Affinage

ATP7A

Copper-transporting ATPase 1 · UniProt Q04656

Length
1500 aa
Mass
163.4 kDa
Annotated
2026-04-28
100 papers in source corpus 26 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATP7A is a P-type Cu(I)-transporting ATPase that forms a copper-activated phosphoenzyme intermediate with cooperative high-affinity Cu(I) binding (K0.5 ~0.6 µM) and mediates ATP-dependent vectorial copper transport across membranes, supplying copper to secretory cuproenzymes including lysyl oxidase, SOD3, and peptidylglycine α-amidating monooxygenase (PMID:17009961, PMID:30890638, PMID:29301787). Under basal conditions ATP7A resides in the trans-Golgi network and undergoes copper-stimulated, AP-1-dependent trafficking to the basolateral plasma membrane, returning via a Rac1-dependent, clathrin-independent endocytic pathway that requires a C-terminal di-leucine motif; in specialized contexts it relocates to phagosomal compartments (macrophage bactericidal copper delivery) or associates with VEGFR2 at the plasma membrane to protect the receptor from autophagic degradation (PMID:9668172, PMID:12812980, PMID:15269005, PMID:38032054, PMID:19808669, PMID:34035268). ATP7A protein stability is maintained by Akt2 phosphorylation and Caveolin-1 binding, which prevent ubiquitination-dependent proteasomal degradation, while clusterin promotes its lysosomal turnover and COMMD1 its proteasomal turnover; loss of ATP7A causes mitochondrial copper accumulation with glutathione oxidation, impairs axon outgrowth, and underlies Menkes disease and an allelic distal motor neuropathy linked to trafficking-defective missense mutations (PMID:29301787, PMID:32936699, PMID:22130675, PMID:27226607, PMID:17483305, PMID:20170900). ATP7A also binds and translocates platinum-based chemotherapeutic agents via its N-terminal CxxC motifs, modulating cisplatin pharmacodynamics (PMID:15213293, PMID:24375922).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 High

    Establishing the copper-dependent TGN-to-plasma-membrane trafficking cycle resolved where ATP7A operates and how cells regulate copper efflux directionally.

    Evidence Immunogold EM and confocal microscopy of stably transfected CHO-K1 cells showed TGN residence at basal copper and redistribution to vesicles/plasma membrane at elevated copper, with functional copper resistance proportional to expression level.

    PMID:9668172

    Open questions at the time
    • Endocytic retrieval mechanism and sorting signals not yet identified
    • Whether trafficking occurs in polarized epithelial cells unknown
  2. 2003 High

    Identifying the Rac1-dependent, clathrin/caveolae-independent internalization pathway defined a novel endocytic route for a polytopic membrane transporter.

    Evidence Dominant-negative dynamin, Eps15, and caveolae inhibitors failed to block ATP7A internalization in transfected cells; constitutively active Rac1 inhibited retrieval, measured by flow cytometry.

    PMID:12812980

    Open questions at the time
    • Coat proteins or adaptors mediating Rac1-dependent endocytosis of ATP7A not identified
    • Upstream signals activating Rac1 in this context unknown
  3. 2004 High

    Mapping the C-terminal di-leucine endocytic motif and N-terminal metal-binding domain requirements for copper-regulated basolateral trafficking dissected the molecular determinants controlling ATP7A directionality in polarized cells.

    Evidence Site-directed mutagenesis in polarized MDCK cells; L1487/L1488 mutations blocked endocytic retrieval; N-MBD deletions impaired copper-stimulated exit from TGN, assessed by confocal microscopy and surface biotinylation.

    PMID:15269005

    Open questions at the time
    • Whether additional sorting motifs contribute in different epithelial contexts
    • Adaptor complexes mediating basolateral targeting not identified
  4. 2004 High

    Demonstrating that ATP7A sequesters platinum drugs into vesicular compartments revealed an unanticipated role in chemotherapy pharmacokinetics and established substrate promiscuity beyond copper.

    Evidence ICP-MS and vesicle fractionation in Menkes fibroblasts reconstituted with ATP7A showed increased vesicular cisplatin/carboplatin without enhanced nuclear delivery; copper but not platinum triggered relocalization.

    PMID:15213293

    Open questions at the time
    • Structural basis for platinum binding to ATP7A not yet resolved
    • In vivo relevance to drug resistance unconfirmed
  5. 2007 High

    Biochemical reconstitution of purified full-length ATP7A in liposomes proved it is a bona fide Cu(I)-translocating ATPase with cooperative copper activation, placing it mechanistically alongside other P-type ATPases.

