocarcinoma SPC-A-1 cells and preliminary exploration of its mechanisms using microarray. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 22 18295443
2009 Acantholytic dermatosis of the crural folds with ATP2C1 mutation is a possible variant of Hailey-Hailey Disease. Journal of cutaneous medicine and surgery 21 19426624
2006 Distribution of secretory pathway Ca2+ ATPase (SPCA1) in neuronal and glial cell cultures. Cellular and molecular neurobiology 21 16758324
2014 The Ca(2+)/H(+) antiporter TMEM165 expression, localization in the developing, lactating and involuting mammary gland parallels the secretory pathway Ca(2+) ATPase (SPCA1). Biochemical and biophysical research communications 20 24530912
2023 Structure and transport mechanism of the human calcium pump SPCA1. Cell research 19 37258749
2018 Secretory pathway calcium ATPase 1 (SPCA1) controls mouse neural tube closure by regulating cytoskeletal dynamics. Development (Cambridge, England) 18 30228103
2014 Crotoxin suppresses the tumorigenic properties and enhances the antitumor activity of Iressa® (gefinitib) in human lung adenocarcinoma SPCA‑1 cells. Molecular medicine reports 17 25310019
2013 The secretory pathway calcium ATPase PMR-1/SPCA1 has essential roles in cell migration during Caenorhabditis elegans embryonic development. PLoS genetics 17 23696750
2007 Eight novel mutations of ATP2C1 identified in 17 Chinese families with Hailey-Hailey disease. Dermatology (Basel, Switzerland) 17 17911984
2005 ATP2C1 gene mutation analysis in Italian patients with Hailey-Hailey disease. The Journal of investigative dermatology 17 16297192
2019 An N-terminal Ca2+-binding motif regulates the secretory pathway Ca2+/Mn2+-transport ATPase SPCA1. The Journal of biological chemistry 16 30923126
2020 Seleno-Chitosan induces apoptosis of lung cancer cell line SPC-A-1 via Fas/FasL pathway. Bioorganic chemistry 15 32146174
2019 Investigating the functional link between TMEM165 and SPCA1. The Biochemical journal 15 31652305
2015 Fangchinoline inhibits the proliferation of SPC-A-1 lung cancer cells by blocking cell cycle progression. Experimental and therapeutic medicine 15 26893655
2012 Bis(2-hydroxy-3-tert-butyl-5-methyl-phenyl)-methane (bis-phenol) is a potent and selective inhibitor of the secretory pathway Ca²⁺ ATPase (SPCA1). Biochemical and biophysical research communications 15 22796571
2010 Aquaporin 5 expression inhibited by LPS via p38/JNK signaling pathways in SPC-A1 cells. Respiratory physiology & neurobiology 15 20362698
2010 Heterogeneous mutations of the ATP2C1 gene causing Hailey-Hailey disease in Hong Kong Chinese. Journal of the European Academy of Dermatology and Venereology : JEADV 14 20236194
2009 Livin abrogates apoptosis of SPC-A1 cell by regulating JNKI signaling pathway. Molecular biology reports 14 19690982
2009 Changes in expression and activity of the secretory pathway Ca2+ ATPase 1 (SPCA1) in A7r5 vascular smooth muscle cells cultured at different glucose concentrations. Bioscience reports 13 19527224
2022 Calcium and the Ca-ATPase SPCA1 modulate plasma membrane abundance of ZIP8 and ZIP14 to regulate Mn(II) uptake in brain microvascular endothelial cells. The Journal of biological chemistry 12 35787370
2018 A novel splice-site mutation in the ATP2C1 gene of a Chinese family with Hailey-Hailey disease. Journal of cellular biochemistry 12 30654607
2019 Characterization of Hailey-Hailey Disease-mutants in presence and absence of wild type SPCA1 using Saccharomyces cerevisiae as model organism. Scientific reports 11 31455819
2014 Successful treatment with narrow-band UVB therapy for a case of generalized Hailey-Hailey disease with a novel splice-site mutation in ATP2C1 gene. Dermatologic therapy 11 24962025
2012 Human lung cancer cell line SPC-A1 contains cells with characteristics of cancer stem cells. Neoplasma 11 22862169
2010 Roles of Ca and secretory pathway Ca-ATPase pump type 1 (SPCA1) in intra-Golgi transport. Communicative & integrative biology 11 21331225
