Affinage

Showing ARL6IP5 — GTRAP3-18 is a alias.

ARL6IP5

PRA1 family protein 3 · UniProt O75915

Length
188 aa
Mass
21.6 kDa
Annotated
2026-06-09
90 papers in source corpus 33 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ARL6IP5 (GTRAP3-18/JWA/PRAF3) is a four-transmembrane PRA1-domain endoplasmic reticulum protein that governs the ER residence and surface delivery of membrane transporters and acts more broadly as an ER membrane-shaping factor (PMID:18167356, PMID:40209949). Its founding function is to bind the C-terminal intracellular domain of the neuronal glutamate/cysteine transporter EAAC1, retaining it in the ER and lowering its substrate affinity, thereby restricting EAAC1-mediated cysteine uptake and dominantly suppressing intracellular glutathione synthesis (PMID:11242046, PMID:18167356, PMID:17646425, PMID:18799673, PMID:21373771); loss of ARL6IP5 in mice raises plasma-membrane EAAC1, elevates neuronal GSH, and confers neuroprotection against oxidative stress (PMID:18799673, PMID:22210510). This trafficking control reflects a general role as a negative regulator of Rab1-dependent ER-to-Golgi transport, an activity rescued by Rab1 co-expression (PMID:18363836, PMID:29872729). Through its PRA1 domain ARL6IP5 constricts ER tubules and shapes the tubular ER network, and is required for FAM134B-mediated ER-phagy (PMID:40209949); consistent with a reticulophagy role, it promotes autophagy/ER-phagy via Ca2+/AMPK signaling and interaction with CALCOCO1 to clear pathological aggregates (PMID:39394963). The protein also retains other secretory cargos in the ER, including POMC—limiting α-MSH secretion to influence food intake (PMID:28904020)—and RANKL, decreasing soluble RANKL and inhibiting osteoclastogenesis (PMID:26220341), while controlling ER calcium and CHOP-dependent ER stress in osteoblasts (PMID:25321471). In a distinct nuclear/cytoplasmic role, ARL6IP5 (as JWA) functions in DNA single-strand-break base excision repair by interacting with XRCC1, being shuttled to the nucleus by XRCC1, transcriptionally upregulating XRCC1 via MAPK/E2F1, and protecting it from ubiquitin-proteasomal degradation (PMID:19208635). ARL6IP5 protein levels are themselves controlled by RNF185-mediated ubiquitination at K158 (PMID:29481911). Acting through MAPK cascades (ERK/FAK/COX-2) and integrin αVβ3/Sp1 signaling, it restrains cancer cell migration, adhesion, and invasion (PMID:19946336, PMID:17336041), and modulates the abundance of multiple receptors and death-pathway components by directing E3-ligase–dependent ubiquitination—promoting HER2 degradation via c-Cbl and SMURF1, and DR4 degradation via MARCH8 to suppress TRAIL-induced apoptosis (PMID:28671676, PMID:27708243, PMID:33875644). It additionally protects dopaminergic neurons by occupying the ferritin-binding site of NCOA4 to inhibit ferritinophagy and ferroptosis (PMID:38744191).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 2001 High

    Established the first molecular function of ARL6IP5 by identifying it as a direct binding partner that down-regulates a neuronal glutamate transporter, answering what protein controls EAAC1 activity.

    Evidence Co-immunoprecipitation and functional transport assays with EAAC1 in cells

    PMID:11242046

    Open questions at the time
    • Did not establish the subcellular site of inhibition
    • Stoichiometry and structural basis of the EAAC1 interaction unresolved
  2. 2007 High

    Defined ARL6IP5 as an ER-resident protein that delays ER exit of EAAC1, linking the inhibitory interaction to retention/trafficking rather than direct catalytic interference.

    Evidence Subcellular fractionation, VSVG ER exit assay, co-IP, and domain-deletion mutagenesis

    PMID:18167356

    Open questions at the time
    • Did not define how self-association is regulated
    • Mechanism linking retention to transport affinity change unclear
  3. 2007 High

    Showed ARL6IP5 dominantly sets intracellular glutathione by controlling EAAC1-mediated cysteine uptake, connecting its trafficking role to redox homeostasis.

    Evidence Bidirectional pharmacological/antisense manipulation of GTRAP3-18 with GSH and oxidative-stress assays

    PMID:17646425 PMID:18799673 PMID:21373771

    Open questions at the time
    • Did not separate plasma-membrane from ER pools of the protein mechanistically
  4. 2008 High

    Identified ARL6IP5 as a negative regulator of Rab1, broadening its role from EAAC1-specific retention to general ER-to-Golgi trafficking control.

    Evidence VSVG transport and neurite outgrowth assays rescued by Rab1 co-expression in CAD cells

    PMID:18363836

    Open questions at the time
    • Did not demonstrate direct ARL6IP5-Rab1 binding
    • Did not define the GEF/GAP relationship to Rab1
  5. 2008 High

    Confirmed in vivo that ARL6IP5 dosage controls brain glutathione via plasma-membrane EAAC1, validating the redox role genetically.

    Evidence Transgenic mouse manipulation, co-IP, and GSH measurement in neurons and brain

    PMID:18799673

    Open questions at the time
    • Behavioral/disease consequences not yet tested in this study
  6. 2009 High

    Revealed a nuclear/cytoplasmic moonlighting function in DNA repair, showing ARL6IP5 (JWA) scaffolds and stabilizes XRCC1 for base excision repair of oxidative single-strand breaks.