    Evidence Purified Sf9-expressed ATP7A formed vanadate-sensitive phosphoenzyme activated by Cu(I) (Hill coefficient 4.6), exhibited Cu(I)-dependent ATPase activity, and mediated 64Cu transport into liposomes.

    PMID:17009961

    Open questions at the time
    • Full-length structural model unavailable
    • How cooperativity is achieved among six N-terminal metal-binding domains mechanistically undefined
  6. 2007 High

    Phenotypic analysis of mottled mouse alleles demonstrated that specific domains control distinct steps—ER exit, copper delivery, and trafficking—linking genotype to Menkes disease severity and establishing ATP7A's developmental role in axon outgrowth.

    Evidence Mutant ATP7A constructs corresponding to mottled alleles showed ER retention (mo11H), constitutive plasma membrane localization (Macular, Viable brindle), and reduced copper delivery; Mottled brindled mice exhibited disrupted olfactory axon projections.

    PMID:17215139 PMID:17483305

    Open questions at the time
    • Specific cuproenzymes mediating ATP7A-dependent axon outgrowth not identified
    • Whether motor neuron pathology in human disease shares the same mechanism unclear
  7. 2009 High

    Linking ATP7A to macrophage bactericidal copper delivery expanded its role beyond biosynthetic copper loading to innate immune defense.

    Evidence IFN-γ stimulated ATP7A translocation to phagosome-adjacent vesicles in RAW264.7 macrophages; siRNA knockdown attenuated killing of copper-sensitive E. coli ΔcopA.

    PMID:19808669

    Open questions at the time
    • Whether ATP7A directly pumps copper into the phagosome lumen or delivers via vesicle fusion
    • Relevance to in vivo human infection not tested
  8. 2010 High

    Characterizing distal motor neuropathy mutations T994I and P1386S as trafficking-defective alleles with preserved catalytic function revealed that aberrant plasma membrane retention (not loss of transport) causes a distinct clinical phenotype, and identified p97/VCP as an unexpected trafficking partner.

    Evidence TIRF microscopy in patient fibroblasts showed exaggerated surface accumulation; IP revealed abnormal p97/VCP binding to T994I; p97/VCP knockdown rescued mislocalization; P1386S placed the di-leucine motif extracellularly.

    PMID:20170900 PMID:22210628

    Open questions at the time
    • How p97/VCP interaction normally facilitates ATP7A retrieval mechanistically undefined
    • Whether p97/VCP is a direct binding partner or acts through an adaptor unknown
  9. 2011 High

    Identification of clusterin (lysosomal) and COMMD1 (proteasomal) as independent degradation mediators for ATP7A defined dual proteolytic quality-control pathways governing transporter abundance.

    Evidence Bidirectional manipulation (overexpression and siRNA) in cultured cells with lysosomal/proteasomal inhibitors; co-IP confirmed distinct, non-competitive interactions with ATP7A.

    PMID:22130675

    Open questions at the time
    • Ubiquitin ligase(s) linking COMMD1 to ATP7A ubiquitination not identified
    • Physiological signals controlling each degradation pathway unclear
  10. 2013 High

    NMR/ESI-MS structural determination of cisplatin binding to the first N-terminal metal-binding domain of ATP7A via Cys19/Cys22 cis-coordination provided an atomic-level explanation for platinum drug transport by copper ATPases.

    Evidence NMR and ESI-MS of Mnk1 domain incubated with cisplatin; electrophysiology on COS-1 microsomes showed ATP-dependent platinum translocation comparable to copper.

    PMID:24375922 PMID:24983998

    Open questions at the time
    • Whether all six N-terminal domains bind platinum and their relative affinities unknown
    • In vivo contribution of ATP7A-mediated platinum efflux to clinical drug resistance not quantified
  11. 2016 High

    Demonstrating that ATP7A loss causes mitochondrial copper overload with consequent glutathione oxidation identified a cytoprotective role for ATP7A in maintaining mitochondrial redox homeostasis.

    Evidence CRISPR/Cas9 KO in 3T3-L1 cells and Menkes patient fibroblasts, live-cell GRX1-roGFP2 and HyPer sensors showed elevated mitochondrial glutathione oxidation and H₂O₂ driven primarily by copper accumulation.

    PMID:27226607

    Open questions at the time
    • Mechanism by which ATP7A normally prevents mitochondrial copper accumulation (direct or indirect) not resolved
    • Whether mitochondrial redox imbalance contributes to Menkes neurodegeneration in vivo unknown
  12. 2018 High

    Identification of Akt2-mediated phosphorylation at three C-terminal serines as a stabilizing signal that prevents ATP7A ubiquitination and promotes plasma membrane translocation linked insulin signaling to copper-dependent SOD3 activation in vasculature.

