Affinage

ATP7A

Copper-transporting ATPase 1 · UniProt Q04656

Length
1500 aa
Mass
163.4 kDa
Annotated
2026-06-09
100 papers in source corpus 23 papers cited in narrative 24 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

ATP7A is a P1B-type copper-transporting ATPase that controls cellular copper homeostasis by both metalating cuproenzymes in the secretory pathway and effluxing excess copper across membranes (PMID:8589689, PMID:17009961). Reconstituted full-length protein exhibits Cu(I)-dependent ATPase activity with strong positive cooperativity, forms a vanadate-sensitive phosphoenzyme intermediate, and mediates active ATP-dependent vectorial copper transport (PMID:17009961). Under basal copper conditions ATP7A resides predominantly in the trans-Golgi network and constitutively cycles via the plasma membrane; elevated copper stimulates exocytic redistribution to the cell surface, and a C-terminal di-leucine motif (L1487/L1488) drives internalization through a Rac1-regulated, clathrin- and caveolae-independent endocytic route (PMID:9668172, PMID:10484781, PMID:12812980). In polarized epithelia copper triggers relocation to the basolateral membrane via di-leucine and PDZ-type targeting signals, and in melanocytes ATP7A is delivered to melanosomes in a BLOC-1-dependent manner to supply copper to tyrosinase for melanin synthesis (PMID:15269005, PMID:18650808). Its trafficking and stability are set by multiple partners: AP-1A confers TGN retention and sorting polarity, WW-PLEKHA/PDZD11 complexes drive anterograde targeting to the cell periphery for copper extrusion, and Akt2-mediated phosphorylation stabilizes the protein and promotes plasma-membrane translocation, whereas clusterin and COMMD1 independently route it to lysosomal and proteasomal degradation (PMID:22130675, PMID:29301787, PMID:34613798, PMID:38032054). Beyond copper export, ATP7A supplies copper to secreted enzymes including SOD3 and lysyl oxidase family members (LOX/LOXL), supporting extracellular antioxidant defense and tumor-promoting LOX activity, and at the plasma membrane it binds VEGFR2 to limit autophagy-mediated VEGFR2 degradation and sustain angiogenesis (PMID:29301787, PMID:30890638, PMID:34035268). Loss-of-function and mislocalizing mutations underlie disease: reduced functional ATP7A causes occipital horn syndrome and Menkes-spectrum defects, while the missense mutations T994I and P1386S shift ATP7A to the plasma membrane through impaired endocytic retrieval and aberrant p97/VCP interaction, causing ATP7A-related distal motor neuropathy (PMID:11431706, PMID:22210628).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1995 High

    Established that ATP7A is functionally responsible for transmembrane copper efflux, not merely correlated with copper resistance.

    Evidence Gene amplification, immunoblot, and copper accumulation assays in copper-resistant CHO variants

    PMID:8589689

    Open questions at the time
    • Did not resolve the catalytic mechanism or transport directionality
    • Subcellular site of action unknown
  2. 1998 High

    Defined the copper-regulated trafficking behavior central to ATP7A function: basal TGN residence with reversible redistribution to the plasma membrane upon copper elevation.

    Evidence Immunogold EM, confocal microscopy, and copper resistance assays in stably transfected CHO-K1 cells

    PMID:9668172

    Open questions at the time
    • Trafficking signals and machinery not identified
    • Whether redistribution reflects altered exit or retrieval unresolved
  3. 1999 High

    Resolved that copper stimulates exocytic delivery rather than blocking retrieval and identified the di-leucine motif as the endocytic signal, defining the basis of constitutive cycling.

    Evidence Extracellular epitope tagging, antibody internalization assays, and di-leucine mutagenesis in living cells

    PMID:10484781

    Open questions at the time
    • Endocytic machinery recognizing the motif not identified
    • Mechanism of copper-stimulated exocytosis unknown
  4. 1999 Medium

    Linked ATP7A localization/redistribution capacity to disease severity using Menkes/OHS mouse models, connecting trafficking competence to copper transport phenotype.

    Evidence Copper transport assays and immunofluorescence in brindled and blotchy mutant fibroblasts

    PMID:10332039

    Open questions at the time
    • Molecular defects in mutant proteins not biochemically defined
    • Single-lab cell-based correlation
  5. 2001 Medium

    Showed that the di-leucine endocytic motif is dispensable for copper efflux per se and that OHS arises from reduced functional ATP7A levels.

    Evidence Mutation analysis, transcript quantification, and genotype-phenotype correlation

    PMID:11431706

    Open questions at the time
    • No biochemical reconstitution of the truncated protein
    • Quantitative threshold for OHS vs Menkes not defined
  6. 2003 High

    Defined ATP7A endocytosis as a novel Rac1-regulated, clathrin- and caveolae-independent pathway, distinguishing it from canonical receptor internalization.

    Evidence Dominant-negative dynamin/Eps15, caveolae inhibitors, and constitutively active Rac1 with internalization reporters

    PMID:12812980

    Open questions at the time
    • Rac1 effectors mediating internalization not identified
    • Apparent conflict with later evidence for clathrin involvement
  7. 2004 High

    Mapped trafficking signals in polarized epithelia, showing N-terminal metal-binding sites gate copper-regulated Golgi exit while di-leucine and PDZ motifs direct basolateral targeting.