    Evidence Co-IP, IF co-localization, comet SSB-repair assay, ubiquitination and reporter assays

    PMID:19208635

    Open questions at the time
    • How an ER transmembrane protein accesses the nucleus mechanistically not resolved
    • Direct vs indirect XRCC1 protection not fully distinguished
  7. 2007 Medium

    Placed ARL6IP5 upstream of MAPK-driven actin remodeling and cell migration, identifying motif requirements (SDR-SLR) for this signaling.

    Evidence Bidirectional manipulation, migration assays, F-actin staining, MAPK phospho-blots, domain mutagenesis

    PMID:17336041

    Open questions at the time
    • Direct upstream receptor link not defined
    • Single lab
  8. 2009 Medium

    Connected the migration-suppressive function to anti-metastatic activity via integrin αVβ3/Sp1 signaling.

    Evidence siRNA, invasion/adhesion assays, in vivo melanoma metastasis model

    PMID:19946336

    Open questions at the time
    • Direct molecular target between JWA and integrin signaling unidentified
    • Single lab
  9. 2011 High

    Demonstrated that ARL6IP5 knockout improves neuronal antioxidant capacity and cognition, establishing physiological relevance of the EAAC1/GSH axis.

    Evidence Gene-targeted knockout mice with fractionation, GSH, behavioral and oxidative-stress readouts

    PMID:22210510

    Open questions at the time
    • Did not address non-neuronal roles of the protein
  10. 2011 Medium

    Extended ARL6IP5's receptor-stability role to delta opioid receptor maintenance during chronic morphine, implicating ubiquitin-proteasome control.

    Evidence siRNA knockdown in rats, chronic morphine cell model, ubiquitin-proteasome assays, behavioral withdrawal scoring

    PMID:21600884

    Open questions at the time
    • Direct E3 ligase not identified
    • Mechanism of DOR stabilization not molecularly resolved
  11. 2014 Medium

    Established ARL6IP5 as an ER calcium/calmodulin regulator in osteoblasts whose loss triggers CHOP-dependent ER stress and apoptosis.

    Evidence Conditional knockout mice, calcium flux, ER stress markers, histomorphometry, in vitro osteoblast/osteoclast assays

    PMID:25321471

    Open questions at the time
    • Molecular link between ARL6IP5 and ER Ca2+ handling not defined
    • Single lab
  12. 2014 Medium

    Showed ARL6IP5 modulates the CK2-phospho-XRCC1 axis context-dependently, switching from XRCC1 stabilization to degradation in cisplatin-resistant cells.

    Evidence Site-directed mutagenesis of XRCC1 CK2 sites, viability assays, resistant cell models

    PMID:25476899

    Open questions at the time
    • Basis of the context-dependent switch unresolved
    • Single lab
  13. 2014 Medium

    Demonstrated neuronal ARL6IP5 loss enhances neurogenesis and lowers LTP threshold via a FAK-PI3K-Akt-mTOR pathway.

    Evidence Neuron-specific knockout mice with behavioral, LTP, BrdU, and pharmacological epistasis

    PMID:25432888

    Open questions at the time
    • Direct molecular target initiating FAK/PI3K signaling unidentified
    • Single lab
  14. 2015 Medium

    Identified RANKL as an ER cargo retained by ARL6IP5, with an N-terminal (1-36) interaction controlling RANKL secretion and osteoclastogenesis.

    Evidence Co-IP, domain-deletion mutagenesis, RANKL ELISA, osteoclast formation assay

    PMID:26220341

    Open questions at the time
    • Generality of cargo selectivity not established
    • Single lab
  15. 2016 Medium

    Linked ARL6IP5 to receptor abundance control by showing it downregulates HER2 via ERK/PEA3 transcriptional and c-Cbl degradation routes, suppressing migration.

    Evidence Migration assays, G-LISA, EMSA, reporter assays, and co-IP of c-Cbl/HER2

    PMID:27167206 PMID:27708243

    Open questions at the time
    • Whether ARL6IP5 directly engages HER2 or its ligases unclear
    • Single lab
  16. 2017 Medium

    Showed ARL6IP5 suppresses TRAIL-induced apoptosis by directing MARCH8-mediated DR4 ubiquitination at K273.

    Evidence Overexpression/knockdown, site-specific ubiquitination, apoptosis assays, tissue correlation

    PMID:28671676

    Open questions at the time
    • Direct ARL6IP5-MARCH8 interaction not demonstrated
    • Single lab
  17. 2017 Medium

    Revealed POMC as an ER cargo whose retention by ARL6IP5 limits α-MSH secretion and regulates feeding via melanocortin signaling.

    Evidence FRET interaction, KO mice, glucose tolerance, ICV antagonist infusion, serum α-MSH

    PMID:28904020

    Open questions at the time
    • Cell-type specificity of the POMC interaction not resolved
    • Single lab
  18. 2018 Medium

    Identified RNF185 as the E3 ligase that ubiquitinates ARL6IP5 at K158 for proteasomal turnover, defining how ARL6IP5 levels are set.

    Evidence Co-IP, ubiquitination assay, K158 mutagenesis, tissue correlation, in vivo metastasis model

    PMID:29481911

    Open questions at the time
    • Signals controlling RNF185 activity toward ARL6IP5 unknown
    • Single lab
  19. 2018 Medium

    Extended glutamate-transporter regulation to astrocytic GLT-1, showing ARL6IP5 supports GLT-1 expression via MAPK and PI3K/CREB signaling.

