{"gene":"PAQR3","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2012,"finding":"PAQR3 is exclusively localized in the Golgi apparatus and negatively regulates insulin signaling by physically interacting with the p110α catalytic subunit of PI3K, shunting cytosolic p110α to the Golgi apparatus. PAQR3 also competes with the p85 regulatory subunit for binding p110α, thereby reducing PI3K complex formation and downstream AKT/GSK3β phosphorylation in response to insulin.","method":"Co-immunoprecipitation, PAQR3 overexpression/deletion in hepatocytes and mouse liver, PI3K activity assay, PIP3 production measurement, AKT/GSK3β phosphorylation, GLUT4 translocation assay","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, deletion/overexpression, enzymatic activity, downstream readouts) in one rigorous study with in vitro and in vivo validation","pmids":["23086038"],"is_preprint":false},{"year":2012,"finding":"PAQR3 suppresses Ras/Raf/MEK/ERK signaling and inhibits EGF-stimulated ERK phosphorylation and EGF-induced nuclear accumulation of β-catenin in colorectal cancer cells; Paqr3 deletion in ApcMin/+ mice accelerates tumor development in the small intestine.","method":"Paqr3-deleted mouse model crossed with ApcMin/+ mice, PAQR3 overexpression/knockdown in SW-480 cells, ERK phosphorylation assay, β-catenin nuclear localization assay, proliferation and anchorage-independent growth assays","journal":"Carcinogenesis","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in vivo plus orthogonal cellular assays with clear pathway placement","pmids":["22828136"],"is_preprint":false},{"year":2015,"finding":"PAQR3, localized in the Golgi apparatus, acts as an anchor protein for the Scap/SREBP complex at the Golgi. PAQR3 interacts with both Scap and SREBP, promotes Scap/SREBP complex formation, potentiates SREBP processing and lipid synthesis. The interaction of Scap with PAQR3 vs. Insig-1 is mutually exclusive and regulated by cholesterol level. PAQR3 knockdown in liver blunts the SREBP pathway and decreases hepatic cholesterol content. A synthetic peptide disrupting PAQR3–Scap/SREBP interaction inhibits SREBP processing.","method":"Co-immunoprecipitation, PAQR3 knockdown in mouse liver, SREBP processing assay, lipid synthesis assay, cholesterol measurement, synthetic peptide competition assay, Golgi co-localization","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vivo liver knockdown, functional SREBP processing assay, mechanistic peptide competition, multiple orthogonal methods","pmids":["26311497"],"is_preprint":false},{"year":2016,"finding":"PAQR3 functions as a scaffold protein at the Golgi that preferentially facilitates formation of the ATG14L-linked VPS34/PI3K complex (for autophagy initiation) over the UVRAG-linked complex, leading to elevated PI(3)P generation. Upon glucose starvation, AMPK directly phosphorylates PAQR3 at threonine 32, switching on PI(3)P production and autophagosome formation. Paqr3-deleted mice show reduced exercise-induced autophagy and disaggregation of the ATG14L-associated VPS34 complex.","method":"Co-immunoprecipitation, PAQR3 deletion in mice, in vitro AMPK phosphorylation assay, PI(3)P production assay, autophagy flux assays, exercise-induced autophagy in vivo","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay identifying phosphorylation site, Co-IP for complex formation, in vivo mouse KO with exercise autophagy phenotype, multiple orthogonal methods","pmids":["26834238"],"is_preprint":false},{"year":2016,"finding":"PAQR3 promotes proteasomal degradation of Twist1 by forming a ternary complex with Twist1 and the E3 ubiquitin ligase BTRC, enhancing Twist1–BTRC interaction and Twist1 polyubiquitination. PAQR3 overexpression mobilizes Twist1 from the nucleus to a cytoplasmic proteasome-containing structure. The Twist1-box domain is required for interaction with both PAQR3 and BTRC. This mechanism suppresses EMT and metastasis of gastric cancer cells in vitro and in vivo.","method":"Co-immunoprecipitation, ubiquitination assay, protein stability assay, domain deletion/mutagenesis, PAQR3/BTRC overexpression, in vivo metastasis model","journal":"Carcinogenesis","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP showing ternary complex, ubiquitination assay, domain mapping, in vivo validation, multiple orthogonal