    Evidence Surface biotinylation, confocal microscopy, and motif mutagenesis in polarized MDCK cells

    PMID:15269005

    Open questions at the time
    • PDZ-binding partner not identified at this stage
    • Did not establish the responsible sorting adaptors
  8. 2004 Medium

    Indicated that ATP7A can use both clathrin-dependent and clathrin-independent endocytosis, nuancing the strictly clathrin-independent model.

    Evidence Dominant-negative dynamin/Eps15 and hypertonic sucrose in MNK-overexpressing HeLa cells

    PMID:14977365

    Open questions at the time
    • Reconciliation with Rac1-only pathway unresolved
    • Possible overexpression artifact not excluded
  9. 2007 High

    Provided definitive biochemical proof of catalytic mechanism: cooperative Cu(I)-dependent ATPase activity, phosphoenzyme formation, and vectorial copper transport by purified protein.

    Evidence Reconstitution of affinity-purified human ATP7A into proteoliposomes with phosphoenzyme, ATPase, and 64Cu transport assays

    PMID:17009961

    Open questions at the time
    • Structural basis of cooperativity not resolved
    • Number of functional metal-binding sites in catalysis not defined
  10. 2007 Medium

    Established a developmental, neuronal requirement for ATP7A in axon outgrowth and synaptogenesis beyond systemic copper supply.

    Evidence Neuroanatomical analysis of the olfactory system in brindled Menkes mouse model

    PMID:17215139

    Open questions at the time
    • Cannot separate cell-autonomous ATP7A loss from systemic copper deficiency
    • Molecular copper-dependent targets in neurons not identified
  11. 2008 High

    Demonstrated that ATP7A metalates cuproenzymes at their organelle of function, supplying copper to tyrosinase within melanosomes via BLOC-1-dependent delivery.

    Evidence Co-localization, fractionation, tyrosinase activity assays, and BLOC-1 mutant melanocytes

    PMID:18650808

    Open questions at the time
    • How BLOC-1 recruits ATP7A mechanistically not defined
    • Generality to other cuproenzymes/organelles unaddressed
  12. 2009 Medium

    Identified transcriptional and downstream functional roles linking ATP7A to retinoid signaling and macrophage lipid oxidation.

    Evidence RARβ2 gain/loss-of-function with copper efflux and viability assays; ATP7A siRNA with cPLA2α promoter and LDL oxidation assays

    PMID:19127267 PMID:19965596

    Open questions at the time
    • Mechanism by which ATP7A regulates cPLA2α transcription unclear
    • Single-lab observations
  13. 2011 High

    Defined degradation control of ATP7A, with clusterin and COMMD1 routing it to lysosomal and proteasomal pathways respectively.

    Evidence Reciprocal Co-IP, overexpression/knockdown, and pathway-specific inhibitors with immunoblot

    PMID:22130675

    Open questions at the time
    • Whether degradation is copper-state dependent not resolved
    • Ubiquitin ligase for proteasomal route not identified
  14. 2011 High

    Established the molecular basis of ATP7A-related distal motor neuropathy: mutations cause exaggerated plasma-membrane accumulation through impaired retrieval and aberrant p97/VCP interaction.

    Evidence TIRF microscopy, co-IP, siRNA rescue, and flow cytometry of Venus-tagged mutants in HEK293T and motor neurons

    PMID:22210628

    Open questions at the time
    • How surface ATP7A causes neuronal toxicity not defined
    • Role of p97/VCP in normal ATP7A retrieval unclear
  15. 2017 High

    Defined Akt2-mediated phosphorylation as a stabilization and trafficking signal that couples ATP7A to extracellular SOD3 activity and vascular protection.

    Evidence In vitro kinase assay with MS phosphosite mapping, Akt2-/- mice, and SOD3 activity rescue in VSMCs

    PMID:29301787

    Open questions at the time
    • Direct effect of phosphosites on transport activity not tested
    • Phosphatase counteracting Akt2 not defined
  16. 2017 Medium

    Showed ATP7A is co-opted for influenza A virus replication, supporting viral polymerase activity and RNA synthesis.

    Evidence siRNA knockdown with minigenome polymerase assay and viral protein/RNA quantification

    PMID:28115001

    Open questions at the time
    • Whether copper transport or a copper-independent function is required unclear
    • Direct viral interaction not demonstrated
  17. 2019 High

    Established ATP7A as essential for LOX/LOXL cuproenzyme activity, linking copper supply to focal-adhesion signaling and tumor metastasis.

    Evidence ATP7A siRNA with LOX activity, FAK phosphorylation, and orthotopic mouse metastasis models

    PMID:30890638

    Open questions at the time
    • Site of LOX metalation by ATP7A not localized
    • Therapeutic targetability not established
  18. 2020 Medium

    Demonstrated functional interplay between metallothioneins and ATP7A in buffering copper, with synthetic lethality upon combined loss.

    Evidence ATP7A and MT-I/II knockouts with trafficking imaging and viability assays under copper stress

    PMID:32398691

    Open questions at the time
    • Molecular basis of MT-controlled ATP7A trafficking unclear
    • Single-lab genetic model
  19. 2021 High

    Identified a copper-independent signaling role: plasma-membrane ATP7A binds VEGFR2 to block p62/SQSTM1-mediated autophagic degradation and sustain angiogenesis.