    Evidence Astrocyte-specific KO mice, GLT-1 assays, pathway inhibitors, CREB siRNA, neurotoxin PD models

    PMID:29500411

    Open questions at the time
    • Direct vs signaling-mediated GLT-1 control not separated
    • Single lab
  20. 2018 Medium

    Demonstrated ARL6IP5 negatively regulates surface CXCR4 through proteasomal degradation to suppress invasion.

    Evidence Invasion assays, surface flow cytometry, proteasome inhibitor and CXCR4 rescue

    PMID:29658570

    Open questions at the time
    • E3 ligase for CXCR4 not identified
    • Single lab
  21. 2021 Medium

    Refined HER2 regulation by identifying SMURF1-mediated ubiquitination at K716 controlled through a JAC1-NEDD4 axis.

    Evidence Site-specific ubiquitination, Western blot, in vitro/in vivo proliferation assays

    PMID:33875644

    Open questions at the time
    • Direct ARL6IP5-SMURF1 binding not shown
    • Single lab
  22. 2022 Medium

    Connected ARL6IP5 to intestinal stem-cell biology through ERK/FBXW7-mediated NOTCH1 stability and the PPARγ/STAT5 axis.

    Evidence Jwa knockout mice, organoids, proteasome and pathway-inhibitor studies

    PMID:36147468

    Open questions at the time
    • Direct molecular partner in NOTCH1 control unidentified
    • Single lab
  23. 2023 Medium

    Linked ARL6IP5 to autophagy induction and α-synuclein clearance by stabilizing free ATG12 and enhancing Rab1-dependent autophagosome formation.

    Evidence Overexpression/knockdown, autophagic flux, ATG12 ubiquitination, co-IP, cellular PD model

    PMID:37445677

    Open questions at the time
    • Direct ATG12 binding not definitively shown
    • Single lab
  24. 2024 Medium

    Identified a neuroprotective ferroptosis mechanism whereby ARL6IP5 occupies the NCOA4 ferritin-binding site to block ferritinophagy.

    Evidence Molecular docking, co-IP, IF, genetic manipulation in cellular and animal PD models

    PMID:38744191

    Open questions at the time
    • Structural validation of the docking model lacking
    • Single lab
  25. 2024 Medium

    Showed ARL6IP5 drives reticulophagy via Ca2+/AMPK and CALCOCO1/LAMP1 to reduce prion burden and ER stress, generalizing its ER-clearance role.

    Evidence Prion-infected cells, autophagic flux, co-IP (CALCOCO1, LAMP1), AMPK inhibition, Ca2+ measurement

    PMID:39394963

    Open questions at the time
    • Relationship to FAM134B ER-phagy pathway not integrated
    • Single lab
  26. 2025 High

    Defined ARL6IP5 as a PRA1-domain ER membrane-shaping protein that constricts ER tubules and is required for FAM134B-mediated ER-phagy, providing a structural basis for its ER functions.

    Evidence Live-cell ER imaging, ER-phagy flux assay, domain mutagenesis, rescue with ARL6IP1, microtubule depolymerization

    PMID:40209949

    Open questions at the time
    • High-resolution structure of the constriction mechanism lacking
    • Link between ER-shaping and cargo-retention functions not unified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the single ER membrane-shaping/cargo-retention activity of ARL6IP5 is reconciled with its reported nuclear DNA-repair and diverse cytoplasmic signaling functions remains unresolved.
  • No structural model unifying the transmembrane and nuclear roles
  • Mechanism of regulated relocalization between ER and nucleus unknown
  • Direct vs indirect nature of many signaling effects undetermined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 2 GO:0005198 structural molecule activity 1
Localization
GO:0005783 endoplasmic reticulum 4 GO:0005886 plasma membrane 3 GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-9612973 Autophagy 3 R-HSA-162582 Signal Transduction 2 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-73894 DNA Repair 1
Partners
CALCOCO1EAAC1NCOA4POMCRAB1RANKLRNF185XRCC1