methods","pmids":["26905590"],"is_preprint":false},{"year":2018,"finding":"PAQR3 directly interacts with PPARα and promotes its polyubiquitination and proteasome-mediated degradation through the E3 ubiquitin ligase HUWE1. PAQR3 enhances the interaction between HUWE1 and PPARα. Paqr3 knockdown/deletion in mouse liver reduces hepatic triglyceride levels and increases fatty acid oxidation and ketogenesis upon fasting via increased PPARα activity.","method":"Co-immunoprecipitation, in vivo and in vitro ubiquitination assay, adenovirus-mediated knockdown, liver-specific Paqr3 knockout mouse, PPARα target gene expression, fatty acid oxidation and ketogenesis measurements","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP for ternary complex, ubiquitination assay, in vivo liver-specific KO, multiple metabolic readouts","pmids":["29331071"],"is_preprint":false},{"year":2018,"finding":"PAQR3 regulates ER-to-Golgi anterograde transport by interacting with the WD domains of Sec13 and Sec31A (COPII outer coat proteins) via its N-terminal end, enhancing Golgi localization of Sec13 and Sec31A and facilitating tethering of COPII vesicles to the Golgi. PAQR3 is localized in ERGIC and cis-Golgi structures. PAQR3 deletion delays ER-to-Golgi trafficking of N-acetylgalactosaminyltransferase-2 and affects cargo transport in RUSH assay.","method":"APEX2 proximity labeling, Co-immunoprecipitation, RUSH assay, brefeldin A washout assay, domain interaction mapping, subcellular fractionation/immunofluorescence","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — proximity labeling plus Co-IP plus functional trafficking assays with domain mapping in one study, single lab but multiple orthogonal methods","pmids":["30466064"],"is_preprint":false},{"year":2015,"finding":"PAQR3 negatively modulates H3K4 trimethylation (H3K4me3) in mammalian cells by interacting with the WRAD sub-complex (WDR5, ASH2, RBBP5, DPY30) regulatory subunits of COMPASS-like complexes and tethering them to the Golgi apparatus, thereby reducing histone methyltransferase activity in the nucleus. PAQR3 also interferes with the interaction of WDR5 with the C-terminus of MLL1. PAQR3 negatively regulates HOXC8 and HOXA9 gene expression.","method":"Co-immunoprecipitation, histone methyltransferase activity assay, subcellular fractionation, PAQR3 overexpression/knockdown, gene expression analysis, hypoxia-induced H3K4me3 measurement","journal":"The Biochemical Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for complex interactions, enzymatic activity assay, functional gene expression readouts, single lab with multiple orthogonal methods","pmids":["25706881"],"is_preprint":false},{"year":2015,"finding":"DDB2 interacts with PAQR3 in vivo and in vitro and promotes PAQR3 ubiquitination and proteasomal degradation, targeting lysine 61 of PAQR3. DDB2 overexpression reduces PAQR3 protein stability and polyubiquitination; knockdown has the opposite effect. The effect of DDB2 on gastric cancer cell proliferation and migration is mediated by PAQR3.","method":"Co-immunoprecipitation, in vitro binding assay, ubiquitination assay, protein stability assay (cycloheximide chase), site-directed mutagenesis (K61), DDB2 knockdown/overexpression, rescue experiments","journal":"The Biochemical Journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro binding, ubiquitination assay with mutagenesis identifying K61 site, rescue experiments, multiple orthogonal methods in one study","pmids":["26205499"],"is_preprint":false},{"year":2017,"finding":"PAQR3 negatively regulates amino acid-induced mTORC1 activation by directly interacting (via its N-terminal end) with the WD domains of Raptor and mLST8, disrupting intact mTORC1 complex formation. PAQR3 reduces the interaction of mTOR with Raptor and mLST8, modulates leucine-induced cell size changes, and knockdown of PAQR3 reduces amino acid deprivation-induced autophagy in a rapamycin-reversible manner.","method":"Co-immunoprecipitation, domain interaction mapping, cell size measurement, PAQR3 knockdown, autophagy flux assay, rapamycin rescue","journal":"Cellular Signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, functional autophagy assay with pharmacological rescue, single lab with multiple orthogonal methods","pmids":["28214587"],"is_preprint":false},{"year":2013,"finding":"Paqr3-deleted