Affinage

ATP2B4

Plasma membrane calcium-transporting ATPase 4 · UniProt P23634

Round 2 corrected
Length
1241 aa
Mass
137.9 kDa
Annotated
2026-04-28
86 papers in source corpus 32 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATP2B4 encodes PMCA4, a ubiquitously expressed P-type Ca²⁺-ATPase that extrudes cytosolic Ca²⁺ across the plasma membrane and is regulated by calmodulin binding to a C-terminal domain subject to alternative splicing (PMCA4a/4b variants with distinct calmodulin sensitivity and tissue distributions) (PMID:2963820, PMID:1531651, PMID:8245032). Beyond its ion-transport function, PMCA4 acts as a structural scaffold that anchors nNOS in membrane microdomains to compartmentalize NO/cGMP/cAMP signaling in cardiomyocytes and sperm, thereby regulating cardiac contractility and sperm hyperactivated motility; accordingly, Pmca4-knockout mice are male-infertile and exhibit enhanced cardiac contractility with delocalized nNOS (PMID:15178683, PMID:21965681, PMID:28247940). PMCA4 controls red blood cell hydration through an erythroid-specific enhancer whose common variants reduce PMCA4b surface expression, slow Ca²⁺ clearance, and confer protection against P. falciparum malaria (PMID:28714864, PMID:36604655). In proliferating cells, PMCA4 Ca²⁺ efflux activity promotes G1-phase progression in vascular smooth muscle via cyclin D1/NFAT signaling, inhibits epithelial–mesenchymal transition in gastric cancer through the NFATc1–ZEB1 axis, and is required for EGF-induced macropinocytosis through regulation of Ca²⁺ oscillations (PMID:24448801, PMID:32860837, PMID:38597132).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1988 High

    Identification of the calmodulin-binding domain of the erythrocyte Ca²⁺ pump established the structural basis for calmodulin-dependent activation of PMCA, answering how pump activity is allosterically regulated.

    Evidence Chymotrypsin proteolysis and calmodulin photoaffinity cross-linking of purified human erythrocyte PMCA, with peptide sequencing

    PMID:2963820

    Open questions at the time
    • Full three-dimensional structure of calmodulin–PMCA complex not resolved
    • Isoform-specific calmodulin affinity differences not yet addressed
  2. 1992 High

    Cloning of PMCA4 as a distinct isoform and discovery of alternative splicing at the C-terminal regulatory domain (generating PMCA4a and PMCA4b) resolved how a single gene produces functionally distinct pump variants with different calmodulin sensitivities and tissue distributions.

    Evidence Molecular cloning, peptide sequencing of erythrocyte Ca²⁺-ATPase revealing two isoforms (PMCA1/PMCA4); PCR-based cDNA characterization and genomic sequencing showing splice site C usage across tissues

    PMID:1531651 PMID:2137451 PMID:8245032

    Open questions at the time
    • Functional consequences of splice variants not yet tested in cellular Ca²⁺ clearance assays
    • Regulation of splice-site choice unknown
  3. 2001 High

    Discovery that PMCA4b's C-terminal PDZ-binding motif interacts with MAGUK scaffolds (SAP97, PSD95, SAP102) and directs basolateral membrane targeting in polarized cells established how PMCA4 is positioned in specific membrane microdomains.

    Evidence Yeast two-hybrid screen, co-immunoprecipitation, confocal imaging in polarized MDCK cells

    PMID:11274188

    Open questions at the time
    • Whether PDZ-mediated targeting is required for PMCA4 physiological function in vivo not tested
    • Identity of all relevant PDZ partners in different tissues incomplete
  4. 2001 High

    Loss-of-function mutagenesis revealed PMCA4 is required for TNF-induced cell death by maintaining low cytosolic Ca²⁺ that prevents premature lysosomal exocytosis, uncovering a role for PMCA4 in regulated cell death beyond simple Ca²⁺ homeostasis.

    Evidence Retroviral insertion mutagenesis in L929 cells with lysosome exocytosis assays and Ca²⁺ measurement; phenotypic rescue by restoring vacuolar acidic compartment volume

    PMID:11713265

    Open questions at the time
    • Generalizability to other cell types and death receptor pathways not established
    • Whether PMCA4 pump activity or scaffold function is the key determinant unclear
  5. 2004 High

    Pmca4-knockout mice revealed PMCA4 is essential for sperm hyperactivated motility and male fertility but dispensable for spermatogenesis, establishing the first organism-level physiological role for PMCA4.