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 GTRAP3-18 (ARL6IP5) specifically interacts with the carboxy-terminal intracellular domain of EAAC1 (neuronal glutamate transporter), localizes to the cell membrane and cytoplasm, and increasing GTRAP3-18 expression reduces EAAC1-mediated glutamate transport by lowering substrate affinity. Co-immunoprecipitation, functional transport assay in cells, overexpression Nature High 11242046
2007 GTRAP3-18 is a resident endoplasmic reticulum protein that delays ER exit of EAAC1 and other excitatory amino acid transporter family members; it self-associates via hydrophobic domain interactions in the ER membrane and uses cytoplasmic C-terminal interactions to regulate trafficking. Subcellular fractionation, ER exit assay (VSVG transport), co-immunoprecipitation, domain deletion mutagenesis The Journal of biological chemistry High 18167356
2007 GTRAP3-18 at the plasma membrane negatively and dominantly regulates intracellular glutathione content by controlling EAAC1-mediated cysteine uptake; increasing cell-surface GTRAP3-18 (via methyl-β-cyclodextrin) decreases GSH, while decreasing it (via antisense oligonucleotides) increases GSH. Pharmacological manipulation of membrane GTRAP3-18 levels, antisense knockdown, GSH measurement, oxidative stress assay Molecular pharmacology High 17646425 18799673 21373771
2008 GTRAP3-18 acts as a negative regulator of Rab1, inhibiting ER-to-Golgi trafficking; overexpression reduces VSVG transport rate, slows cargo concentration of EAAC1 into transport complexes, and inhibits neurite outgrowth in CAD cells—effects rescued by Rab1 co-expression. VSVG transport assay, Brefeldin A treatment, neurite length measurement, rescue by Rab1 co-expression Journal of cellular and molecular medicine High 18363836
2008 GTRAP3-18 interacts with EAAC1 at the plasma membrane and dominantly determines intracellular neuronal glutathione levels; genetic reduction of GTRAP3-18 in mouse brain increases plasma membrane EAAC1 and raises brain GSH, while overexpression suppresses GSH. Genetic manipulation (transgenic mice), co-immunoprecipitation, GSH measurement in primary neurons and mouse brain The Journal of neuroscience High 18799673
2009 JWA interacts with XRCC1 and functions as a base excision repair protein for oxidative-stress-induced DNA single-strand breaks: JWA is translocated to the nucleus by XRCC1, co-localizes with XRCC1 foci after DNA damage, regulates XRCC1 transcriptionally via MAPK/E2F1, and protects XRCC1 from ubiquitination and proteasomal degradation. Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, SSB repair assay (comet assay), ubiquitination assay, reporter assay Nucleic acids research High 19208635
2009 JWA knockdown increases melanoma cell adhesion and invasion and promotes metastatic colony formation in vivo by intensifying integrin αVβ3 signaling through regulation of nuclear factor Sp1. siRNA knockdown, invasion/adhesion assays, in vivo metastasis model (B16-F10, A375), Western blot Oncogene Medium 19946336
2007 JWA is required for rearrangement of F-actin cytoskeleton and activation of MAPK cascades (ERK, downstream FAK and COX-2) induced by As2O3 and PMA; JWA overexpression alone inhibits cancer cell migration, while JWA deficiency accelerates migration. SDR-SLR motifs of JWA are critical for MAPK cascade activation and cell migration. Overexpression and antisense knockdown, cell migration assay (wound healing/transwell), F-actin staining, MAPK phosphorylation western blot, domain mutagenesis Cellular signalling Medium 17336041
2011 GTRAP3-18-deficient mice show increased EAAC1 expression at the plasma membrane, increased neuronal GSH content, and neuroprotection against oxidative stress, as well as improved motor/spatial learning and memory. Gene-targeting knockout mice, membrane fractionation, GSH measurement, behavioral testing, oxidative stress challenge Neurobiology of disease High 22210510
2014 JWA regulates cisplatin-induced DNA damage and apoptosis through the CK2-phospho-XRCC1-XRCC1 pathway: in normal cells JWA upregulates XRCC1, but in cisplatin-resistant gastric cancer cells JWA promotes XRCC1 degradation; mutation of CK2-targeted 518S/519T/523T residues of XRCC1 blocks this negative regulation. Site-directed mutagenesis of XRCC1 phosphorylation sites, Western blot, cell viability assay, cisplatin-resistant cell models Cell death & disease Medium 25476899
2018 E3 ubiquitin ligase RNF185 directly interacts with JWA and promotes its ubiquitination at K158, leading to proteasomal degradation; RNF185 expression is negatively correlated with JWA in gastric cancer tissues. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K158), Western blot, in vivo metastasis model Biochimica et biophysica acta. Molecular basis of disease Medium 29481911