mice are resistant to high-fat diet-induced obesity and hepatic steatosis, with improved insulin resistance and insulin signaling. PAQR3 modulates leptin signaling in the hypothalamus: PAQR3 overexpression reduces leptin signaling whereas Paqr3 deletion enhances it. Paqr3-deleted mice show increased energy expenditure and physical activity.","method":"Paqr3 knockout mouse model, high-fat diet feeding, metabolic rate measurement, leptin signaling assay in hypothalamus, insulin tolerance test, hepatic steatosis analysis","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo genetic KO with multiple metabolic phenotypes and defined pathway (leptin signaling), single lab with multiple orthogonal physiological readouts","pmids":["24035996"],"is_preprint":false},{"year":2009,"finding":"Using a yeast-based functional assay, adiponectin was identified as an agonist of PAQR3, consistent with PAQR3's close homology to AdipoR1 (PAQR1) and AdipoR2 (PAQR2).","method":"Yeast-based receptor activity assay with adiponectin as ligand","journal":"Journal of Receptor and Signal Transduction Research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single yeast-based assay in one study, heterologous system with no mammalian cell validation","pmids":["19519172"],"is_preprint":false},{"year":2015,"finding":"PAQR3 promotes Gβγ signaling specifically at the Golgi apparatus to regulate Golgi vesicle fission and Golgi-to-plasma membrane protein transport via the Gβγ–PKD signaling pathway. PAQR3 expression causes Golgi fragmentation dependent on its Gβ binding; a Gβ binding-deficient PAQR3 mutant fails to cause fragmentation and acts as a dominant negative to inhibit Golgi-to-PM transport of VSV-G cargo.","method":"PAQR3 overexpression/mutagenesis, Golgi fragmentation assay, VSV-G Golgi-to-PM transport assay, Gβγ inhibitor (gallein) and GRK2ct, PKD dominant-negative and inhibitor (Gö6976)","journal":"Cellular Signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis, pharmacological inhibitors, and cargo transport assay in one study, single lab with multiple orthogonal methods","pmids":["26327583"],"is_preprint":false},{"year":2019,"finding":"PAQR3 modulates blood LDL-C and cholesterol levels by interacting with both LDLR (via its β-sheet domain) and PCSK9 (via its P-domain) and enhancing LDLR–PCSK9 interaction, thereby accelerating LDLR degradation. PAQR3 co-localizes with LDLR, PCSK9, and LDL in early endosomes. Paqr3 hepatic deletion reduces blood LDL-C and increases LDLR half-life.","method":"Co-immunoprecipitation, domain interaction mapping, LDLR half-life assay (cycloheximide chase), Paqr3 liver-specific knockout mouse, blood cholesterol measurement, immunofluorescent co-localization","journal":"Metabolism: Clinical and Experimental","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, in vivo hepatic KO, LDLR half-life measurement, co-localization, single lab with multiple orthogonal methods","pmids":["30831144"],"is_preprint":false},{"year":2019,"finding":"PAQR3 suppresses tumor growth in NSCLC by potentiating autophagy induced by the EGFR inhibitor erlotinib. PAQR3 blocks the interaction of BECN1 with activated EGFR, inhibits tyrosine phosphorylation of BECN1, and abrogates BECN1 interaction with autophagy inhibitory proteins RUBCN/Rubicon and BCL2. Knockdown of ATG7 abolishes the tumor suppressive activity of PAQR3.","method":"Co-immunoprecipitation, BECN1 tyrosine phosphorylation assay, ATG7 knockdown rescue, erlotinib treatment, in vitro and in vivo tumor growth assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP showing PAQR3 disrupts EGFR–BECN1 interaction, phosphorylation assay, genetic epistasis with ATG7 KD, single lab","pmids":["31448672"],"is_preprint":false},{"year":2022,"finding":"GPS (gentiopicroside) directly binds to the NH2-terminus of PAQR3 (residues Leu40, Asp42, Glu69, Tyr125, Ser129), spatially inhibiting the interaction between PAQR3 and PI3K p110α and restoring PI3K/AKT signaling. GPS also promotes DDB2-mediated ubiquitinated degradation of PAQR3.","method":"Surface plasmon resonance (SPR), microscale thermophoresis (MST), thermal shift assay (TSA), cellular thermal shift assay (CETSA), molecular docking, PAQR3–p110α Co-IP competition assay, DDB2-mediated ubiquitination assay","journal":"Acta Pharmaceutica Sinica