    Evidence Gene-targeted knockout mice; sperm motility assays, immunohistochemistry showing PMCA4 in sperm principal piece, ultrastructural Ca²⁺ overload evidence

    PMID:15178683

    Open questions at the time
    • Molecular mechanism linking Ca²⁺ overload to motility failure not fully dissected
    • Contribution of individual splice variants (4a vs 4b) to sperm function not resolved
  6. 2008 High

    Discovery that PMCA4b scaffolds nNOS within a cardiac SNTA1–SCN5A complex, and that disruption of this interaction causes unrestrained nNOS activity leading to long QT syndrome, revealed PMCA4's scaffold function as distinct from its pump activity.

    Evidence GST pull-down, co-immunoprecipitation, patch-clamp electrophysiology in heterologous cells and cardiomyocytes; disease-associated SNTA1 A390V mutation disrupting PMCA4b binding

    PMID:18591664

    Open questions at the time
    • Direct structural interface between PMCA4b and nNOS not resolved
    • Whether PMCA4 pump activity also contributes to cardiac nNOS regulation not separated from scaffold role
  7. 2011 High

    In vivo cardiac studies in Pmca4-knockout mice demonstrated that PMCA4 controls contractility not through beat-to-beat Ca²⁺ transport but by scaffolding nNOS to maintain compartmentalized cGMP/cAMP signaling, resolving a long-standing question about PMCA4's cardiac function.

    Evidence PMCA4 KO mice with in vivo contractility, FRET-based cAMP/cGMP sensors, nNOS localization assays, L-type Ca²⁺ channel recordings, RyR phosphorylation analysis

    PMID:21965681

    Open questions at the time
    • Whether PMCA4 scaffold function similarly dominates in non-cardiac tissues not established
    • Structural basis for nNOS anchoring to PMCA4 remains unresolved
  8. 2014 High

    Rescue experiments in Pmca4-KO vascular smooth muscle cells showed that Ca²⁺ efflux activity (not PDZ-binding) is required for G1 cell-cycle progression, with PMCA4a and PMCA4b converging on cyclin D1 upregulation through distinct intermediates, demonstrating splice-variant-specific signaling downstream of Ca²⁺ clearance.

    Evidence PMCA4 KO primary VSMCs, [³H]thymidine incorporation, flow cytometry, rescue with WT, splice variant, and pump-dead mutant constructs, microarray

    PMID:24448801

    Open questions at the time
    • In vivo relevance to vascular remodeling not confirmed
    • How reduced Ca²⁺ leads to different transcriptional responses depending on splice variant is unclear
  9. 2017 High

    PMCA4 was shown to form a quaternary complex with eNOS, nNOS, and Caveolin-1 in sperm, with Pmca4-KO leading to elevated NOS activity and peroxynitrite-driven germ cell apoptosis—unifying the Ca²⁺ clearance and NO-scaffolding functions in the context of male fertility.

    Evidence Reciprocal co-immunoprecipitation, FRET in sperm, NOS activity and peroxynitrite measurement in Pmca4⁻/⁻ mice

    PMID:28247940

    Open questions at the time
    • Whether pharmacological NOS inhibition can rescue Pmca4-KO infertility not tested
    • Stoichiometry and structural arrangement of the quaternary complex unknown
  10. 2017 High

    CRISPR deletion of an erythroid-specific enhancer and analysis of Atp2b4-KO mice established that ATP2B4 is the causal gene at a malaria GWAS locus, controlling RBC Ca²⁺ homeostasis and hydration (MCHC), with reduced PMCA4b surface expression slowing Ca²⁺ clearance and impairing P. falciparum growth.