    Evidence EC-specific ATP7A knockout and mutant mice, reciprocal co-IP, autophagy reporter mice, and neovascularization assays

    PMID:34035268

    Open questions at the time
    • Whether ATP7A catalytic activity is required for VEGFR2 protection unresolved
    • Structural basis of ATP7A-VEGFR2 binding undefined
  20. 2021 High

    Defined the WW-PLEKHA/PDZD11 module as the adaptor system that targets ATP7A to the cell periphery for copper extrusion, fulfilling the earlier-predicted PDZ-dependent targeting.

    Evidence CRISPR knockout of PLEKHA5/6/7 and PDZD11 with pull-downs and copper efflux assays in kidney epithelial cells

    PMID:34613798

    Open questions at the time
    • How the module is regulated by copper status unclear
    • Relationship to AP-1-dependent sorting not integrated
  21. 2022 Medium

    Implicated PKD phosphorylation in maintaining ATP7A stability against proteasomal degradation.

    Evidence PKD and proteasome inhibitor treatments with immunoblot and RT-PCR in HeLa and HepG2 cells

    PMID:35908410

    Open questions at the time
    • No direct kinase assay confirming PKD phosphorylation of ATP7A
    • Phosphosites not mapped
  22. 2023 High

    Established AP-1A as the adaptor providing ATP7A sorting polarity and TGN retention, completing the sorting-machinery picture.

    Evidence Isoform-specific AP-1 CRISPR knockouts with trafficking imaging and MS partner identification in polarized epithelia

    PMID:38032054

    Open questions at the time
    • Direct AP-1A recognition motif on ATP7A not mapped
    • Interplay with WW-PLEKHA/PDZD11 targeting unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How copper status, multiple kinases (Akt2, PKD), and competing adaptor/degradation systems are integrated to set ATP7A localization in real time, and whether its copper-independent VEGFR2 signaling role requires catalytic activity, remain unresolved.
  • No unified regulatory model linking phosphorylation, adaptors, and degradation
  • Catalytic requirement for non-canonical (VEGFR2, viral) functions undefined
  • No high-resolution structure to explain copper-cooperative catalysis and trafficking signals

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 2 GO:0016787 hydrolase activity 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005886 plasma membrane 5 GO:0005794 Golgi apparatus 3 GO:0005768 endosome 2 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2 R-HSA-382551 Transport of small molecules 2 R-HSA-9612973 Autophagy 1
Partners
AKT2CLUCOMMD1PDZD11PLEKHA5PLEKHA7VCPVEGFR2