    Evidence In vitro kinase assay, MS phosphosite mapping, Akt2−/− mice showed reduced ATP7A and SOD3 activity; constitutively active Akt rescued ATP7A stability.

    PMID:29301787

    Open questions at the time
    • E3 ligase counteracting Akt2-mediated stabilization not identified
    • Whether other kinases regulate ATP7A trafficking in non-vascular contexts unknown
  13. 2020 High

    Caveolin-1 was established as a second stabilizing partner for ATP7A, preventing its ubiquitination in vascular tissue and coupling copper delivery to SOD3 within caveolae/lipid rafts.

    Evidence Cav-1−/− mice showed reduced ATP7A protein but not mRNA, increased ubiquitination, decreased SOD3 activity, and endothelial dysfunction rescued by SOD3 gene transfer or ATP7A overexpression.

    PMID:32936699

    Open questions at the time
    • Whether Cav-1 and Akt2 act on the same or distinct ubiquitin signals on ATP7A
    • Structural basis of Cav-1/ATP7A interaction not defined
  14. 2021 High

    Discovery that ATP7A binds VEGFR2 at the plasma membrane and shields it from p62/SQSTM1-mediated autophagic degradation revealed a copper-transport-independent scaffolding function critical for post-ischemic neovascularization.

    Evidence Inducible EC-specific ATP7A KO and ATP7Amut mice showed impaired VEGFR2 signaling and neovascularization; co-IP showed ATP7A–VEGFR2 interaction; autophagy reporter mice confirmed increased VEGFR2 autophagic flux upon ATP7A loss.

    PMID:34035268

    Open questions at the time
    • Whether the scaffolding function requires copper occupancy or is purely structural
    • Domain on ATP7A mediating VEGFR2 binding not mapped
  15. 2023 High

    Resolving AP-1 adaptor complex isoform-specific roles in ATP7A versus ATP7B sorting from the TGN explained how two homologous transporters achieve opposite polarity in the same polarized epithelial cell.

    Evidence Pan-AP-1, AP-1A, and AP-1B isoform-specific knockouts in polarized cells; MS interactome; confocal imaging showed AP-1A provides TGN retention and directionality for both ATPases, while AP-1B specifically controls copper-independent ATP7B trafficking.

    PMID:38032054

    Open questions at the time
    • Motifs on ATP7A recognized by AP-1A not mapped
    • Whether post-translational modifications modulate AP-1 interaction affinity

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution full-length structure of ATP7A, the identity of the E3 ubiquitin ligase(s) governing its turnover, the mechanism linking ATP7A to mitochondrial copper homeostasis, and the structural basis of its non-transport scaffolding interaction with VEGFR2 remain unresolved.
  • No full-length atomic structure of ATP7A available
  • E3 ligase(s) mediating ATP7A ubiquitination not identified
  • How ATP7A prevents mitochondrial copper accumulation mechanistically unclear
  • Domain mapping of the ATP7A–VEGFR2 scaffolding interaction not performed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0140657 ATP-dependent activity 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005886 plasma membrane 5 GO:0005794 Golgi apparatus 3 GO:0031410 cytoplasmic vesicle 3
Pathway
R-HSA-382551 Transport of small molecules 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-9609507 Protein localization 3 R-HSA-1430728 Metabolism 2 R-HSA-168256 Immune System 1
Partners
AKT2CAV1CLUCOMMD1GLRXRAC1VCPVEGFR2