    Evidence eQTL mapping, CRISPR enhancer deletion in erythroid cells, Atp2b4-KO mice (MCHC phenotype), recall-by-genotype functional Ca²⁺ assays, in vitro parasite growth with field isolates and pharmacological PMCA4b inhibition

    PMID:28216081 PMID:28714864 PMID:36604655

    Open questions at the time
    • Precise mechanism by which altered RBC Ca²⁺ impairs parasite development unknown
    • Whether other RBC membrane properties beyond Ca²⁺/hydration contribute to protection not resolved
  11. 2020 Medium

    Multiple studies extended PMCA4's role to cancer cell biology: PMCA4 inhibits EMT via the NFATc1–ZEB1 axis in gastric cancer, supports migration and apoptotic resistance in pancreatic cancer, and its downregulation by PDGF-BB/MEK/ERK drives proliferation of pulmonary arterial smooth muscle cells, establishing PMCA4 as a context-dependent modulator of proliferation, migration, and cell death.

    Evidence siRNA/overexpression with in vivo xenograft (gastric cancer), PMCA4 knockdown in MIA PaCa-2 cells (pancreatic cancer), PDGF-BB stimulation with MEK/ERK inhibitors and in vivo PAH rat models

    PMID:31963119 PMID:32860837 PMID:32966125

    Open questions at the time
    • Cancer phenotypes studied in single cell lines each; generalizability uncertain
    • Whether PMCA4's scaffold vs. pump function drives these cancer phenotypes not distinguished
    • Patient-level clinical significance of PMCA4 expression changes not established
  12. 2024 Medium

    CRISPR knockout demonstrated ATP2B4 is required for EGF-induced macropinocytosis via its Ca²⁺ pump activity (not PDZ interactions), regulating ruffle closure through Ca²⁺ oscillations—revealing a new cellular process dependent on PMCA4.

    Evidence CRISPR/Cas9 ATP2B4 KO in A431 cells, live-cell imaging of ruffles, Ca²⁺ oscillation measurement, rescue with PDZ-binding-domain mutant

    PMID:38597132

    Open questions at the time
    • Whether this function generalizes beyond EGF-stimulated A431 cells is untested
    • Downstream effectors linking Ca²⁺ oscillations to ruffle closure not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the high-resolution structure of PMCA4 with its regulatory and scaffolding domains, how pump vs. scaffold functions are differentially deployed across tissues, and whether PMCA4 variants or inhibitors can be therapeutically exploited for malaria protection, cancer, or cardiovascular disease.
  • No high-resolution structure of full-length PMCA4 available
  • Relative contribution of pump vs. scaffold function not systematically dissected across physiological contexts
  • No clinical trials targeting PMCA4