B","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — multiple direct binding assays (SPR, MST, TSA, CETSA) with site identification, Co-IP competition, single lab","pmids":["35755276"],"is_preprint":false},{"year":2021,"finding":"PAQR3 overexpression promotes BTRC-mediated ubiquitin degradation of the transcription factor Twist1 in endothelial progenitor cells, reducing Twist1 protein level and impairing angiogenesis. This is consistent with the mechanism established in gastric cancer cells (PMID:26905590).","method":"PAQR3 overexpression, ubiquitination assay for Twist1, BTRC knockdown/overexpression, protein level measurement, angiogenesis (tube formation) assay","journal":"Diabetes Research and Clinical Practice","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mechanistic detail relies on prior gastric cancer study; limited new in vitro evidence for this cell type","pmids":["34461141"],"is_preprint":false},{"year":2022,"finding":"PAQR3 silencing in macrophages inhibits STUB1-mediated PPARγ ubiquitination and degradation, thereby increasing PPARγ protein level and promoting M2 macrophage polarization, which accelerates diabetic wound healing and angiogenesis.","method":"PAQR3 knockdown in macrophages, ubiquitination assay for PPARγ, Co-IP of STUB1 with PPARγ, PPARγ inhibitor rescue, STUB1 overexpression rescue, in vivo diabetic wound healing model","journal":"Laboratory Investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP showing STUB1–PPARγ interaction altered by PAQR3 KD, ubiquitination assay, rescue experiments, in vivo model, single lab","pmids":["35710596"],"is_preprint":false},{"year":2021,"finding":"PAQR3 binds Nrf2 (as shown by pull-down assay) and modulates Nrf2 stability through ubiquitination in acute lymphoblastic leukemia cells, promoting ferroptosis. Nrf2 overexpression reverses the anti-proliferative and pro-ferroptotic effects of PAQR3.","method":"Pull-down assay, ubiquitination assay, PAQR3 overexpression, Nrf2 overexpression rescue, ferroptosis markers (MDA, ROS, Fe2+), proliferation assay","journal":"Immunity, Inflammation and Disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pulldown, single lab, limited mechanistic detail in abstract","pmids":["33955706"],"is_preprint":false},{"year":2024,"finding":"METTL14 (delivered via M1 macrophage-derived exosomes) induces m6A modification of PAQR3 mRNA, increasing PAQR3 expression in glomerular endothelial cells under high glucose conditions. Elevated PAQR3 promotes apoptosis, inflammation, and oxidative stress; METTL14 knockdown in exosomes reverses these effects by reducing PAQR3.","method":"Methylated RNA immunoprecipitation (MeRIP) assay, dual-luciferase reporter assay, exosome isolation and co-culture, METTL14 knockdown in M1 macrophages, PAQR3 knockdown/overexpression, cell function assays","journal":"Clinical and Experimental Nephrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP assay demonstrating m6A modification, dual-luciferase validation, exosome mechanistic model, single lab with multiple orthogonal methods","pmids":["39080055"],"is_preprint":false},{"year":2021,"finding":"CHD7 directly transcriptionally activates paqr3b expression in zebrafish; loss of CHD7 downregulates paqr3b, leading to upregulation of MAPK/ERK signaling and defective GABAergic neuron development. This was confirmed in CHD7-mutant human cells. Restoration of paqr3b or pharmacological reduction of ERK signaling rescues GABAergic defects.","method":"chd7 knockout zebrafish model, paqr3b expression analysis (ChIP/reporter implied), MAPK/ERK signaling measurement, GABAergic neuron quantification, behavioral assay, rescue experiments with ephedrine, CHD7 mutant human cell validation","journal":"EMBO Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in zebrafish KO, human cell validation, behavioral and neuronal phenotypes with pathway placement, single lab","pmids":["33900016"],"is_preprint":false},{"year":2023,"finding":"PAQR3 reduces LDLR mRNA stability (as shown by RIP assay and pull-down) to suppress LDLR expression in diffuse large B-cell lymphoma cells, thereby inhibiting PI3K/AKT signaling and promoting ferroptosis.","method":"RIP (RNA immunoprecipitation) assay, pull-down assay, PAQR3 overexpression, LDLR knockdown/overexpression, ferroptosis markers, PI3K/AKT inhibitor rescue, in