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 ATP7A (MNK) localizes to the trans-Golgi network under basal copper conditions and redistributes to cytoplasmic vesicles and plasma membrane upon elevated copper, returning to TGN when copper is reduced; stable expression of full-length cDNA in CHO-K1 cells conferred copper resistance proportional to expression level, providing first ultrastructural evidence for TGN/vesicle/plasma membrane cycling. Stable transfection, immunogold electron microscopy, confocal microscopy, copper resistance assays Human molecular genetics High 9668172
2003 ATP7A is internalized from the plasma membrane via a clathrin- and caveolae-independent pathway that requires Rac1 GTPase activity; dominant-negative dynamin, Eps15, and caveolae inhibitors did not block ATP7A internalization, whereas constitutively active Rac1 inhibited internalization. Dominant-negative mutant expression, pharmacological inhibition, flow cytometry Human molecular genetics High 12812980
2004 A di-leucine motif near the C-terminus of ATP7A (L1487/L1488) is required for endocytic retrieval from the plasma membrane; the N-terminal metal-binding domains are required for copper-regulated trafficking from TGN to plasma membrane in polarized MDCK cells, where ATP7A traffics to the basolateral membrane under elevated copper. Site-directed mutagenesis, confocal microscopy, surface biotinylation in polarized MDCK cells American journal of physiology. Cell physiology High 15269005
2004 ATP7A and ATP7B sequester cisplatin, carboplatin, and oxaliplatin into vesicular compartments, modulating platinum pharmacodynamics; ATP7A-expressing Menkes fibroblast sublines showed increased vesicular platinum sequestration for cisplatin and carboplatin without increasing nuclear platinum delivery, whereas oxaliplatin reached DNA more efficiently; copper (but not platinum drugs) triggered ATP7A relocalization from perinuclear to peripheral locations. Engineered human Menkes fibroblasts expressing ATP7A or ATP7B, ICP-MS platinum measurement, vesicle fractionation, confocal microscopy Molecular pharmacology High 15213293
2005 ATP7A traffics from TGN to a vesicular compartment adjacent to the basolateral membrane in copper-exposed intestinal epithelium of transgenic mice, supporting a model of vesicular exocytosis for copper export rather than direct pumping across the basolateral membrane. Copper perfusion of isolated jejunal segment, immunofluorescence of frozen sections in ATP7A transgenic mice The Journal of nutrition Medium 16317117
2005 ATP7A interacts with AIPP1 (ATPase-interacting PDZ protein) via its C-terminal class I PDZ-binding motif; interaction confirmed by yeast two-hybrid and co-immunoprecipitation from mammalian cells. Yeast two-hybrid screen, co-immunoprecipitation The Journal of biological chemistry Medium 16051599
2006 Glutaredoxin 1 (GRX1) interacts with the N-terminal copper-binding domain of ATP7A in a copper-dependent manner requiring intact MxCxxC motifs; proposed to reduce disulfide bonds or deglutathionylate cysteines in the CxxC motifs to facilitate copper binding and transport. Yeast two-hybrid, co-immunoprecipitation from mammalian cells Biochemical and biophysical research communications Medium 16884690
2007 ATP7A is expressed in extending axons during synaptogenesis; loss of ATP7A in mottled brindled mice causes disrupted olfactory sensory neuron axonal projections, impaired mitral/tufted cell dendritic growth, and glomerular disorganization in the olfactory bulb, establishing a developmental role for ATP7A in axon outgrowth and synaptogenesis. In vivo analysis of Atp7aMobr (mottled brindled) mouse olfactory system, immunostaining, confocal microscopy Molecular and cellular neurosciences Medium 17215139
2007 Purified full-length human ATP7A (MNK) expressed in Sf9 insect cells forms a vanadate-sensitive phosphoenzyme intermediate activated by Cu(I) (EC50 = 0.7 µM, Hill coefficient 4.6), exhibits Cu(I)-dependent ATPase activity (K0.5 = 0.6 µM), and mediates active ATP-dependent vectorial 64Cu transport when reconstituted into liposomes, demonstrating cooperative high-affinity Cu(I) interaction. Purification by antibody affinity chromatography, phosphoenzyme assay, ATPase activity assay, liposome reconstitution with 64Cu transport The Biochemical journal High 17009961