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140657 ATP-dependent activity 8 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 8
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1474165 Reproduction 3 R-HSA-1640170 Cell Cycle 1 R-HSA-397014 Muscle contraction 1
Partners
BSGCAV1DLG1DLG4NOS1NOS3SLC6A11SNTA1
Complex memberships
Caveolin-1-eNOS-nNOS complex (sperm)SNTA1-nNOS-SCN5A complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1988 Identification of the calmodulin-binding domain of the human erythrocyte Ca2+ pump (PMCA): chymotrypsin cleavage and photoaffinity cross-linking with calmodulin identified a ~12 kDa fragment containing the calmodulin-binding region, and its amino acid sequence was determined, establishing the structural basis for calmodulin-dependent activation of the pump. Chymotrypsin proteolysis, calmodulin photoaffinity cross-linking, reverse-phase HPLC peptide isolation, amino acid sequencing The Journal of biological chemistry High 2963820
1990 Peptide sequencing and molecular cloning of purified human erythrocyte Ca2+-ATPase revealed two distinct isoforms (PMCA1/hPMCA1 and a novel isoform hPMCA4) coexpressed in erythrocyte membranes, with sequence divergence in the extracellular loop between TM1-TM2, the negatively charged Ca2+-binding region, and the cAMP-dependent protein kinase phosphorylation site. Peptide sequence analysis, molecular cloning, Northern blot The Journal of biological chemistry High 2137451
1992 Alternative splicing of the PMCA4 (ATP2B4) primary transcript generates at least two major variants (PMCA4a and PMCA4b) at the C-terminal regulatory domain; PMCA4b contains an additional exon inserted immediately after the calmodulin-binding domain sequence that shifts the reading frame and truncates the C-terminal regulatory domain. Each splice variant has a distinct tissue distribution. PCR amplification of cDNA, Southern blotting, cDNA isolation and characterization, genomic sequencing The Journal of biological chemistry High 1531651
1993 Quantitative PCR analysis showed that PMCA4 (ATP2B4) mRNA is ubiquitously expressed in all tissues examined (cerebral cortex, skeletal and heart muscle, stomach, liver, lung, kidney), similar to PMCA1. Alternative splicing at site A (36-bp exon inclusion) and site C (178-bp exon exclusion) generates the major PMCA4 splice variants present across all tissues. Quantitative RT-PCR with GAPDH as internal standard, across seven human tissues The Journal of biological chemistry High 8245032
2001 PMCA4b interacts with multiple members of the membrane-associated guanylate kinase (MAGUK) family via its C-terminal PDZ-binding domain: SAP90/PSD95, PSD93/chapsyn-110, SAP97, and SAP102 all bind the C-terminal tail of PMCA4b. Co-immunoprecipitation confirmed the PMCA4b–SAP102 interaction, and confocal microscopy showed PMCA4b and SAP97 colocalize exclusively in the basolateral membrane of polarized MDCK cells, demonstrating PDZ-domain-mediated targeting of PMCA4b to specific membrane microdomains. Yeast two-hybrid screen, co-immunoprecipitation, confocal immunofluorescence microscopy in polarized MDCK cells The Journal of biological chemistry High 11274188
2001 PMCA4 is required for TNF-induced cell death in L929 cells. PMCA4-deficient cells show abnormally elevated intracellular Ca2+ following TNF stimulation. The elevated Ca2+ promotes lysosome exocytosis, which inhibits the TNF-induced increase in vacuolar acidic compartment (VAC) volume, thereby conferring resistance to TNF-induced cell death. Restoration of lysosome exocytosis inhibition or increase in VAC volume reversed resistance in PMCA4-mutant cells. Retrovirus insertion mutagenesis, intracellular Ca2+ measurement, lysosome exocytosis assays, sucrose treatment to modulate VAC Molecular and cellular biology High 11713265
2001 PMCA isoforms 1 and 4 are expressed ubiquitously in adult tissues, while PMCA2 and 3 are primarily in excitable cells. Alternative splicing at the first intracellular loop and the C-terminal tail (calmodulin-binding domain) generates isoform diversity with functional consequences: the C-terminal region regulates calmodulin sensitivity, phosphorylation, and differential interaction with PDZ domain-containing proteins. Review of functional studies, including splice variant characterization and knockout phenotypes Physiological reviews High 11152753