2017 JWA suppresses TRAIL-induced apoptosis in cisplatin-resistant gastric cancer cells by promoting ubiquitination of death receptor 4 (DR4) at K273 via upregulation of the E3 ubiquitin ligase MARCH8; JWA and DR4 protein levels are negatively correlated in gastric cancer tissues. Overexpression/knockdown, ubiquitination assay, site-directed mutagenesis (DR4 K273), Western blot, apoptosis assay Oncogenesis Medium 28671676
2014 Arl6ip5 is expressed in osteoblasts and functions as an ER calcium regulator controlling calmodulin signaling for osteoblast proliferation; Arl6ip5 deficiency induces ER stress and ER stress-mediated apoptosis (via CHOP), impairs osteoblast differentiation, and increases RANKL expression to enhance osteoclastogenesis. Conditional knockout mice, calcium flux assay, ER stress markers (Western blot), siRNA knockdown, histomorphometry, in vitro osteoblast/osteoclast assays Cell death & disease Medium 25321471
2015 Overexpression of Arl6ip5 in osteoblasts retains RANKL in the ER, decreases soluble RANKL secretion, and inhibits osteoclastogenesis; Arl6ip5 physically binds RANKL and disrupts the RANKL-OPG complex. Deletion of the NH2-terminal 1–36 amino acids of Arl6ip5 abolishes its interaction with RANKL and restores RANKL secretion. Co-immunoprecipitation, domain deletion mutagenesis, conditioned medium RANKL ELISA, osteoclast formation assay, immunofluorescence Biochemical and biophysical research communications Medium 26220341
2017 GTRAP3-18 interacts with pro-opiomelanocortin (POMC) in the ER, retaining it and reducing α-MSH secretion; GTRAP3-18-deficient mice show hypophagia, lean bodies, elevated α-MSH levels, and AMPK inhibition, effects reversed by melanocortin 4 receptor antagonist. FRET (fluorescence resonance energy transfer) interaction assay, GTRAP3-18-deficient mice, intraperitoneal glucose tolerance test, intracerebroventricular antagonist infusion, serum α-MSH measurement FASEB journal Medium 28904020
2018 Astrocytic JWA deficiency reduces expression of the glutamate transporter GLT-1 and glutamate uptake in vivo and in vitro; this occurs via suppression of MAPK and PI3K/CREB signaling. JWA-increased GLT-1 expression is abolished by MEK and PI3K inhibitors and by CREB silencing. Astrocyte-specific conditional JWA knockout mice, in vitro GLT-1 expression assay, pharmacological pathway inhibitors, CREB siRNA, MPTP/paraquat neurotoxin models Cell death & disease Medium 29500411
2011 JWA is required for chronic morphine-induced maintenance of delta opioid receptor (DOR) stability via the ubiquitin-proteasome pathway; JWA knockdown in rats reduces morphine withdrawal response and suppresses DOR expression as well as DARPP-32 and MAP kinase activation. siRNA knockdown in rats, in vitro chronic morphine cell model, Western blot, ubiquitin-proteasome pathway assay, behavioral withdrawal scoring Biochemical and biophysical research communications Medium 21600884
2024 JWA physically occupies the ferritin binding site of NCOA4 (nuclear receptor coactivator 4), thereby inhibiting NCOA4-mediated ferritinophagy and reducing iron-dependent ferroptosis in dopaminergic neurons; molecular docking, co-immunoprecipitation, and immunofluorescence confirm direct JWA-NCOA4 interaction. Molecular docking, co-immunoprecipitation, immunofluorescence, genetic manipulation (JWA overexpression/knockdown), cellular and animal PD models Redox biology Medium 38744191
2025 ARL6IP5 is an ER membrane-shaping protein containing the PRA1 domain; upon overexpression it induces extensive ER tubular networks and constricts the ER membrane (excluding luminal ER enzymes from tubules). ARL6IP5 knockdown impairs ER morphology and reduces FAM134B-mediated ER-phagy flux. Disruption of putative short hairpin structures in the PRA1 domain abolishes membrane constriction. ARL6IP5 and ARL6IP1 (an RHD-containing protein) can functionally substitute for each other in ER shaping. siRNA knockdown, overexpression, live-cell imaging of ER morphology, ER-phagy flux assay, domain mutagenesis, microtubule depolymerization assay The Journal of biological chemistry High 40209949
2023 ARL6IP5 induces autophagy and reduces α-synuclein aggregate burden by stabilizing free ATG12 (preventing its ubiquitination and degradation) and enhancing Rab1-dependent autophagosome initiation and elongation. ARL6IP5 overexpression/knockdown, autophagic flux assay, ATG12 ubiquitination assay, co-immunoprecipitation, cellular PD model (A53T α-synuclein) International journal of molecular sciences Medium 37445677
2024 ARL6IP5 induces reticulophagy to reduce PrPSc burden and alleviate ER stress; ARL6IP5-induced reticulophagy depends on Ca2+-mediated AMPK activation and involves physical interaction with reticulophagy receptor CALCOCO1 and lysosomal marker LAMP1 for lysosomal degradation. Overexpression/knockdown in prion-infected cells (RML-ScN2a), autophagic flux assay, co-immunoprecipitation (CALCOCO1, LAMP1), AMPK inhibition, Ca2+ measurement Autophagy Medium 39394963