2007 Mottled mouse mutations differentially impair ATP7A copper transport and trafficking: the embryonic-lethal Atp7amo11H mutation mislocalizes ATP7A to the ER, impairs glycosylation, and abolishes copper delivery to the secretory pathway; perinatal-lethal (Macular) and viable (Viable brindle) mutations reduce copper delivery and cause constitutive trafficking to the plasma membrane, with Viable brindle hypertrafficking dependent on the catalytic phosphorylation site. Site-directed mutagenesis, immunofluorescence, copper transport assays in cell lines expressing mutant ATP7A Journal of medical genetics High 17483305
2009 ATP7A traffics from the TGN to vesicles that partially overlap with phagosomal compartments in macrophages upon IFN-γ stimulation; siRNA silencing of ATP7A attenuates bactericidal killing, and copper-sensitive E. coli (ΔcopA) are hypersensitive to macrophage killing in an ATP7A-dependent manner, establishing ATP7A-mediated copper transport as a component of the macrophage bactericidal mechanism. siRNA knockdown, confocal microscopy, bacterial killing assays in RAW264.7 macrophages, 64Cu uptake The Journal of biological chemistry High 19808669
2009 ATP7A is required for macrophage-mediated oxidation of LDL; siRNA knockdown of ATP7A in THP-1 macrophages attenuates LDL oxidation and reduces expression and enzymatic activity of cytosolic phospholipase A2α (cPLA2α), with reduced cPLA2α promoter activity, suggesting ATP7A transcriptionally regulates cPLA2α. siRNA knockdown, LDL oxidation assay, promoter activity assay, enzyme activity assay Journal of lipid research Medium 19965596
2010 ATP7A missense mutations T994I and P1386S (causing distal motor neuropathy) show normal mRNA and protein levels but defective intracellular trafficking, with exaggerated plasma membrane localization and impaired endocytic retrieval to TGN; ATP7A(T994I) shows abnormal interaction with p97/VCP, and siRNA knockdown of p97/VCP corrects ATP7A(T994I) mislocalization; ATP7A(P1386S) places its C-terminal di-leucine endocytic motif extracellularly, impeding internalization. TIRF microscopy in patient fibroblasts, transfection of NSC-34 motor neurons, immunoprecipitation, siRNA knockdown, flow cytometry American journal of human genetics High 20170900
2011 Clusterin and COMMD1 independently interact with ATP7A and ATP7B to facilitate their degradation: clusterin promotes lysosomal degradation and COMMD1 promotes proteasomal degradation; overexpression of either reduces endogenous ATP7A/B levels, knockdown increases them, and their interactions with ATP7A/B are neither competitive nor cooperative. Overexpression and siRNA knockdown, co-immunoprecipitation, lysosomal/proteasomal inhibitors, immunoblotting The Journal of biological chemistry High 22130675
2011 The TIRF microscopy and flow cytometry analyses of ATP7A(T994I) and ATP7A(P1386S) mutations in patient fibroblasts and Hek293T cells further confirmed preferential plasma membrane accumulation and impaired endocytic retrieval; p97/VCP abnormally binds ATP7A(T994I) and its siRNA knockdown corrects mislocalization. Total internal reflection fluorescence microscopy, transfection, immunoprecipitation, siRNA, flow cytometry Human molecular genetics High 22210628
2012 ATP7A/B Cu-ATPases form a phosphoenzyme intermediate (E-P) in an ATP-dependent manner; unlike SERCA, ATP7A/B phosphoenzyme formation is slow and highly temperature-sensitive; ATP-dependent charge transfer occurs without Cu+/H+ exchange; copper-deprived ATP7A undergoes inactivating interaction of its N-metal binding extension with headpiece domains preventing reverse phosphorylation, which is relieved by deletion of the N-MBD. Solid supported membrane electrical measurements, pH variation experiments, charge transfer measurements, Glu-309 mutation comparison, N-MBD deletion The Journal of biological chemistry High 22854969
2013 Cisplatin, carboplatin, and oxaliplatin activate Cu-ATPases ATP7A and ATP7B and undergo ATP-dependent translocation similar to copper; NMR and ESI-MS show that cisplatin binds the first N-terminal metal-binding domain of ATP7A (Mnk1) via cis-coordination of Cys19 and Cys22 sulfur atoms to the [Pt(NH3)2]2+ moiety. Solid supported membrane electrical measurements on COS-1 microsomes expressing recombinant ATP7A/B, NMR spectroscopy, ESI-MS Angewandte Chemie (International ed. in English) High 24375922
2013 Transcription factors Sp1 and Hif2α cooperatively induce ATP7A (Atp7a) gene expression during hypoxia/iron deficiency; four functional Sp1 binding sites in the Atp7a promoter are necessary for Hif2α-mediated induction; ChIP confirmed Sp1 binding to the Atp7a promoter in IEC-6 cells and rat duodenal enterocytes. Mithramycin inhibition, Sp1 overexpression, site-directed mutagenesis of promoter, ChIP, reporter assay in IEC-6 cells The Journal of biological chemistry Medium 23814049