vivo xenograft","journal":"Hematological Oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RIP and pulldown for RNA binding are unusual for a membrane protein; single lab, mechanism not fully validated","pmids":["37690092"],"is_preprint":false}],"current_model":"PAQR3 is a Golgi-resident seven-transmembrane scaffold protein that negatively regulates multiple oncogenic signaling pathways by spatially sequestering key signaling components to the Golgi: it sequesters PI3K p110α to the Golgi (blocking insulin/PI3K/AKT signaling), anchors the Scap/SREBP complex at the Golgi (regulating cholesterol biosynthesis), scaffolds the ATG14L–VPS34 autophagy-initiating complex (with AMPK-mediated phosphorylation at T32 as a switch), disrupts mTORC1 assembly by binding Raptor/mLST8, promotes proteasomal degradation of PPARα (via HUWE1) and Twist1 (via BTRC), facilitates tethering of COPII vesicles to the Golgi via Sec13/Sec31A interaction, modulates LDLR degradation by enhancing LDLR–PCSK9 interaction, sequesters WRAD sub-complex components to suppress nuclear H3K4me3, and promotes Gβγ–PKD-mediated Golgi vesicle fission; PAQR3 protein stability is itself regulated by DDB2-mediated ubiquitination at K61."},"narrative":{"mechanistic_narrative":"PAQR3 is a Golgi-resident seven-transmembrane scaffold that acts as a spatial regulator of signaling by sequestering or assembling pathway components at the Golgi apparatus, thereby restraining several growth- and metabolism-promoting programs [PMID:23086038, PMID:26311497]. In insulin signaling it physically captures the PI3K catalytic subunit p110α, shunting it to the Golgi and competing with the p85 regulatory subunit to suppress PIP3 production and AKT/GSK3β activation, and it parallels this by dampening Ras/Raf/MEK/ERK output and β-catenin nuclear accumulation — an activity that is tumor-suppressive in vivo, since Paqr3 loss accelerates intestinal tumorigenesis in ApcMin/+ mice [PMID:23086038, PMID:22828136]. The same scaffold logic recurs across distinct pathways: PAQR3 anchors the Scap/SREBP complex at the Golgi to potentiate SREBP processing and cholesterol synthesis in a cholesterol-sensitive, Insig-1-competitive manner [PMID:26311497]; it preferentially nucleates the ATG14L–VPS34 autophagy-initiating complex to drive PI(3)P generation, a function switched on by direct AMPK phosphorylation at threonine 32 during glucose starvation and exercise [PMID:26834238]; and it disrupts mTORC1 assembly by binding the WD domains of Raptor and mLST8 [PMID:28214587]. PAQR3 additionally serves as an adaptor that delivers substrates to E3 ligases, forming ternary complexes that promote proteasomal degradation of Twist1 (via BTRC, suppressing EMT and metastasis) and PPARα (via HUWE1, restraining hepatic fatty-acid oxidation) [PMID:26905590, PMID:29331071]. At the membrane-trafficking level it tethers COPII vesicles to the cis-Golgi/ERGIC through its N-terminus binding the WD domains of Sec13 and Sec31A, and it promotes Gβγ–PKD-mediated Golgi vesicle fission [PMID:30466064, PMID:26327583]. PAQR3 also enhances LDLR–PCSK9 interaction to accelerate LDLR degradation and modulate blood LDL-C [PMID:30831144], and tethers the WRAD/COMPASS-like regulatory subunits to the Golgi to suppress nuclear H3K4 trimethylation [PMID:25706881]. Consistent with these molecular roles, Paqr3-null mice resist high-fat-diet obesity and hepatic steatosis with improved insulin signaling [PMID:24035996]. PAQR3 protein stability is itself controlled by DDB2-mediated ubiquitination at lysine 61 [PMID:26205499].","teleology":[{"year":2009,"claim":"An early question was whether PAQR3, by homology to the adiponectin receptors, functions as a ligand-activated receptor, addressed by testing adiponectin as an agonist.","evidence":"Yeast-based receptor activity assay with adiponectin","pmids":["19519172"],"confidence":"Low","gaps":["Heterologous yeast system with no mammalian validation","No demonstration of adiponectin-dependent signaling output in cells","Receptor function not reconciled with later scaffold/sequestration roles"]},{"year":2012,"claim":"Established that PAQR3 is a Golgi-localized negative regulator of growth signaling, defining its core mechanism as spatial sequestration of signaling enzymes (p110α) and suppression of Ras/ERK output.","evidence":"Co-IP, p85 