2011 A case of Hailey-Hailey disease in an infant with a new ATP2C1 gene mutation. Pediatric dermatology 10 20403116
2011 Detection and comparison of two types of ATP2C1 gene mutations in Chinese patients with Hailey-Hailey disease. Archives of dermatological research 10 22124882
2006 ATP2C1 is specifically localized in the basal layer of normal epidermis and its depletion triggers keratinocyte differentiation. Journal of dermatological science 10 16621454
2020 Identification of ATP2C1 mutations in the patients of Hailey-Hailey disease. BMC medical genetics 9 32487029
2015 Identification of several mutations in ATP2C1 in Lebanese families: insight into the pathogenesis of Hailey-Hailey disease. PloS one 9 25658765
2008 Genetic diagnosis in a Chinese Hailey-Hailey disease pedigree with novel ATP2C1 gene mutation. Archives of dermatological research 9 18259764
2021 A Negative Feedback Loop in Ultraviolet A-Induced Senescence in Human Dermal Fibroblasts Formed by SPCA1 and MAPK. Frontiers in cell and developmental biology 8 34239867
2020 SPCA1 governs the stability of TMEM165 in Hailey-Hailey disease. Biochimie 8 32335229
2016 Synergistic and attenuated effect of HSS in combination treatment with docetaxel plus cisplatin in human non-small-cell lung SPC-A-1 tumor xenograft. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 8 27044809
2016 Four novel ATP2C1 mutations in Chinese patients with Hailey-Hailey disease. The Journal of dermatology 8 27095120
2007 Two novel mutations of the ATP2C1 gene in Chinese patients with Hailey-Hailey disease. Archives of dermatological research 8 17503064
2006 Mutations in the ATP2C1 gene in Chinese patients with Hailey-Hailey disease. Clinical and experimental dermatology 8 16901313
2005 Novel mutations in the ATP2C1 gene in two patients with Hailey-Hailey disease. Clinical and experimental dermatology 8 16045696
2020 Generalized Hailey-Hailey disease: Novel splice-site mutations of ATP2C1 gene in Chinese population and a literature review. Molecular genetics & genomic medicine 7 33345454
2018 The nuclear transcription factor RelB functions as an oncogene in human lung adenocarcinoma SPC-A1 cells. Cancer cell international 7 29983639
2011 A novel missense mutation of the ATP2C1 gene in a Chinese patient with Hailey-Hailey disease. Biochemical and biophysical research communications 7 21329674
2021 Case Report: A Case of Hailey-Hailey Disease Mimicking Condyloma Acuminatum and a Novel Splice-Site Mutation of ATP2C1 Gene. Frontiers in genetics 6 34970303
2014 Hailey-Hailey disease: investigation of a possible compensatory SERCA2 up-regulation and analysis of SPCA1, p63, and IRF6 expression. Archives of dermatological research 6 25256005
2012 A novel splice mutation in the ATP2C1 gene in a woman with concomitant psoriasis vulgaris and disseminated Hailey-Hailey disease. International journal of dermatology 6 22788811
2023 Circular RNA ATP2C1 (has_circ_0005797) sponges miR-432/miR-335 to promote breast cancer progression through regulating CCND1 expression. American journal of cancer research 5 37693160
2019 Mosaic variant in ATP2C1 presenting as relapsing linear acantholytic dermatosis. The British journal of dermatology 5 31605620
2016 Synergistic cytotoxicity of ampelopsin sodium and carboplatin in human non-small cell lung cancer cell line SPC-A1 by G1 cell cycle arrested. Chinese journal of integrative medicine 5 27299463
2016 Overexpression of Inhibitor of Growth 4 Enhances Radiosensitivity in Non-Small Cell Lung Cancer Cell Line SPC-A1. Technology in cancer research & treatment 5 27381846
2015 Different maspin functions in the lung adenocarcinoma A549 and SPC-A1 cell lines. International journal of molecular medicine 5 26329803
2005 Prokaryotic expression and polyclonal antibody preparation of novel ZLG10 protein involved in infection of RSV on SPC-A1 cells. Protein expression and purification 5 15802235

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