2014 Cisplatin binds the first N-terminal soluble domain of ATP7A with cis-coordination of [Pt(NH3)2]2+ to Cys19 and Cys22; Car-Parrinello QM/MM simulations and computational spectroscopy validated against CD spectra and NMR chemical shifts provide the first quantitative 3D atomic view of platinum binding to ATP7A. ESI-MS, 1H/13C/15N NMR, QM/MM simulations, CD spectroscopy Dalton transactions High 24983998
2016 Loss of ATP7A activity in Menkes patient fibroblasts and CRISPR/Cas9-inactivated 3T3-L1 cells causes copper accumulation in mitochondria leading to glutathione oxidation and elevated H2O2 in mitochondria (measured by GRX1-roGFP2 and HyPer sensors), markedly increasing sensitivity to glutathione depletion; elevated copper rather than H2O2 is the primary cause of glutathione oxidation. CRISPR/Cas9 inactivation, patient-derived fibroblasts, live-cell ratiometric sensors (GRX1-roGFP2, HyPer), MitoQ treatment The Journal of biological chemistry High 27226607
2017 The ATP7A interactome (541 co-isolated proteins by immunoaffinity chromatography) includes subunits of the conserved oligomeric Golgi (COG) complex; COG-null cells show altered ATP7A and CTR1 content and localization, decreased total cellular copper, and impaired copper-dependent metabolic responses; genetic manipulation of ATP7A and COG subunits in Drosophila neurons alters synapse development and copper-induced mortality. ATP7A immunoaffinity chromatography/MS, COG-null cell analysis, subcellular fractionation, Drosophila genetics eLife High 28355134
2018 Akt2 (protein kinase B beta) phosphorylates ATP7A at Ser1424/Ser1463/Ser1466 upon insulin stimulation, stabilizing ATP7A by preventing ubiquitination/proteasomal degradation and promoting its translocation to the plasma membrane in vascular smooth muscle cells, thereby enabling full activation of extracellular SOD3. Immunoprecipitation, in vitro kinase assay, mass spectrometry, Akt2-/- mice, constitutively active Akt, ATP7A overexpression rescue of SOD3 activity Arteriosclerosis, thrombosis, and vascular biology High 29301787
2019 ATP7A is necessary for the enzymatic activity of lysyl oxidase (LOX) and LOXL copper-dependent metalloenzymes; siRNA silencing of ATP7A inhibits LOX activity in 4T1 cells and attenuates LOX-dependent FAK phosphorylation and myeloid cell lung recruitment in an orthotopic mouse breast cancer model, as well as Lewis lung carcinoma metastasis. siRNA knockdown, LOX activity assay, orthotopic mouse models, lung metastasis analysis Proceedings of the National Academy of Sciences of the United States of America High 30890638
2020 Caveolin-1 stabilizes ATP7A protein in vascular tissue by preventing its ubiquitination and proteasomal degradation; ATP7A binds Cav-1 and co-localizes with SOD3 in caveolae/lipid rafts; loss of Cav-1 reduces ATP7A protein (not mRNA) and SOD3 activity, causing endothelial dysfunction rescuable by SOD3 gene transfer or ATP7A-overexpressing transgenic mice. Cav-1-/- mice, immunoprecipitation, ubiquitination assay, SOD3 activity, vascular relaxation, gene transfer rescue American journal of physiology. Cell physiology High 32936699
2021 VEGF stimulates ATP7A translocation from the TGN to the plasma membrane where it binds VEGFR2, preventing autophagy-mediated lysosomal degradation of VEGFR2 by blocking p62/SQSTM1 binding to ubiquitinated VEGFR2; EC-specific ATP7A-deficient and ATP7Amut mice show impaired post-ischemic neovascularization and reduced VEGFR2 signaling. Inducible EC-specific knockout mice, ATP7Amut transgenic mice, co-immunoprecipitation, autophagy reporter transgenic mice (CAG-RFP-EGFP-LC3), VEGFR2 signaling assays Nature communications High 34035268
2023 In polarized epithelia, ATP7A and ATP7B reside on distinct TGN domains under low copper; upon copper elevation ATP7A traffics to the basolateral membrane while ATP7B traverses recycling and apical sorting endosomes to the apical membrane; AP-1 complex is required for sorting of both Cu-ATPases: AP-1A provides directionality and TGN retention, while AP-1B governs copper-independent ATP7B trafficking specifically. Pan-AP-1 knockout and AP-1A/AP-1B isoform-specific knockouts, mass spectrometry, confocal microscopy in polarized cells Journal of cell science High 38032054