competition, PI3K/PIP3 assays in hepatocytes and liver, plus ApcMin/+ genetic epistasis and cellular ERK/β-catenin assays","pmids":["23086038","22828136"],"confidence":"High","gaps":["Structural basis of p110α capture not resolved","How Golgi anchoring is reconciled with cytosolic p110α pool kinetics unclear"]},{"year":2013,"claim":"Showed the organismal consequence of PAQR3 loss — resistance to diet-induced obesity and steatosis with enhanced leptin signaling — linking the molecular scaffold to whole-body energy metabolism.","evidence":"Paqr3 knockout mice, high-fat-diet feeding, metabolic rate and hypothalamic leptin signaling assays","pmids":["24035996"],"confidence":"High","gaps":["Tissue-specific contributions to the phenotype not dissected","Molecular target of PAQR3 in hypothalamic leptin signaling not identified"]},{"year":2015,"claim":"Extended the scaffold paradigm beyond signaling kinases to cholesterol biosynthesis and chromatin, showing PAQR3 anchors Scap/SREBP at the Golgi and tethers WRAD subunits away from nuclear COMPASS-like complexes.","evidence":"Reciprocal Co-IP, in vivo liver knockdown, SREBP processing and peptide competition assays; HMT activity assay and H3K4me3 measurement","pmids":["26311497","25706881"],"confidence":"High","gaps":["WRAD tethering shown at Medium confidence with single-lab Co-IP","How a Golgi protein accesses nuclear chromatin regulators mechanistically unresolved"]},{"year":2015,"claim":"Defined how PAQR3 abundance is controlled, identifying DDB2 as an E3-associated factor that ubiquitinates PAQR3 at K61 to drive its degradation.","evidence":"Co-IP, in vitro binding, ubiquitination and cycloheximide-chase assays with K61 mutagenesis and rescue in gastric cancer cells","pmids":["26205499"],"confidence":"High","gaps":["Whether DDB2 acts as the direct ligase or an adaptor not fully defined","Physiological signals controlling DDB2–PAQR3 axis unknown"]},{"year":2016,"claim":"Resolved how PAQR3 acts on autophagy and as an E3-ligase adaptor, showing AMPK-T32 phosphorylation switches PAQR3 to favor the ATG14L–VPS34 complex, and that PAQR3 bridges Twist1 to BTRC for degradation.","evidence":"In vitro AMPK kinase assay, Co-IP for complex composition, PI(3)P and exercise-autophagy in KO mice; ternary-complex Co-IP, ubiquitination and domain mapping with in vivo metastasis model","pmids":["26834238","26905590"],"confidence":"High","gaps":["Structural mechanism of preferential ATG14L vs UVRAG selection unknown","Whether BTRC and ATG14L scaffolding use distinct PAQR3 surfaces unclear"]},{"year":2017,"claim":"Showed PAQR3 antagonizes mTORC1 by binding the WD domains of Raptor and mLST8 to block complex assembly, placing it as a brake on amino-acid-driven growth.","evidence":"Co-IP with N-terminal domain mapping, cell-size and rapamycin-reversible autophagy assays","pmids":["28214587"],"confidence":"Medium","gaps":["Single-lab evidence without in vivo validation","Whether Golgi localization is required for mTORC1 disruption not tested"]},{"year":2018,"claim":"Established two further mechanistic roles: PAQR3 as a HUWE1-adaptor degrading PPARα to restrain hepatic lipid oxidation, and as a COPII-tethering factor binding Sec13/Sec31A WD domains to control ER-to-Golgi transport.","evidence":"Co-IP, in vivo/in vitro ubiquitination and liver-specific KO metabolic readouts; APEX2 proximity labeling, RUSH and brefeldin-A washout trafficking assays with domain mapping","pmids":["29331071","30466064"],"confidence":"High","gaps":["COPII work is single-lab Medium-strength","How substrate-adaptor specificity (PPARα/HUWE1) is achieved structurally unknown"]},{"year":2019,"claim":"Connected PAQR3 to cholesterol clearance and to EGFR-inhibitor-induced autophagy, showing it enhances LDLR–PCSK9 interaction to accelerate LDLR degradation and blocks EGFR–BECN1 association to relieve autophagy inhibition.","evidence":"Co-IP with domain mapping, LDLR half-life and hepatic KO LDL-C measurements; BECN1 phosphorylation and ATG7-KD epistasis with erlotinib tumor assays","pmids":["30831144","31448672"],"confidence":"Medium","gaps":["BECN1/EGFR work at Medium confidence single-lab","How endosomal LDLR/PCSK9 role relates to Golgi residence unclear"]},{"year":2015,"claim":"Demonstrated PAQR3 promotes Gβγ–PKD signaling at the Golgi to drive vesicle fission