2004 Targeted knockout of Atp2b4 (PMCA4) in mice causes male infertility due to failure to achieve hyperactivated sperm motility, without affecting basal motility or spermatogenesis. PMCA4 is localized to the principal piece of the sperm tail (co-localizing with the CatSper Ca2+ channel), and its loss leads to mitochondrial condensation indicative of Ca2+ overload. PMCA4 knockout also impairs phasic contractions and causes apoptosis in portal vein smooth muscle in vitro (strain-dependent). Loss of PMCA1 (Atp2b1) causes embryolethality, establishing PMCA1 as an essential housekeeping gene and PMCA4 as specifically required for sperm hyperactivation. Gene targeting/knockout mice, sperm motility assays, immunoblotting, immunohistochemistry, ultrastructural analysis, in vitro smooth muscle contractility The Journal of biological chemistry High 15178683
2008 Alpha1-syntrophin (SNTA1) links PMCA4b (encoded by ATP2B4) to neuronal nitric oxide synthase (nNOS) and the cardiac sodium channel SCN5A in a macromolecular complex. A disease-associated A390V-SNTA1 mutation selectively disrupts PMCA4b binding to this complex, releasing nNOS inhibition and causing S-nitrosylation of SCN5A, increasing late sodium current and causing long QT syndrome. This identifies PMCA4b as a critical inhibitor of nNOS within a cardiac membrane signaling complex. GST pull-down, co-immunoprecipitation, heterologous cell expression, patch-clamp electrophysiology, cardiac myocyte expression Proceedings of the National Academy of Sciences of the United States of America High 18591664
2010 In bovine epididymis, a splice variant switch occurs during sperm maturation: PMCA4b is the major variant in testis and caput/corpus epididymidis, whereas PMCA4a becomes the dominant isoform in cauda epididymidis. PMCA4a has higher basal Ca2+ transport activity and is more effective than PMCA4b at returning Ca2+ to resting levels. Immunohistochemical and Western blot analyses show PMCA4a is transferred to sperm membranes in the cauda epididymidis, suggesting this isoform switch facilitates higher Ca2+ turnover needed for hyperactivated motility. Quantitative PCR, immunohistochemistry with novel anti-PMCA4a antibody, Western blotting of sperm from caput vs. cauda epididymidis The Journal of biological chemistry Medium 21187283
2010 PMCA4 is localized in both detergent-resistant membrane (DRM/lipid raft) and detergent-soluble fractions of bovine sperm plasma membrane, and co-localizes with caveolin in the mid-piece. The seminal vesicle protein PDC-109 enhances Ca2+-ATPase activity preferentially in the detergent-soluble fractions of cauda sperm, suggesting functional compartmentalization of PMCA4 in sperm membrane microdomains. Sucrose density gradient fractionation (DRM isolation), immunocytochemistry, Ca2+-ATPase functional assays, lipid overlay experiments International journal of andrology Medium 20050939
2011 PMCA4 forms a signaling complex with neuronal nitric oxide synthase (nNOS) in the cardiac cell membrane and acts as a structural scaffold that maintains nNOS in a defined microdomain. In PMCA4-/- mice, >36% of membrane-associated nNOS is delocalized to cytosol without change in total nNOS, leading to decreased microdomain cGMP, decreased PDE2 activity, elevated local cAMP, increased L-type calcium channel activity and ryanodine receptor phosphorylation, and enhanced cardiac contractility. This demonstrates PMCA4 regulates cardiac contractility via compartmentalized cyclic nucleotide signaling rather than beat-to-beat Ca2+ transport. PMCA4 knockout mice, in vivo contractility measurements, Ca2+ amplitude measurements, nNOS localization/activity assays, FRET-based cAMP/cGMP sensors, L-type channel recordings, ryanodine receptor phosphorylation analysis The Journal of biological chemistry High 21965681
2013 A novel PMCA4-GCaMP2 fusion protein (Ca2+ sensor fused to N-terminus of PMCA4) correctly targets to the plasma membrane in cardiomyocytes, co-localizes with caveolin-3, and monitors subsarcolemmal Ca2+ dynamics in real time. The active pump generates higher signal amplitude and faster Ca2+ decay than an inactive mutant form. A novel small-molecule PMCA4-specific inhibitor was identified by library screening, which reduces Ca2+ clearance near the pump comparable to the inactive mutant, confirming PMCA4 Ca2+ transport activity at the cardiac membrane microdomain. Adenoviral expression, live-cell fluorescence imaging of Ca2+ sensor fusion protein, small molecule library screen, electrically stimulated neonatal and adult rat cardiomyocytes Journal of molecular and cellular cardiology Medium 23880607