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 Gene amplification of ATP7A (MNK) in copper-resistant CHO cell variants is associated with increased MNK mRNA and protein (~178 kDa on SDS gels) and enhanced copper efflux, providing direct experimental evidence that ATP7A mediates transmembrane copper efflux. Southern blot, FISH, SDS-PAGE/immunoblot, copper accumulation assays in copper-resistant CHO cell variants Human molecular genetics High 8589689
1998 ATP7A (MNK) protein localizes primarily to the trans-Golgi network (TGN) under basal copper conditions and redistributes to the cytoplasm and plasma membrane upon elevated extracellular copper, returning to the TGN when copper is reduced; stable cDNA expression in CHO-K1 cells conferred copper resistance proportional to protein levels. Immunogold electron microscopy, confocal microscopy, immunofluorescence, stable transfection in CHO-K1 cells, copper resistance assays Human molecular genetics High 9668172
1999 ATP7A constitutively cycles via the plasma membrane even under basal copper conditions; elevated copper stimulates exocytic movement of ATP7A to the plasma membrane rather than reducing retrieval; a C-terminal di-leucine motif (L1487/L1488) functions as an endocytic signal required for internalization from the plasma membrane. c-myc epitope tagging within the first extracellular loop; antibody internalization assays in living cells; site-directed mutagenesis of di-leucine motif; co-localization with transferrin Human molecular genetics High 10484781
1999 In cells from brindled (Mo-br) and blotchy (Mo-blo) mouse mutants (models for Menkes disease and occipital horn syndrome), the Mnk protein shows altered intracellular localization and loss of copper-regulated redistribution; the severity of copper transport defect correlates with the amount of Mnk protein, its intracellular location, and its ability to redistribute in elevated copper. Copper transport assays, immunofluorescence localization in cultured fibroblasts from mouse mutants Human molecular genetics Medium 10332039
2001 A frameshift mutation in ATP7A exon 23 producing a truncated protein lacking the di-leucine endocytic motif (L1487/L1488) results in occipital horn syndrome rather than classic Menkes disease, supporting that OHS results from lower levels of functional ATP7A and that ATP7A does not require the di-leucine motif for copper efflux per se. Mutation analysis, transcript quantification, clinical phenotype-genotype correlation American journal of human genetics Medium 11431706
2003 ATP7A internalization from the plasma membrane is independent of clathrin-mediated endocytosis (dominant-negative dynamin-I, dynamin-II, and Eps15 do not inhibit it) and caveolae-mediated uptake; internalization is inhibited by constitutively active Rac1 GTPase, defining a novel Rac1-regulated endocytic pathway for ATP7A. Expression of dominant-negative dynamin-I, dynamin-II, Eps15 mutants; caveolae inhibitors; constitutively active Rac1 expression; internalization assays with ATP7A reporter (CD8-MCF1) Human molecular genetics High 12812980
2004 In polarized MDCK epithelial cells, ATP7A relocalizes from the Golgi to the basolateral membrane under elevated copper; N-terminal metal-binding sites are required for copper-regulated Golgi-to-plasma-membrane trafficking; a C-terminal di-leucine motif is critical for basolateral targeting; a putative PDZ target motif is required for basolateral membrane localization in elevated copper. Confocal microscopy, surface biotinylation, site-directed mutagenesis of trafficking motifs in polarized MDCK cells American journal of physiology. Cell physiology High 15269005
2004 ATP7A endocytosis in HeLa cells is not inhibited by dominant-negative dynamin or Eps15, but is inhibited by hypertonic sucrose, suggesting that MNK can utilize both clathrin-dependent and clathrin-independent endocytosis. Transient expression of dominant-negative dynamin and Eps15; hypertonic sucrose treatment; internalization assays in MNK-overexpressing HeLa cells Biometals Medium 14977365
2007 Purified full-length human ATP7A (MNK) reconstituted into liposomes exhibits Cu(I)-dependent ATPase activity (K0.5 = 0.6 µM, Hill coefficient ~5.0), forms a vanadate-sensitive phosphoenzyme intermediate activated by Cu(I) (EC50 = 0.7 µM), and mediates active ATP-dependent vectorial 64Cu transport, demonstrating cooperative Cu(I) interaction in the sub-micromolar range. Affinity purification from Sf9 insect cells, size-exclusion chromatography, vanadate-sensitive phosphoenzyme assay, ATPase activity assay, 64Cu transport in proteoliposomes The Biochemical journal High 17009961
2007 ATP7A has a role in axonal targeting and synaptogenesis: in the mottled brindled mouse model of Menkes disease, loss of ATP7A disrupts olfactory sensory neuron axonal projections, mitral/tufted cell dendritic growth, synapse integrity, and glomerular organization in the olfactory bulb, demonstrating a developmental requirement for ATP7A (and/or copper) in axon outgrowth. In vivo immunostaining and morphological analysis of olfactory system in Atp7a(Mobr) mice; developmental expression analysis Molecular and cellular neurosciences Medium 17215139
2008 ATP7A localizes to melanosomes in a BLOC-1-dependent manner in melanocytes, where it supplies copper to tyrosinase within melanosomes (not merely the TGN), enabling sustained tyrosinase activity and melanin synthesis; BLOC-1 subunit mutations disrupt this ATP7A localization and cause hypopigmentation. Immunofluorescence co-localization, subcellular fractionation, tyrosinase activity assays, analysis of BLOC-1 mutant melanocytes, live-cell imaging Nature High 18650808
2011 Clusterin and COMMD1 independently interact with ATP7A and regulate its degradation: clusterin promotes ATP7A degradation via the lysosomal pathway, while COMMD1 promotes degradation via the proteasomal pathway; overexpression of either protein decreases endogenous ATP7A, and knockdown increases it. Co-immunoprecipitation, overexpression and knockdown experiments, lysosomal and proteasomal inhibitor assays, immunoblot The Journal of biological chemistry High 22130675