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 420 21221114
2009 A role for the ATP7A copper-transporting ATPase in macrophage bactericidal activity. The Journal of biological chemistry 411 19808669
2007 Trafficking of the copper-ATPases, ATP7A and ATP7B: role in copper homeostasis. Archives of biochemistry and biophysics 352 17531189
2004 Increased expression of the copper efflux transporter ATP7A mediates resistance to cisplatin, carboplatin, and oxaliplatin in ovarian cancer cells. Clinical cancer research : an official journal of the American Association for Cancer Research 276 15269138
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 192 30890638
2004 Phosphorylation of eIF4E by Mnk-1 enhances HSV-1 translation and replication in quiescent cells. Genes & development 164 15075293
2014 Mnk kinase pathway: Cellular functions and biological outcomes. World journal of biological chemistry 139 25225600
2010 Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy. American journal of human genetics 133 20170900
2013 Role of the P-Type ATPases, ATP7A and ATP7B in brain copper homeostasis. Frontiers in aging neuroscience 129 23986700
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
2013 Targeting of the MNK-eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function. Proceedings of the National Academy of Sciences of the United States of America 125 23737503
2002 Activation of a meiotic checkpoint during Drosophila oogenesis regulates the translation of Gurken through Chk2/Mnk. Current biology : CB 120 12361566
2004 Modulation of the cellular pharmacology of cisplatin and its analogs by the copper exporters ATP7A and ATP7B. Molecular pharmacology 119 15213293
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 111 28674170
2013 An overview and update of ATP7A mutations leading to Menkes disease and occipital horn syndrome. Human mutation 101 23281160
2007 Copper-transporting ATPases ATP7A and ATP7B: cousins, not twins. Journal of bioenergetics and biomembranes 91 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 84 27527252
2005 Copper exposure induces trafficking of the menkes protein in intestinal epithelium of ATP7A transgenic mice. The Journal of nutrition 81 16317117
2013 Translocation of platinum anticancer drugs by human copper ATPases ATP7A and ATP7B. Angewandte Chemie (International ed. in English) 78 24375922
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
2020 MNK Inhibition Sensitizes KRAS-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression. Cancer discovery 72 33328217
2011 Clusterin and COMMD1 independently regulate degradation of the mammalian copper ATPases ATP7A and ATP7B. The Journal of biological chemistry 72 22130675
2006 Developmental changes in the expression of ATP7A during a critical period in postnatal neurodevelopment. Neuroscience 71 16549268
2021 The P-type ATPase transporter ATP7A promotes angiogenesis by limiting autophagic degradation of VEGFR2. Nature communications 70 34035268
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 64 18032482
2001 ATP7A gene mutations in 16 patients with Menkes disease and a patient with occipital horn syndrome. American journal of medical genetics 63 11241493
2021 ATP7A-Regulated Enzyme Metalation and Trafficking in the Menkes Disease Puzzle. Biomedicines 61 33917579
2017 The interactome of the copper transporter ATP7A belongs to a network of neurodevelopmental and neurodegeneration factors. eLife 60 28355134
2017 A Role for The ATP7A Copper Transporter in Tumorigenesis and Cisplatin Resistance. Journal of Cancer 56 28819394
2016 The Activity of Menkes Disease Protein ATP7A Is Essential for Redox Balance in Mitochondria. The Journal of biological chemistry 56 27226607
2016 Ammonium tetrathiomolybdate treatment targets the copper transporter ATP7A and enhances sensitivity of breast cancer to cisplatin. Oncotarget 55 27806319
2007 Altered ATP7A expression and other compensatory responses in a murine model of Menkes disease. Neurobiology of disease 55 17588765
2006 Copper-dependent interaction of glutaredoxin with the N termini of the copper-ATPases (ATP7A and ATP7B) defective in Menkes and Wilson diseases. Biochemical and biophysical research communications 53 16884690
2018 XIAP Regulation by MNK Links MAPK and NFκB Signaling to Determine an Aggressive Breast Cancer Phenotype. Cancer research 48 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 44 27289018
2015 Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia. Leukemia 42 26165234
2006 Alteration of copper physiology in mice overexpressing the human Menkes protein ATP7A. American journal of physiology. Regulatory, integrative and comparative physiology 42 16397091
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 41 35136028
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
2011 Altered intracellular localization and valosin-containing protein (p97 VCP) interaction underlie ATP7A-related distal motor neuropathy. Human molecular genetics 41 22210628
2017 Dynamics of the metal binding domains and regulation of the human copper transporters ATP7B and ATP7A. IUBMB life 40 28271598
2021 Progress in developing MNK inhibitors. European journal of medicinal chemistry 39 33892273
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 Update on the Development of MNK Inhibitors as Therapeutic Agents. Journal of medicinal chemistry 36 34533957