2014 Ca2+ efflux activity of PMCA4 is required for G1 phase progression in vascular smooth muscle cells (VSMCs). PMCA4 knockout VSMCs show impaired [3H]thymidine incorporation and G1 arrest. Rescue with PMCA4a, PMCA4b, or a PMCA4b PDZ-binding mutant restores proliferation, but a mutant with only 10% of normal Ca2+ efflux activity cannot rescue. The PMCA4a and PMCA4b splice variants differentially regulate downstream mediators: PMCA4a rescue reduces AP-2β (anti-proliferative), while PMCA4b rescue reduces p15 (Cyclin D1/Cdk4 inhibitor), both converging on Cyclin D1/NFATc3 upregulation. PMCA4 knockout primary VSMCs, [3H]thymidine incorporation, flow cytometry (cell cycle), electroporation of expression constructs, microarray, Western blotting, laser capture microdissection The Journal of biological chemistry High 24448801
2014 A novel missense mutation (c.803G>A, p.R268Q) in ATP2B4 (PMCA4) co-segregates with autosomal dominant familial spastic paraplegia in a Chinese family. Computational modeling predicts the R268Q mutation destabilizes PMCA4 protein structure, increases folding free energy, and is located in a protein aggregation-prone segment susceptible to misfolding. Whole-exome sequencing, Sanger sequencing, co-segregation analysis, computational protein stability modeling PloS one Low 25119969
2015 The R268Q mutation in PMCA4 (ATP2B4) causes delayed intracellular Ca2+ extrusion in human neuroblastoma cells. Overexpression of mutant R268Q PMCA4 in SH-SY5Y cells results in significantly higher peak Ca2+ surge after KCl-induced depolarization and persistently elevated steady-state cytosolic Ca2+ after SERCA inhibition with thapsigargin, compared to wild-type PMCA4, demonstrating a loss-of-function effect on Ca2+ clearance. Fura-2 fluorescence Ca2+ imaging with confocal microscopy in SH-SY5Y neuroblastoma cells overexpressing WT or R268Q PMCA4, KCl depolarization, thapsigargin treatment Brain and behavior Medium 25798335
2016 PMCA4 interacts with CD147 (Ig superfamily member) via CD147's transmembrane domain and Ig-like domain II. This interaction is required for CD147-dependent inhibition of IL-2 expression in T cells via a calcium-independent mechanism. CD147 does not control PMCA4 membrane localization, but PMCA4 is essential for the immunosuppressive effect of CD147, bypassing TCR proximal signaling. Affinity purification combined with mass spectrometry, siRNA silencing, domain-mapping experiments, IL-2 reporter assays in human T cells Journal of immunology Medium 26729804
2017 PMCA4 coordinates Ca2+ and nitric oxide (NO) signaling in murine sperm to maintain motility. Co-immunoprecipitation and FRET demonstrate PMCA4 associates with eNOS and nNOS in sperm, forming a quaternary complex that also includes Caveolin-1. In Pmca4-/- sperm, NOS activity is elevated twofold, accompanied by a twofold increase in peroxynitrite and increased apoptotic germ cells, establishing PMCA4 as a negative regulator of NOS in sperm that coordinates Ca2+ clearance and NO production to maintain motility. Co-immunoprecipitation (Co-IP), FRET in capacitated and uncapacitated sperm, NOS activity assay, peroxynitrite measurement, apoptosis assay in Pmca4-/- mice Journal of cellular physiology High 28247940
2017 An erythroid-specific enhancer element in the ATP2B4 locus regulates PMCA4 expression in red blood cells. CRISPR-Cas9 deletion of this enhancer in erythroid cells causes abnormally high intracellular Ca2+ levels. Atp2b4-/- mice show increased mean corpuscular hemoglobin concentration (MCHC), confirming ATP2B4 as the causal gene at a malaria-susceptibility GWAS locus and demonstrating that ATP2B4 controls RBC hydration through Ca2+ regulation. eQTL mapping in erythroblasts, CRISPR-Cas9 enhancer deletion, Atp2b4 knockout mice, intracellular Ca2+ measurement, MCHC quantification The Journal of clinical investigation High 28714864
2017 Reduced PMCA4b protein expression in human red blood cells correlates with a minor haplotype in the predicted second promoter region of ATP2B4 (not coding mutations), and reduced PMCA4b levels result in lower Ca2+ extrusion capacity. This haplotype corresponds to GWAS SNPs linked to reduced mean corpuscular hemoglobin concentration and malaria protection. Flow cytometry with specific antibody binding (quantitative), Western blot of RBC membranes, Ca2+ extrusion assays, DNA sequencing of ATP2B4 coding and promoter regions Cell calcium Medium 28216081