2011 Two ATP7A missense mutations causing distal motor neuropathy (T994I and P1386S) shift the steady-state distribution of ATP7A to the plasma membrane (exaggerated PM localization) due to impaired endocytic retrieval from the PM to the TGN; ATP7A(T994I) shows abnormal interaction with p97/VCP, and siRNA knockdown of p97/VCP corrects the mislocalization; ATP7A(P1386S) has destabilized insertion of the eighth transmembrane helix. Total internal reflection fluorescence microscopy, transfection of Venus-tagged mutants in HEK293T and NSC-34 motor neurons, immunoprecipitation, siRNA knockdown, flow cytometry Human molecular genetics High 22210628
2009 ATP7A is a target gene of retinoic acid receptor beta2 (RARβ2) in neuroblastoma cells: RARβ2 overexpression upregulates ATP7A expression; RARβ2 siRNA blocks retinoid-induced ATP7A induction; forced downregulation of ATP7A reduces copper efflux and increases cell viability during retinoid treatment. siRNA knockdown, ectopic overexpression of RARβ2 domains, copper efflux assays, cell viability assays British journal of cancer Medium 19127267
2017 Akt2 (protein kinase B beta) binds ATP7A and phosphorylates it at Ser1424/Ser1463/Ser1466, promoting ATP7A protein stabilization (preventing ubiquitination/degradation) and translocation to the plasma membrane in vascular smooth muscle cells; this stabilization is required for full activation of extracellular SOD3 and protection against endothelial dysfunction in type 2 diabetes. Immunoprecipitation, in vitro kinase assay, mass spectrometry, Akt2 knockout mice, constitutively active Akt overexpression, ATP7A overexpression rescue, SOD3 activity assays Arteriosclerosis, thrombosis, and vascular biology High 29301787
2019 ATP7A is required for the activity of LOX and LOXL (lysyl oxidase family) copper-dependent enzymes: siRNA silencing of ATP7A inhibits LOX activity in mammary carcinoma cells, resulting in loss of LOX-dependent focal adhesion kinase phosphorylation and reduced myeloid cell lung recruitment; ATP7A silencing also attenuates LOX activity and metastasis of Lewis lung carcinoma cells. siRNA knockdown, LOX enzymatic activity assays, orthotopic mouse tumor models, FAK phosphorylation assays, lung metastasis quantification Proceedings of the National Academy of Sciences of the United States of America High 30890638
2020 Metallothioneins (MT-I and MT-II) regulate ATP7A trafficking: loss of MTs causes copper-dependent trafficking of ATP7A from the trans-Golgi complex; combined absence of ATP7A and MTs causes synthetic lethality due to extreme copper sensitivity; MTs and ATP7A compete with essential copper-dependent pathways under copper deficiency. Genetic knockout of ATP7A and/or MT-I/MT-II, confocal immunofluorescence, cell viability assays under copper excess/deficiency Scientific reports Medium 32398691
2021 Upon VEGF stimulation, ATP7A translocates from the TGN to the plasma membrane where it binds VEGFR2, preventing autophagy-mediated lysosomal VEGFR2 degradation by inhibiting the autophagic cargo adapter p62/SQSTM1 from binding ubiquitinated VEGFR2; loss of ATP7A in endothelial cells promotes VEGFR2 degradation and impairs angiogenesis. Inducible EC-specific ATP7A knockout mice, ATP7A-dysfunctional mutant mice, co-immunoprecipitation (ATP7A-VEGFR2), autophagy reporter mice (RFP-EGFP-LC3), VEGFR2 signaling assays, neovascularization assays Nature communications High 34035268
2021 PLEKHA5, PLEKHA6, and PLEKHA7 (WW-PLEKHAs) bind to PDZD11 through their WW domains; PDZD11 interacts with the C-terminus of ATP7A; WW-PLEKHAs recruit PDZD11 to distinct plasma membrane localizations and are required for efficient anterograde targeting of ATP7A to the cell periphery under elevated copper; loss of WW-PLEKHAs or PDZD11 impairs copper extrusion but does not affect ATP7A Golgi localization or copper-induced exit from Golgi. CRISPR knockout of PLEKHA5/6/7 and PDZD11 in kidney epithelial cells, immunofluorescence microscopy, pull-down assays, bioavailable and total copper measurements, metallothionein-1 expression, cell viability Molecular biology of the cell High 34613798
2023 The adaptor protein-1 (AP-1) complex regulates ATP7A sorting polarity: upon pan-AP-1 knockout, ATP7A loses its trafficking polarity and localizes to both apical and basolateral surfaces under high copper; AP-1A specifically provides directionality and TGN retention for ATP7A; mass spectrometry identified AP-1 as a regulatory partner of ATP7A. CRISPR knockout of AP-1 isoforms (pan-AP-1, AP-1A, AP-1B), immunofluorescence microscopy, mass spectrometry of regulatory partners, analysis in polarized epithelial cells Journal of cell science High 38032054
2022 Protein kinase D (PKD) phosphorylates ATP7A/ATP7B, and PKD inhibition reduces PKD-mediated phosphorylation of ATP7A, leading to enhanced proteasome-mediated degradation of ATP7A; proteasome inhibitor (MG132) reverses the PKD inhibitor effect, indicating phosphorylation by PKD is required for ATP7A stability. PKD inhibitor (CID2011756), proteasome inhibitor (MG132), immunoblot, RT-PCR in HeLa and HepG2 cells Cancer treatment and research communications Medium 35908410
2017 ATP7A is required for influenza A virus replication: knockdown of ATP7A significantly reduced polymerase activity in a minigenome assay and impaired authentic viral RNA synthesis and nucleoprotein/matrix protein accumulation in infected cells. RNAi knockdown, influenza minigenome assay, viral titer measurements, immunofluorescence for NP localization Virology journal Medium 28115001
2009 ATP7A downregulation in macrophages by siRNA attenuates cell-mediated LDL oxidation and decreases expression and enzymatic activity of cytosolic phospholipase A2 alpha (cPLA2α); ATP7A transcriptionally regulates cPLA2α promoter activity; cPLA2α overexpression increases LDL oxidation, which is blocked by co-administration of ATP7A siRNA. siRNA knockdown of ATP7A, LDL oxidation assays, cPLA2α promoter activity assay, cPLA2α enzymatic activity assay, cPLA2α overexpression rescue Journal of lipid research Medium 19965596
2017 ATP7A protein is markedly downregulated in vessels from type 2 diabetes mellitus patients and mouse models; in VSMCs, Akt2 promotes ATP7A stabilization by preventing ubiquitination/degradation and promotes its translocation to the plasma membrane; ATP7A overexpression rescues reduced SOD3 activity in Akt2-/- VSMCs. Vascular tissue from T2DM patients and db/db mice, Akt2-/- mice, immunoprecipitation, in vitro kinase assay with MS, constitutive active Akt constructs, ATP7A overexpression, SOD3 activity assay Arteriosclerosis, thrombosis, and vascular biology High 29301787