2018 Rab1a can rescue the cytotoxicity caused by PRAF3 (ARL6IP5) overexpression, presumably by positively regulating ER-to-Golgi trafficking and counteracting the negative modulation by PRAF3. Co-expression rescue assay, cell viability assay Biochemistry and biophysics reports Low 29872729
2016 JWA suppresses EGF-induced cell migration and actin cytoskeletal rearrangement in HER2-overexpressing gastric cancer cells by downregulating HER2 expression through ERK activation and consequent PEA3 upregulation; modulation of HER2 by JWA is ERK/PEA3-dependent. Transwell migration assay, G-LISA (Rho GTPase activity), Western blot, real-time PCR, EMSA, luciferase reporter assay Oncotarget Medium 27167206
2016 JWA promotes HER2 degradation via the E3 ubiquitin ligase c-Cbl, representing a mechanism for JWA-induced HER2 downregulation that confers lapatinib resistance while reversing cisplatin resistance in gastric cancer cells. Western blot, co-immunoprecipitation (c-Cbl/HER2), overexpression/knockdown, cell viability assay Oncotarget Medium 27708243
2021 JWA suppresses HER2 ubiquitination and proliferation of HER2-positive breast cancer through the E3 ubiquitin ligase SMURF1 (increased by JAC1-mediated decrease of NEDD4, the E3 ligase for SMURF1); JWA promotes HER2 ubiquitination at K716 via SMURF1. Ubiquitination assay (K716 site), Western blot, overexpression, in vitro and in vivo proliferation assay Cell death discovery Medium 33875644
2018 JWA suppresses breast cancer cell invasion by negatively regulating cell-surface CXCR4 expression via proteasome-mediated degradation (not transcriptional inhibition); normalizing CXCR4 reverses JWA's inhibitory effect on invasion. Overexpression/knockdown, invasion assay, flow cytometry (surface CXCR4), proteasome inhibitor rescue, CXCR4 rescue experiment Molecular medicine reports Medium 29658570
2022 JWA deficiency promotes NOTCH1 degradation via the ERK/FBXW7-mediated ubiquitin-proteasome pathway, thus disturbing the PPARγ/STAT5 axis and reducing intestinal stem cell function and epithelial cell lineage distribution. Jwa knockout mice, intestinal organoids, Western blot, proteasome assay, pathway inhibitor studies International journal of biological sciences Medium 36147468
2023 JWA negatively regulates CD44 expression in lung cancer by inhibiting ubiquitination-mediated degradation of SP1 (Specificity Protein 1); nicotine downregulates JWA via the CHRNA5-mediated AKT pathway, leading to elevated SP1 and CD44. Western blot, ubiquitination assay, in vivo xenograft, siRNA/overexpression, pharmacological AKT pathway inhibition Ecotoxicology and environmental safety Medium 37224781
2023 JAC4 promotes NEDD4L stability via AMPK-mediated phosphorylation at Thr367; the WW domain of NEDD4L (E3 ubiquitin ligase) interacts with EGFR and promotes its ubiquitination at K716, leading to EGFR degradation; this cascade is initiated by JAC4 directly binding CTBP1 and blocking its nuclear translocation, thereby de-repressing JWA gene transcription. Co-immunoprecipitation, ubiquitination assay (K716), mass spectrometry, cellular thermal shift assay, molecular docking, qRT-PCR, in vivo xenograft International journal of molecular sciences Medium 37240137
2022 JAC1 specifically binds YY1 and eliminates its transcriptional repression of the JWA gene; JAC1 also promotes ubiquitination and degradation of YY1, and disrupts the YY1-HSF1 interaction. Co-immunoprecipitation, ubiquitination assay, luciferase reporter assay, Western blot Cell death discovery Medium 35383155
2008 JWA knockdown attenuates arsenic trioxide (As2O3)-induced apoptosis in HeLa and MCF-7 cells; JWA is required for As2O3-induced mitochondrial transmembrane potential loss, caspase-9 activation, and MEK1/2, ERK1/2, and JNK phosphorylations. JWA expression is induced by intracellular ROS generated by As2O3. siRNA knockdown, apoptosis assay (caspase activity, mitochondrial membrane potential), MAPK phosphorylation western blot, ROS measurement Toxicology and applied pharmacology Medium 18387645
2014 JWA deficiency in neurons (JWA-nKO mice) enhances neurogenesis (survival/migration of newborn neurons and neurite growth) and lowers the LTP threshold in hippocampal dentate gyrus via the FAK-PI3K-Akt-mTOR pathway; PI3K or FAK inhibition abolishes enhanced neurogenesis and LTP; telomerase inhibition suppresses both neurogenesis and LTP enhancement. Neuronal-specific JWA knockout mice, Morris water maze, LTP electrophysiology, BrdU labeling, pharmacological inhibitor epistasis (PI3K, FAK, mTOR), telomerase inhibitor Molecular neurobiology Medium 25432888