2020 PMCA4 inhibits epithelial-mesenchymal transition (EMT) in gastric cancer cells via the NFATc1-ZEB1 pathway. PMCA4 knockdown increases nuclear NFATc1 accumulation and ZEB1 expression, suppresses E-cadherin/GRHL2/OVOL1, and promotes vimentin upregulation, increased migration/invasion, and drug resistance. These effects are prevented by knockdown of NFATc1 or ZEB1, or by cyclosporine A (calcineurin/NFAT inhibitor), placing PMCA4 upstream of the NFATc1-ZEB1 EMT axis. siRNA knockdown, overexpression, in vivo xenograft metastasis assay, Western blot, migration/invasion assays, cyclosporine A treatment Biochimica et biophysica acta. Molecular cell research Medium 32860837
2020 PMCA4 expression in pancreatic ductal adenocarcinoma (PDAC) cells supports cytosolic Ca2+ clearance, cell migration, and apoptotic resistance. siRNA knockdown of PMCA4 in MIA PaCa-2 cells (which almost exclusively express PMCA4) reduces Ca2+ clearance rate, decreases cell migration, and sensitizes cells to apoptosis without affecting cell growth or metabolic parameters. siRNA knockdown, Ca2+ clearance assays, migration assays, apoptosis assays, Seahorse XF metabolic analysis, Western blot, RT-qPCR Cancers Medium 31963119
2020 PDGF-BB signaling downregulates PMCA4 expression in pulmonary arterial smooth muscle cells (PASMCs) via the MEK/ERK pathway. PMCA4 suppression attenuates Ca2+ clearance, promotes cell proliferation, and elevates cell locomotion through formation of focal adhesions. PMCA4 expression is also decreased in pulmonary arteries of monocrotaline- and hypoxia-induced PAH rats, and knockdown of PMCA4 in normal rats increases right ventricular systolic pressure and pulmonary artery wall thickness. PDGF-BB stimulation with MEK/ERK inhibitors, siRNA knockdown, Ca2+ clearance assays, proliferation assays, focal adhesion imaging, in vivo rat PAH models, hemodynamic measurements American journal of physiology. Cell physiology Medium 32966125
2020 PMCA4 (ATP2B4) is expressed in adrenal tissue (HAC15 cells) and contributes to membrane conductance. ATP2B4 knockdown in HAC15 cells reduced angiotensin II-stimulated responses in some clones. Whole-cell recordings confirmed robust endogenous ATP2B4 conductance, and overexpression of WT or variant ATP2B4 reduced conductance compared to endogenous levels. shRNA knockdown, doxycycline-inducible stable cell lines, whole-cell patch-clamp electrophysiology, aldosterone synthase (CYP11B2) expression assays Hormones & cancer Low 32002807
2022 CRISPR/Cas9-mediated deletion of a regulatory region containing five ATP2B4 SNPs (rs11240734, rs1541252, rs1541253, rs1541254, rs1541255) in K562 cells decreases ATP2B4 transcript and protein levels and increases intracellular Ca2+ concentration, demonstrating that this non-coding regulatory element controls PMCA4 expression and thereby Ca2+ homeostasis in erythroid cells. CRISPR/Cas9 regulatory region deletion, RT-qPCR, Western blot, intracellular Ca2+ measurement in K562 cells, SNP association analysis International journal of molecular sciences Medium 35563239
2022 Multiple myeloma-derived exosomal miR-4261 is transferred into red blood cells and downregulates ATP2B4 expression by directly targeting its mRNA (confirmed by dual-luciferase assay), reducing PMCA4 protein levels and causing calcium overload in RBCs. Transwell exosome transfer assay, dual-luciferase reporter assay, flow cytometry, Western blot, atomic absorption spectroscopy for Ca2+ Frontiers in oncology Medium 36091107
2023 RBCs from homozygous carriers of the minor ATP2B4 haplotype (rs1541252 C/C) show significantly reduced PMCA4b protein surface expression and markedly slower rates of Ca2+ expulsion (calcium t½ = 4.7 min vs 1.9 min for wildtype). P. falciparum growth (both laboratory strain and field isolates) is decreased in RBCs from homozygotes, and PMCA4b inhibition with aurintricarboxylic acid (IC50=122 µM) also inhibits parasite growth, supporting Ca2+ channel blockade as the protective mechanism. Recall-by-genotype study design, flow cytometry (PMCA4b surface expression), Ca2+ expulsion kinetics, in vitro P. falciparum growth assays with field isolates, pharmacological PMCA4b inhibition Malaria journal Medium 36604655
2024 ATP2B4 (encoding PMCA4) is an essential gene for EGF-induced macropinocytosis in A431 cells. ATP2B4 knockout inhibits ruffle closure and macropinosome formation without affecting ruffle formation. PMCA4 Ca2+ pump activity itself (independent of C-terminal PDZ-binding interactions) is required, as it regulates EGF-stimulated Ca2+ oscillations during macropinocytosis. Both intracellular and extracellular Ca2+ are required for this process. CRISPR/Cas9 ATP2B4 knockout, fluid-phase uptake assays, live-cell imaging of ruffle formation and closure, Ca2+ oscillation measurement, expression of PMCA4 mutant lacking PDZ-binding motif Genes to cells Medium 38597132