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 ATP7A-related copper transport diseases-emerging concepts and future trends. Nature reviews. Neurology 424 21221114
2007 Trafficking of the copper-ATPases, ATP7A and ATP7B: role in copper homeostasis. Archives of biochemistry and biophysics 357 17531189
2004 Drosophila melanogaster MNK/Chk2 and p53 regulate multiple DNA repair and apoptotic pathways following DNA damage. Molecular and cellular biology 263 14729967
2008 Cell-specific ATP7A transport sustains copper-dependent tyrosinase activity in melanosomes. Nature 205 18650808
2019 ATP7A delivers copper to the lysyl oxidase family of enzymes and promotes tumorigenesis and metastasis. Proceedings of the National Academy of Sciences of the United States of America 195 30890638
1995 Gene amplification of the Menkes (MNK; ATP7A) P-type ATPase gene of CHO cells is associated with copper resistance and enhanced copper efflux. Human molecular genetics 147 8589689
2014 Mnk kinase pathway: Cellular functions and biological outcomes. World journal of biological chemistry 140 25225600
1999 The Menkes protein (ATP7A; MNK) cycles via the plasma membrane both in basal and elevated extracellular copper using a C-terminal di-leucine endocytic signal. Human molecular genetics 133 10484781
2007 Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and Mnk-mediated eukaryotic translation initiation factor 4E phosphorylation. Molecular and cellular biology 129 17724079
2014 Two-stage translational control of dentate gyrus LTP consolidation is mediated by sustained BDNF-TrkB signaling to MNK. Cell reports 119 25453757
2017 The MNK-eIF4E Signaling Axis Contributes to Injury-Induced Nociceptive Plasticity and the Development of Chronic Pain. The Journal of neuroscience : the official journal of the Society for Neuroscience 112 28674170
2013 An overview and update of ATP7A mutations leading to Menkes disease and occipital horn syndrome. Human mutation 102 23281160
2007 Copper-transporting ATPases ATP7A and ATP7B: cousins, not twins. Journal of bioenergetics and biomembranes 92 18000748
2004 Signals regulating trafficking of Menkes (MNK; ATP7A) copper-translocating P-type ATPase in polarized MDCK cells. American journal of physiology. Cell physiology 91 15269005
2013 Inhibition of Mnk kinase activity by cercosporamide and suppressive effects on acute myeloid leukemia precursors. Blood 89 23509154
2016 Tuning Specific Translation in Cancer Metastasis and Synaptic Memory: Control at the MNK-eIF4E Axis. Trends in biochemical sciences 85 27527252
2020 MNK Inhibition Sensitizes KRAS-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression. Cancer discovery 75 33328217
2011 Clusterin and COMMD1 independently regulate degradation of the mammalian copper ATPases ATP7A and ATP7B. The Journal of biological chemistry 74 22130675
2007 ATP7A (Menkes protein) functions in axonal targeting and synaptogenesis. Molecular and cellular neurosciences 74 17215139
1998 Functional analysis and intracellular localization of the human menkes protein (MNK) stably expressed from a cDNA construct in Chinese hamster ovary cells (CHO-K1). Human molecular genetics 73 9668172
2021 The P-type ATPase transporter ATP7A promotes angiogenesis by limiting autophagic degradation of VEGFR2. Nature communications 71 34035268
2006 Developmental changes in the expression of ATP7A during a critical period in postnatal neurodevelopment. Neuroscience 71 16549268
2010 The role of MNK proteins and eIF4E phosphorylation in breast cancer cell proliferation and survival. Cancer biology & therapy 68 20686366
2010 Protein phosphatase 2A negatively regulates eukaryotic initiation factor 4E phosphorylation and eIF4F assembly through direct dephosphorylation of Mnk and eIF4E. Neoplasia (New York, N.Y.) 68 20927323
1995 Molecular structure of the Menkes disease gene (ATP7A). Genomics 67 7490081
2007 MNK kinases regulate multiple TLR pathways and innate proinflammatory cytokines in macrophages. American journal of physiology. Gastrointestinal and liver physiology 65 18032482
2021 ATP7A-Regulated Enzyme Metalation and Trafficking in the Menkes Disease Puzzle. Biomedicines 64 33917579
2001 ATP7A gene mutations in 16 patients with Menkes disease and a patient with occipital horn syndrome. American journal of medical genetics 63 11241493
2017 A Role for The ATP7A Copper Transporter in Tumorigenesis and Cisplatin Resistance. Journal of Cancer 58 28819394
2020 Metallothioneins regulate ATP7A trafficking and control cell viability during copper deficiency and excess. Scientific reports 57 32398691
2017 Mitogen-activated Protein Kinase (MAPK) Interacting Kinases 1 and 2 (MNK1 and MNK2) as Targets for Cancer Therapy: Recent Progress in the Development of MNK Inhibitors. Current medicinal chemistry 57 28164761
2017 MNK Controls mTORC1:Substrate Association through Regulation of TELO2 Binding with mTORC1. Cell reports 57 28178522
2007 Altered ATP7A expression and other compensatory responses in a murine model of Menkes disease. Neurobiology of disease 55 17588765
2002 Menkes copper-translocating P-type ATPase (ATP7A): biochemical and cell biology properties, and role in Menkes disease. Journal of bioenergetics and biomembranes 54 12539963