Source papers

Stage 0 corpus · 90 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Modulation of the neuronal glutamate transporter EAAC1 by the interacting protein GTRAP3-18. Nature 187 11242046
2009 JWA regulates melanoma metastasis by integrin alphaVbeta3 signaling. Oncogene 65 19946336
2007 The endoplasmic reticulum exit of glutamate transporter is regulated by the inducible mammalian Yip6b/GTRAP3-18 protein. The Journal of biological chemistry 60 18167356
2009 JWA regulates XRCC1 and functions as a novel base excision repair protein in oxidative-stress-induced DNA single-strand breaks. Nucleic acids research 58 19208635
2007 JWA as a functional molecule to regulate cancer cells migration via MAPK cascades and F-actin cytoskeleton. Cellular signalling 57 17336041
2014 JWA reverses cisplatin resistance via the CK2-XRCC1 pathway in human gastric cancer cells. Cell death & disease 52 25476899
2007 Identification of JWA as a novel functional gene responsive to environmental oxidative stress induced by benzo[a]pyrene and hydrogen peroxide. Free radical biology & medicine 49 17462538
2008 JWA is required for arsenic trioxide induced apoptosis in HeLa and MCF-7 cells via reactive oxygen species and mitochondria linked signal pathway. Toxicology and applied pharmacology 47 18387645
2012 Inhibition of GTRAP3-18 may increase neuroprotective glutathione (GSH) synthesis. International journal of molecular sciences 45 23109897
2008 A dominant role of GTRAP3-18 in neuronal glutathione synthesis. The Journal of neuroscience : the official journal of the Society for Neuroscience 44 18799673
2011 Modulation of neuronal glutathione synthesis by EAAC1 and its interacting protein GTRAP3-18. Amino acids 42 21373771
2002 Identification of addicsin/GTRAP3-18 as a chronic morphine-augmented gene in amygdala. Neuroreport 37 12438930
2011 Increased neuronal glutathione and neuroprotection in GTRAP3-18-deficient mice. Neurobiology of disease 35 22210510
2008 GTRAP3-18 serves as a negative regulator of Rab1 in protein transport and neuronal differentiation. Journal of cellular and molecular medicine 33 18363836
2007 Regulation of glutathione synthesis via interaction between glutamate transport-associated protein 3-18 (GTRAP3-18) and excitatory amino acid carrier-1 (EAAC1) at plasma membrane. Molecular pharmacology 33 17646425
2014 Deficiency of osteoblastic Arl6ip5 impaired osteoblast differentiation and enhanced osteoclastogenesis via disturbance of ER calcium homeostasis and induction of ER stress-mediated apoptosis. Cell death & disease 32 25321471
2018 RNF185 modulates JWA ubiquitination and promotes gastric cancer metastasis. Biochimica et biophysica acta. Molecular basis of disease 29 29481911
2011 JWA enhances As₂O₃-induced tubulin polymerization and apoptosis via p38 in HeLa and MCF-7 cells. Apoptosis : an international journal on programmed cell death 29 21847655
2003 Methyl-beta-cyclodextrin but not retinoic acid reduces EAAT3-mediated glutamate uptake and increases GTRAP3-18 expression. Journal of neurochemistry 28 12562531
2017 JWA regulates TRAIL-induced apoptosis via MARCH8-mediated DR4 ubiquitination in cisplatin-resistant gastric cancer cells. Oncogenesis 27 28671676
2006 JWA, a novel signaling molecule, involved in the induction of differentiation of human myeloid leukemia cells. Biochemical and biophysical research communications 27 16430862
2022 JAC1 targets YY1 mediated JWA/p38 MAPK signaling to inhibit proliferation and induce apoptosis in TNBC. Cell death discovery 26 35383155
2018 Astrocytic JWA deletion exacerbates dopaminergic neurodegeneration by decreasing glutamate transporters in mice. Cell death & disease 23 29500411
2021 JAC1 suppresses proliferation of breast cancer through the JWA/p38/SMURF1/HER2 signaling. Cell death discovery 22 33875644
2015 EGCG regulates the cross-talk between JWA and topoisomerase IIα in non-small-cell lung cancer (NSCLC) cells. Scientific reports 22 26046674
2006 JWA, a novel signaling molecule, involved in all-trans retinoic acid induced differentiation of HL-60 cells. Journal of biomedical science 22 16468075
2017 JWA antagonizes paraquat-induced neurotoxicity via activation of Nrf2. Toxicology letters 21 28428137
2006 JWA is required for the antiproliferative and pro-apoptotic effects of all-trans retinoic acid in Hela cells. Clinical and experimental pharmacology & physiology 20 16922813
2024 JWA binding to NCOA4 alleviates degeneration in dopaminergic neurons through suppression of ferritinophagy in Parkinson's disease. Redox biology 19 38744191
2012 PRAF3 induces apoptosis and inhibits migration and invasion in human esophageal squamous cell carcinoma. BMC cancer 19 22433565
2008 The Drosophila homolog of jwa is required for ethanol tolerance. Alcohol and alcoholism (Oxford, Oxfordshire) 19 18503079
2014 Astrocytic JWA expression is essential to dopaminergic neuron survival in the pathogenesis of Parkinson's disease. CNS neuroscience & therapeutics 18 24628733
2005 Regulation of a novel cell differentiation-associated gene, JWA during oxidative damage in K562 and MCF-7 cells. Journal of biomedical science 17 15864752
2022 ARL6IP5 reduces cisplatin-resistance by suppressing DNA repair and promoting apoptosis pathways in ovarian carcinoma. Cell death & disease 15 35293383
2014 Lack of JWA Enhances Neurogenesis and Long-Term Potentiation in Hippocampal Dentate Gyrus Leading to Spatial Cognitive Potentiation. Molecular neurobiology 15 25432888
2023 JWA inhibits nicotine-induced lung cancer stemness and progression through CHRNA5/AKT-mediated JWA/SP1/CD44 axis. Ecotoxicology and environmental safety 14 37224781
2006 JWA as a novel molecule involved in oxidative stress-associated signal pathway in myelogenous leukemia cells. Journal of toxicology and environmental health. Part A 14 16766476
2012 JWA deficiency suppresses dimethylbenz[a]anthracene-phorbol ester induced skin papillomas via inactivation of MAPK pathway in mice. PloS one 13 22461904
2007 JWA gene is involved in cadmium-induced growth inhibition and apoptosis in HEK-293T cells. Journal of toxicology and environmental health. Part A 13 17479408
2009 JWA sensitizes P-glycoprotein-mediated drug-resistant choriocarcinoma cells to etoposide via JNK and mitochondrial-associated signal pathway. Journal of toxicology and environmental health. Part A 12 19492242
2023 ARL6IP5 Ameliorates α-Synuclein Burden by Inducing Autophagy via Preventing Ubiquitination and Degradation of ATG12. International journal of molecular sciences 11 37445677
2019 Emerging JWA-targeted Pt(IV) prodrugs conjugated with CX-4945 to overcome chemo-immune-resistance. Biochemical and biophysical research communications 11 31703842
2015 Effects of JWA, XRCC1 and BRCA1 mRNA expression on molecular staging for personalized therapy in patients with advanced esophageal squamous cell carcinoma. BMC cancer 11 25925371
2014 JWA gene regulates PANC-1 pancreatic cancer cell behaviors through MEK-ERK1/2 of the MAPK signaling pathway. Oncology letters 11 25202426
2007 Functional polymorphisms of JWA gene are associated with risk of bladder cancer. Journal of toxicology and environmental health. Part A 11 17479401
2022 Jwa participates the maintenance of intestinal epithelial homeostasis via ERK/FBXW7-mediated NOTCH1/PPARγ/STAT5 axis and acts as a novel putative aging related gene. International journal of biological sciences 10 36147468