and Golgi-to-plasma-membrane cargo transport, with Gβ binding required.","evidence":"Mutagenesis, Golgi fragmentation and VSV-G transport assays with gallein/GRK2ct and PKD inhibition","pmids":["26327583"],"confidence":"Medium","gaps":["Single-lab study","Endogenous physiological context of Golgi fission role not established"]},{"year":2024,"claim":"Recent work explored disease-context regulation and additional effectors of PAQR3, including m6A-dependent induction by METTL14, pharmacological disruption by gentiopicroside, and roles in macrophage PPARγ, Nrf2/ferroptosis, LDLR mRNA, angiogenesis, and CHD7-dependent neuronal development.","evidence":"MeRIP/luciferase exosome model, SPR/MST/CETSA binding with site mapping, ubiquitination/RIP/pull-down assays, and zebrafish chd7-KO genetic epistasis","pmids":["39080055","35755276","35710596","33955706","37690092","34461141","33900016"],"confidence":"Low","gaps":["Several findings (Nrf2 binding, LDLR-mRNA binding, angiogenesis) are single low-confidence reports","RNA-binding claims unusual for a transmembrane protein and not reconciled with its scaffold mechanism","Direct vs indirect effects in disease models not separated"]},{"year":null,"claim":"How a single Golgi-anchored multipass scaffold selects among its many partners (PI3K, SREBP, ATG14L, Raptor, COPII, E3 ligases) in a cell- and signal-specific manner remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of PAQR3 with any partner","No unified accounting of how localization, phosphorylation, and ligand state route PAQR3 toward distinct complexes","Whether reported nuclear/chromatin and RNA-level activities reflect a common mechanism is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,3,4,5,9,6,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,9]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,2,3,6,12]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,9]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3,14]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,5,10,13]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[6,12]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,5,8]}],"complexes":[],"partners":["PIK3CA","SCAP","ATG14","RPTOR","MLST8","BTRC","HUWE1","SEC31A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6TCH7","full_name":"Progestin and adipoQ receptor family member 3","aliases":["Progestin and adipoQ receptor family member III","Raf kinase trapping to Golgi","RKTG"],"length_aa":311,"mass_kda":36.2,"function":"Golgi-scaffold protein which modulates its interactors acitivies by anchoring them to the Golgi apparatus (PubMed:18547165, PubMed:26311497). Functions as a spatial regulator of RAF1 kinase by sequestrating it to the Golgi apparatus (PubMed:18547165). Acts as a positive regulator of cholesterol biosynthesis by mediating the anchoring of the SCAP:SREBP complex in the Golgi apparatus, thereby promoting SCAP:SREBF2 complex formation, potentiating SREBF2 and SREBF1 processing and enhancing lipid synthesis (PubMed:26311497). Also regulates PPARA and PPARG functions by mediating their interaction with E3 ubiquitin ligases, such as STUB1 or HUWE1, leading to their polyubiquitination and proteasome-mediated degradation (By similarity)","subcellular_location":"Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/Q6TCH7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PAQR3","classification":"Not Classified","n_dependent_lines":19,"n_total_lines":1208,"dependency_fraction":0.015728476821192054},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PAQR3","total_profiled":1310},"omim":[{"mim_id":"614577","title":"PROGESTIN AND ADIPOQ RECEPTOR FAMILY, MEMBER 3; PAQR3","url":"https://www.omim.org/entry/614577"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in some","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PAQR3"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q6TCH7","domains":[{"cath_id":"1.20.1070,1.20.1070","chopping":"64-301","consensus_level":"high","plddt":95.901,"start":64,"end":301}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6TCH7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6TCH7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6TCH7-F1-predicted_aligned_error_v6.png","plddt_mean":89.