2024 GATA1 binds to the erythroid-specific ATP2B4 promoter in a sequence-specific manner. Using a native holdup (nHU) assay, the short isoform GATA1s (lacking N-terminal transactivation domain) binds this promoter with increased affinity relative to full-length GATA1, while the disease-associated R307C mutation reduces binding affinity. These binding differences translate into altered functional activity at the ATP2B4 erythroid promoter. Native holdup (nHU) assay for quantitative DNA-protein interaction analysis, luciferase reporter assay for functional validation bioRxivpreprint Low
2025 Pooled CRISPR screens in erythroid cells identified ATP2B4 as a regulator of red blood cell density, confirming its role in RBC biology as established by prior GWAS and functional studies. Pooled CRISPR perturbation screen with density gradient separation in erythroid cell line bioRxivpreprint Low
2025 In C6 glioma cells, PMCA4 localizes to lipid raft microdomains and interacts with GAT3 (GABA transporter 3). Knockdown of PMCA4 increases resting Ca2+ and Ca2+ accumulation in lipid rafts following GABA stimulation, impairing glioma cell migration and invasion. Long-term GABA stimulation disrupts the PMCA4/GAT3 complex and overloads lipid rafts with Ca2+. PMCA4 interacts with calmodulin (a key PMCA4 regulator) and participates in GAT3/CaMKII-dependent CREB phosphorylation at Ser133 required for glioma invasiveness. siRNA knockdown, lipid raft fractionation, Ca2+ imaging, migration and invasion assays, Co-IP, CREB phosphorylation analysis Cell calcium Medium 40580687
2026 FOXM1 inhibitor RCM-1 downregulates ATP2B4 expression in rhabdomyosarcoma (RMS) cells. ATP2B4 knockdown decreases RMS cell proliferation, migration, and colony formation, increases apoptosis, and reduces tumor growth in animal models. ATP2B4 overexpression decreases apoptosis. RCM-1 combined with venetoclax (Bcl-2 inhibitor) uniquely decreases ATP2B4 expression and sensitizes RMS cells to apoptosis. siRNA knockdown, overexpression, in vivo tumor growth assay, RNA-sequencing, apoptosis assays, colony formation, migration assays International journal of oncology Medium 41789627
2026 Sodium pentachlorophenol (PCP-Na) reduces ATP2B4 protein expression in mouse testes, preventing normal Ca2+ efflux, causing intracellular Ca2+ accumulation and Ca2+ overload. This Ca2+ overload drives oxidative stress (ROS increase) and inflammation, and is correlated with reduced testosterone levels. siRNA knockdown of ATP2B4 in vitro recapitulates the Ca2+ accumulation, confirming ATP2B4 as the upstream key protein in this signaling axis. ATP2B4 siRNA transfection in vitro, NAC and BAPTA-AM inhibitor treatment, Ca2+ measurement, ROS assay, testosterone assay, Western blot Pesticide biochemistry and physiology Low 41831900
2026 In multiple myeloma, miR-4261 targets and downregulates YWHAE (14-3-3ε), CAST (calpastatin), and GPX1, which are regulators of PMCA4 function in erythrocytes. Downregulation of these three proteins impairs PMCA4 function, leading to Ca2+ overload and oxidative stress in RBCs. Dual-luciferase assays confirmed direct miR-4261 binding to YWHAE, CAST, and GPX1 mRNAs. Dual-luciferase reporter assays, qRT-PCR, Western blot, ROS/H2O2/GSH measurement, atomic absorption spectroscopy for Ca2+, targeted drug (calpain-1 and PMCA4 inhibitors) treatment Indian journal of pathology & microbiology Low 41983776

Source papers

Stage 0 corpus · 86 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Blood-Brain Barrier: From Physiology to Disease and Back. Physiological reviews 1645 30280653
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2000 DNA cloning using in vitro site-specific recombination. Genome research 815 11076863
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1996 Structural organization, ion transport, and energy transduction of P-type ATPases. Biochimica et biophysica acta 618 8634322
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
2001 Role of alternative splicing in generating isoform diversity among plasma membrane calcium pumps. Physiological reviews 469 11152753
2004 Biology, structure and mechanism of P-type ATPases. Nature reviews. Molecular cell biology 447 15071553
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2012 Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature 319 22810586
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