2018 Dynamic changes in copper homeostasis and post-transcriptional regulation of Atp7a during myogenic differentiation. Metallomics : integrated biometal science 36 29333545
2017 Inhibiting the MNK-eIF4E-β-catenin axis increases the responsiveness of aggressive breast cancer cells to chemotherapy. Oncotarget 36 27926520
2018 MircroRNA-139 sensitizes ovarian cancer cell to cisplatin-based chemotherapy through regulation of ATP7A/B. Cancer chemotherapy and pharmacology 35 29594361
2017 Host Cell Copper Transporters CTR1 and ATP7A are important for Influenza A virus replication. Virology journal 35 28115001
2013 Transcription factors Sp1 and Hif2α mediate induction of the copper-transporting ATPase (Atp7a) gene in intestinal epithelial cells during hypoxia. The Journal of biological chemistry 35 23814049
2012 Distinctive features of catalytic and transport mechanisms in mammalian sarco-endoplasmic reticulum Ca2+ ATPase (SERCA) and Cu+ (ATP7A/B) ATPases. The Journal of biological chemistry 35 22854969
2020 IL-6 induced upregulation of T-type Ca2+ currents and sensitization of DRG nociceptors is attenuated by MNK inhibition. Journal of neurophysiology 34 32519575
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 MNK Inhibition Disrupts Mesenchymal Glioma Stem Cells and Prolongs Survival in a Mouse Model of Glioblastoma. Molecular cancer research : MCR 34 27364770
2015 Inhibition of mTORC1 Enhances the Translation of Chikungunya Proteins via the Activation of the MnK/eIF4E Pathway. PLoS pathogens 34 26317997
2004 Phosphorylation of Mnk1 by caspase-activated Pak2/gamma-PAK inhibits phosphorylation and interaction of eIF4G with Mnk. The Journal of biological chemistry 34 15234964
1996 A repeated element in the regulatory region of the MNK gene and its deletion in a patient with occipital horn syndrome. Human molecular genetics 34 8923001
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
2016 Cotargeting MNK and MEK kinases induces the regression of NF1-mutant cancers. The Journal of clinical investigation 32 27159396
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
2010 Differential expression of ATP7A, ATP7B and CTR1 in adult rat dorsal root ganglion tissue. Molecular pain 31 20836889
2005 A single PDZ domain protein interacts with the Menkes copper ATPase, ATP7A. A new protein implicated in copper homeostasis. The Journal of biological chemistry 31 16051599
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
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 27 39394530
2007 Phenotypic diversity of Menkes disease in mottled mice is associated with defects in localisation and trafficking of the ATP7A protein. Journal of medical genetics 27 17483305
2020 The M1311V variant of ATP7A is associated with impaired trafficking and copper homeostasis in models of motor neuron disease. Neurobiology of disease 26 33359139
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
2013 Silencing the Menkes copper-transporting ATPase (Atp7a) gene in rat intestinal epithelial (IEC-6) cells increases iron flux via transcriptional induction of ferroportin 1 (Fpn1). The Journal of nutrition 26 24174620
2002 Expression in mouse kidney of membrane copper transporters Atp7a and Atp7b. Nephron 26 12372948
2020 Disabling MNK protein kinases promotes oxidative metabolism and protects against diet-induced obesity. Molecular metabolism 25 32712434
2017 Dual abrogation of MNK and mTOR: a novel therapeutic approach for the treatment of aggressive cancers. Future medicinal chemistry 25 28841037
2014 Platination of the copper transporter ATP7A involved in anticancer drug resistance. Dalton transactions (Cambridge, England : 2003) 25 24983998
2013 Involvement of CTR1 and ATP7A in lead (Pb)-induced copper (Cu) accumulation in choroidal epithelial cells. Toxicology letters 25 24316150
2021 MiR-495 Inhibits Cisplatin Resistance and Angiogenesis in Esophageal Cancer by Targeting ATP7A. Technology in cancer research & treatment 24 34747666
2017 The Role of the p38-MNK-eIF4E Signaling Axis in TNF Production Downstream of the NOD1 Receptor. Journal of immunology (Baltimore, Md. : 1950) 24 28087669
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
1994 Analysis of Mnk, the murine homologue of the locus for Menkes disease, in normal and mottled (Mo) mice. Genomics 24 7959788
2018 Synergistic effects of inhibiting the MNK-eIF4E and PI3K/AKT/ mTOR pathways on cell migration in MDA-MB-231 cells. Oncotarget 23 29581834
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
2007 Effect of copper and role of the copper transporters ATP7A and CTR1 in intracellular accumulation of cisplatin. Anticancer research 23 17695505
2020 Caveolin-1 stabilizes ATP7A, a copper transporter for extracellular SOD, in vascular tissue to maintain endothelial function. American journal of physiology. Cell physiology 22 32936699
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
2023 Regulation of the apico-basolateral trafficking polarity of the homologous copper-ATPases ATP7A and ATP7B. Journal of cell science 20 38032054
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
2009 Alternative splicing of the Menkes copper Atpase (Atp7a) transcript in the rat intestinal epithelium. American journal of physiology. Gastrointestinal and liver physiology 20 19679821
2007 Loss of MNK function sensitizes fibroblasts to serum-withdrawal induced apoptosis. Genes to cells : devoted to molecular & cellular mechanisms 20 17903173