1999 Intracellular localization and loss of copper responsiveness of Mnk, the murine homologue of the Menkes protein, in cells from blotchy (Mo blo) and brindled (Mo br) mouse mutants. Human molecular genetics 51 10332039
2018 XIAP Regulation by MNK Links MAPK and NFκB Signaling to Determine an Aggressive Breast Cancer Phenotype. Cancer research 49 29351901
1999 Mutation spectrum of ATP7A, the gene defective in Menkes disease. Advances in experimental medicine and biology 48 10079817
2011 Simultaneous inhibition of mTOR-containing complex 1 (mTORC1) and MNK induces apoptosis of cutaneous T-cell lymphoma (CTCL) cells. PloS one 46 21949767
2019 Reversal of peripheral nerve injury-induced neuropathic pain and cognitive dysfunction via genetic and tomivosertib targeting of MNK. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 45 31590180
2016 Inhibition of MNK pathways enhances cancer cell response to chemotherapy with temozolomide and targeted radionuclide therapy. Cellular signalling 45 27289018
2015 Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia. Leukemia 43 26165234
2022 Exosome-mediated miR-7-5p delivery enhances the anticancer effect of Everolimus via blocking MNK/eIF4E axis in non-small cell lung cancer. Cell death & disease 42 35136028
2021 Progress in developing MNK inhibitors. European journal of medicinal chemistry 42 33892273
2017 Dynamics of the metal binding domains and regulation of the human copper transporters ATP7B and ATP7A. IUBMB life 42 28271598
2011 Altered intracellular localization and valosin-containing protein (p97 VCP) interaction underlie ATP7A-related distal motor neuropathy. Human molecular genetics 42 22210628
2018 Akt2 (Protein Kinase B Beta) Stabilizes ATP7A, a Copper Transporter for Extracellular Superoxide Dismutase, in Vascular Smooth Muscle: Novel Mechanism to Limit Endothelial Dysfunction in Type 2 Diabetes Mellitus. Arteriosclerosis, thrombosis, and vascular biology 41 29301787
2016 Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo. Blood 40 27307295
2021 Update on the Development of MNK Inhibitors as Therapeutic Agents. Journal of medicinal chemistry 39 34533957
2001 A novel frameshift mutation in exon 23 of ATP7A (MNK) results in occipital horn syndrome and not in Menkes disease. American journal of human genetics 39 11431706
2007 MNK, EIF4E and targeting translation for therapy. Cell cycle (Georgetown, Tex.) 38 18256539
2020 TSC patient-derived isogenic neural progenitor cells reveal altered early neurodevelopmental phenotypes and rapamycin-induced MNK-eIF4E signaling. Molecular autism 37 31921404
2003 The Menkes disease ATPase (ATP7A) is internalized via a Rac1-regulated, clathrin- and caveolae-independent pathway. Human molecular genetics 37 12812980
2021 PLEKHA5, PLEKHA6, and PLEKHA7 bind to PDZD11 to target the Menkes ATPase ATP7A to the cell periphery and regulate copper homeostasis. Molecular biology of the cell 36 34613798
2017 Host Cell Copper Transporters CTR1 and ATP7A are important for Influenza A virus replication. Virology journal 35 28115001
2016 Cotargeting MNK and MEK kinases induces the regression of NF1-mutant cancers. The Journal of clinical investigation 35 27159396
2016 MNK Inhibition Disrupts Mesenchymal Glioma Stem Cells and Prolongs Survival in a Mouse Model of Glioblastoma. Molecular cancer research : MCR 35 27364770
2016 Galeterone and VNPT55 disrupt Mnk-eIF4E to inhibit prostate cancer cell migration and invasion. The FEBS journal 35 27618366
2015 Differential Regulation of ZEB1 and EMT by MAPK-Interacting Protein Kinases (MNK) and eIF4E in Pancreatic Cancer. Molecular cancer research : MCR 35 26609108
2017 Inhibiting ERK/Mnk/eIF4E broadly sensitizes ovarian cancer response to chemotherapy. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 34 28766096
2016 Dual targeting of eIF4E by blocking MNK and mTOR pathways in leukemia. Cytokine 33 27094611
2010 Negative regulatory effects of Mnk kinases in the generation of chemotherapy-induced antileukemic responses. Molecular pharmacology 33 20664001
2007 Purification and membrane reconstitution of catalytically active Menkes copper-transporting P-type ATPase (MNK; ATP7A). The Biochemical journal 33 17009961
2010 Essential role for Mnk kinases in type II interferon (IFNgamma) signaling and its suppressive effects on normal hematopoiesis. The Journal of biological chemistry 32 21149447
2022 Circular RNA circPBX3 promotes cisplatin resistance of ovarian cancer cells via interacting with IGF2BP2 to stabilize ATP7A mRNA expression. Human cell 31 35907138
2018 The retinamide VNLG-152 inhibits f-AR/AR-V7 and MNK-eIF4E signaling pathways to suppress EMT and castration-resistant prostate cancer xenograft growth. The FEBS journal 31 29323792
2015 Inhibition of Mitogen-activated Protein Kinase (MAPK)-interacting Kinase (MNK) Preferentially Affects Translation of mRNAs Containing Both a 5'-Terminal Cap and Hairpin. The Journal of biological chemistry 31 26668315
2010 Differential expression of ATP7A, ATP7B and CTR1 in adult rat dorsal root ganglion tissue. Molecular pain 31 20836889
2024 Sirtuin 7 ameliorates cuproptosis, myocardial remodeling and heart dysfunction in hypertension through the modulation of YAP/ATP7A signaling. Apoptosis : an international journal on programmed cell death 30 39394530