2021 JWA suppresses proliferation in trastuzumab-resistant breast cancer by downregulating CDK12. Cell death discovery 10 34686673
2018 JWA suppresses the invasion of human breast carcinoma cells by downregulating the expression of CXCR4. Molecular medicine reports 9 29658570
2016 JWA loss promotes cell migration and cytoskeletal rearrangement by affecting HER2 expression and identifies a high-risk subgroup of HER2-positive gastric carcinoma patients. Oncotarget 9 27167206
2016 JWA down-regulates HER2 expression via c-Cbl and induces lapatinib resistance in human gastric cancer cells. Oncotarget 9 27708243
2011 JWA regulates chronic morphine dependence via the delta opioid receptor. Biochemical and biophysical research communications 9 21600884
2007 Identification and functional characterization of JWA polymorphisms and their association with risk of gastric cancer and esophageal squamous cell carcinoma in a Chinese population. Journal of toxicology and environmental health. Part A 9 17479402
2005 JWA--a novel environmental-responsive gene, involved in estrogen receptor-associated signal pathway in MCF-7 and MDA-MB-231 breast carcinoma cells. Journal of toxicology and environmental health. Part A 9 15799245
2015 Effects of the JWA gene in the regulation of human breast cancer cells. Molecular medicine reports 8 25586271
2023 JAC4 Inhibits EGFR-Driven Lung Adenocarcinoma Growth and Metastasis through CTBP1-Mediated JWA/AMPK/NEDD4L/EGFR Axis. International journal of molecular sciences 7 37240137
2022 JAC4 Protects from X-ray Radiation-Induced Intestinal Injury by JWA-Mediated Anti-Oxidation/Inflammation Signaling. Antioxidants (Basel, Switzerland) 7 35739964
2019 Jwa Kum Whan Attenuates Nonalcoholic Fatty Liver Disease by Modulating Glucose Metabolism and the Insulin Signaling Pathway. Evidence-based complementary and alternative medicine : eCAM 7 30881473
2003 [Effect of differentiation inducer and heat stress on the expression of JWA protein and Hsp70 of K562 cells]. Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases 7 14761432
2012 Downregulation of JWA expression in human esophageal squamous cell carcinoma and its clinical significance. Oncology research 6 23461062
2004 [Expressions of JWA protein and heat stress protein 70 induced by cell differentiation inducers combined with heat stress in K562 cells]. Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases 6 15033023
2022 Targeting JWA for Cancer Therapy: Functions, Mechanisms and Drug Discovery. Cancers 5 36230577
2006 [The role of JWA in N-methyl-N'-nitro-N-nitrosoguanidine induced human bronchial epithelial cell apoptosis]. Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases 5 16701030
2006 Functional variations in the JWA gene are associated with increased odds of leukemias. Leukemia research 5 17049984
2005 [A case-control study on JWA promoter -76G-->C polymorphism and the susceptibility of bladder cancer]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 5 16331563
2003 [The mechanism of JWA gene involved in oxidative stress of cells]. Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases 5 14761492
2014 JWA regulates human esophageal squamous cell carcinoma and human esophageal cells through different mitogen-activated protein kinase signaling pathways. Experimental and therapeutic medicine 4 24926382
2020 Disruption of SSBs repair to combat platinum resistance via the JWA-targeted Pt(IV) prodrug conjugated with a wogonin derivative. Die Pharmazie 3 32213241
2018 Hepatic glutamate transport and glutamine synthesis capacities are decreased in finished vs. growing beef steers, concomitant with increased GTRAP3-18 content. Amino acids 3 29392419
2017 [Autophagy regulated by JWA influenced sensitivity of esophageal cancer to cisplatin]. Zhonghua yi xue za zhi 3 28763891
2017 GTRAP3-18 regulates food intake and body weight by interacting with pro-opiomelanocortin. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 3 28904020
2015 Overexpression of Arl6ip5 in osteoblast regulates RANKL subcellualr localization. Biochemical and biophysical research communications 3 26220341
2007 Single nucleotide polymorphism of the JWA gene is associated with risk of leukemia: a case-control study in a Chinese population. Journal of toxicology and environmental health. Part A 3 17479403
2006 [Effects of hemin and thermal stress exposure on JWA expression]. Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases 3 16701031
2005 [JWA gene acts as sensitive molecule responsive to oxidative stress and apoptosis in K562 cells]. Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine] 3 15938852
2005 [Relationship between JWA expression and DNA damage-repair in human embryonic lung cells by benzo(a) pyrene]. Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine] 3 15938853
2005 [Expression of novel environmental responsive protein JWA involved in the oxidative stress responsiveness in MCF-7 cells]. Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases 3 16105456
2005 [JWA gene in regulating committed differentiation of HL-60 cells induced by ATRA, Ara-C and TPA]. Zhongguo shi yan xue ye xue za zhi 3 16277846
2025 ADP ribosylation factor-like GTPase 6-interacting protein 5 (Arl6IP5) is an ER membrane-shaping protein that modulates ER-phagy. The Journal of biological chemistry 2 40209949
2024 A novel ER stress regulator ARL6IP5 induces reticulophagy to ameliorate the prion burden. Autophagy 2 39394963
2011 [The relationship between single nucleotide polymorphisms of JWA gene and susceptibility to hypertension in workers exposed to heat stress]. Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases 2 22357531
2005 [Influence of Qingdai compound on expression of bcr/abl and JWA in K562 cells]. Zhongguo shi yan xue ye xue za zhi 2 16277847
2025 JWA mediates oxidative stress to promote vascular endothelial repair in obstructive sleep apnea-hypopnea syndrome. Sleep medicine 1 40714583
2018 JWA deficiency induces malignant transformation of murine embryonic fibroblast cells. Experimental and therapeutic medicine 1 29545876
2007 [The effect of PKC phosphorylation sites mutation in JWA coding region on TPA-induced MCF-7 cell differentiation]. Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases 1 17908428
2007 Effects of hemin and thermal stress exposure on JWA expression. Frontiers of medicine in China 1 24557627
2006 [Expression deficiency of JWA enhanced DNA damage and delayed DNA repair in HeLa cells induced by benzo (a) pyrene exposure]. Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine] 1 16640902
2025 ARL6IP5 in cancers: bidirectional function and therapeutic value. Cancer gene therapy 0 40253526
2025 ADP ribosylation factor-like GTPase 6-interacting protein 5 (ARL6IP5): a prenylated Rab acceptor protein 1 (PRA1) family protein that shapes the ER membrane and regulates ER-phagy. Autophagy reports 0 40503170
2018 Rab1a rescues the toxicity of PRAF3. Biochemistry and biophysics reports 0 29872729
2008 [JWA regulates N-methyl-N'-nitro-N-nitrosoguanidine induced malignant transformation in human bronchial epithelial cells]. Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases 0 19080375

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