2015 Novel C-4 heteroaryl 13-cis-retinamide Mnk/AR degrading agents inhibit cell proliferation and migration and induce apoptosis in human breast and prostate cancer cells and suppress growth of MDA-MB-231 human breast and CWR22Rv1 human prostate tumor xenografts in mice. Journal of medicinal chemistry 29 25634130
2004 Studies on endocytic mechanisms of the Menkes copper-translocating P-type ATPase (ATP7A; MNK). Endocytosis of the Menkes protein. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 29 14977365
2020 Disabling MNK protein kinases promotes oxidative metabolism and protects against diet-induced obesity. Molecular metabolism 26 32712434
2017 The Role of the p38-MNK-eIF4E Signaling Axis in TNF Production Downstream of the NOD1 Receptor. Journal of immunology (Baltimore, Md. : 1950) 26 28087669
2014 ATP7A trafficking and mechanisms underlying the distal motor neuropathy induced by mutations in ATP7A. Annals of the New York Academy of Sciences 26 24754450
2002 Expression in mouse kidney of membrane copper transporters Atp7a and Atp7b. Nephron 26 12372948
2017 Dual abrogation of MNK and mTOR: a novel therapeutic approach for the treatment of aggressive cancers. Future medicinal chemistry 25 28841037
2013 Involvement of CTR1 and ATP7A in lead (Pb)-induced copper (Cu) accumulation in choroidal epithelial cells. Toxicology letters 25 24316150
2012 MNK kinases facilitate c-myc IRES activity in rapamycin-treated multiple myeloma cells. Oncogene 25 22370634
2021 MNK as a potential pharmacological target for suppressing LPS-induced acute lung injury in mice. Biochemical pharmacology 24 33675774
2021 MiR-495 Inhibits Cisplatin Resistance and Angiogenesis in Esophageal Cancer by Targeting ATP7A. Technology in cancer research & treatment 24 34747666
2016 Inhibition of Mnk enhances apoptotic activity of cytarabine in acute myeloid leukemia cells. Oncotarget 24 27462781
2014 Translational research investigations on ATP7A: an important human copper ATPase. Annals of the New York Academy of Sciences 24 24735419
2014 Probing the binding mechanism of Mnk inhibitors by docking and molecular dynamics simulations. Biochemistry 23 25431995
2009 Participation of ATP7A in macrophage mediated oxidation of LDL. Journal of lipid research 23 19965596
2023 Regulation of the apico-basolateral trafficking polarity of the homologous copper-ATPases ATP7A and ATP7B. Journal of cell science 22 38032054
2015 An integrated approach for discovery of highly potent and selective Mnk inhibitors: Screening, synthesis and SAR analysis. European journal of medicinal chemistry 22 26408454
2019 MNK-eIF4E signalling is a highly conserved mechanism for sensory neuron axonal plasticity: evidence from Aplysia californica. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 21 31544610
2018 Induction of MNK Kinase-dependent eIF4E Phosphorylation by Inhibitors Targeting BET Proteins Limits Efficacy of BET Inhibitors. Molecular cancer therapeutics 20 30446586
2010 Differential contribution of the MTOR and MNK pathways to the regulation of mRNA translation in meiotic and postmeiotic mouse male germ cells. Biology of reproduction 20 20574055
2009 ATP7A is a novel target of retinoic acid receptor beta2 in neuroblastoma cells. British journal of cancer 20 19127267
2006 Mnk is a negative regulator of cap-dependent translation in Aplysia neurons. Journal of neurochemistry 20 16515558
2022 Sensitization of cancer cells towards Cisplatin and Carboplatin by protein kinase D inhibitors through modulation of ATP7A/B (copper transport ATPases). Cancer treatment and research communications 19 35908410
2016 Dual modulation of Ras-Mnk and PI3K-AKT-mTOR pathways: A Novel c-FLIP inhibitory mechanism of 3-AWA mediated translational attenuation through dephosphorylation of eIF4E. Scientific reports 19 26728896
2016 Unveiling new chemical scaffolds as Mnk inhibitors. Future medicinal chemistry 19 26910782
2022 Circadian activities of the brain MNK-eIF4E signalling axis contribute to diurnal rhythms of some cognitive functions. The European journal of neuroscience 18 35481869
2016 Structure-Activity Relationship Studies of Mitogen Activated Protein Kinase Interacting Kinase (MNK) 1 and 2 and BCR-ABL1 Inhibitors Targeting Chronic Myeloid Leukemic Cells. Journal of medicinal chemistry 18 27011159
2016 Galeterone and its analogs inhibit Mnk-eIF4E axis, synergize with gemcitabine, impede pancreatic cancer cell migration, invasion and proliferation and inhibit tumor growth in mice. Oncotarget 18 28881737
2013 TGFβ-induced PI 3 kinase-dependent Mnk-1 activation is necessary for Ser-209 phosphorylation of eIF4E and mesangial cell hypertrophy. Journal of cellular physiology 18 23359369
2010 Developmental changes in the expression of the Atp7a gene in the liver of mice during the postnatal period. Journal of experimental zoology. Part A, Ecological genetics and physiology 18 20084666
2017 Oncogenic MNK signalling regulates the metastasis suppressor NDRG1. Oncotarget 17 28545025
2016 The MNK-1/eIF4E pathway as a new therapeutic pathway to target inflammation and remodelling in asthma. Cellular signalling 17 27418099

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