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PAQR3","jax_strain_url":"https://www.jax.org/strain/search?query=PAQR3"},"sequence":{"accession":"Q6TCH7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6TCH7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6TCH7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6TCH7"}},"corpus_meta":[{"pmid":"35755276","id":"PMC_35755276","title":"Gentiopicroside targets PAQR3 to activate the PI3K/AKT signaling pathway and ameliorate disordered glucose and lipid metabolism.","date":"2022","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/35755276","citation_count":148,"is_preprint":false},{"pmid":"26311497","id":"PMC_26311497","title":"PAQR3 modulates cholesterol homeostasis by anchoring Scap/SREBP complex to the Golgi apparatus.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26311497","citation_count":70,"is_preprint":false},{"pmid":"25520877","id":"PMC_25520877","title":"MicroRNA-543 acts as an oncogene by targeting PAQR3 in hepatocellular carcinoma.","date":"2014","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/25520877","citation_count":68,"is_preprint":false},{"pmid":"26834238","id":"PMC_26834238","title":"PAQR3 controls autophagy by integrating AMPK signaling to enhance ATG14L-associated PI3K activity.","date":"2016","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/26834238","citation_count":66,"is_preprint":false},{"pmid":"25330156","id":"PMC_25330156","title":"MicroRNA-137 upregulation increases bladder cancer cell proliferation and invasion by targeting PAQR3.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25330156","citation_count":64,"is_preprint":false},{"pmid":"31448672","id":"PMC_31448672","title":"PAQR3 suppresses the growth of non-small cell lung cancer cells via modulation of EGFR-mediated autophagy.","date":"2019","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/31448672","citation_count":61,"is_preprint":false},{"pmid":"34461141","id":"PMC_34461141","title":"Exosomes from linc00511-overexpressing ADSCs accelerates angiogenesis in diabetic foot ulcers healing by suppressing PAQR3-induced Twist1 degradation.","date":"2021","source":"Diabetes research and clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/34461141","citation_count":54,"is_preprint":false},{"pmid":"29331071","id":"PMC_29331071","title":"Hepatic PPARα function is controlled by polyubiquitination and proteasome-mediated degradation through the coordinated actions of PAQR3 and HUWE1.","date":"2018","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/29331071","citation_count":53,"is_preprint":false},{"pmid":"23086038","id":"PMC_23086038","title":"PAQR3 modulates insulin signaling by shunting phosphoinositide 3-kinase p110α to the Golgi apparatus.","date":"2012","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/23086038","citation_count":52,"is_preprint":false},{"pmid":"22828136","id":"PMC_22828136","title":"PAQR3 plays a suppressive role in the tumorigenesis of colorectal cancers.","date":"2012","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/22828136","citation_count":50,"is_preprint":false},{"pmid":"26905590","id":"PMC_26905590","title":"PAQR3 enhances Twist1 degradation to suppress epithelial-mesenchymal transition and metastasis of gastric cancer cells.","date":"2016","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/26905590","citation_count":45,"is_preprint":false},{"pmid":"28560431","id":"PMC_28560431","title":"Overexpression of miR-15b-5p promotes gastric cancer metastasis by regulating PAQR3.","date":"2017","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/28560431","citation_count":45,"is_preprint":false},{"pmid":"38525833","id":"PMC_38525833","title":"Chicoric acid advanced PAQR3 ubiquitination to ameliorate ferroptosis in diabetes nephropathy through the relieving of the interaction between PAQR3 and P110α pathway.","date":"2024","source":"Clinical and experimental hypertension (New York, N.Y. : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/38525833","citation_count":44,"is_preprint":false},{"pmid":"34588429","id":"PMC_34588429","title":"Circular RNA hsa_circ_0043280 inhibits cervical cancer tumor growth and metastasis via miR-203a-3p/PAQR3 axis.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34588429","citation_count":43,"is_preprint":false},{"pmid":"24035996","id":"PMC_24035996","title":"PAQR3 has modulatory roles in obesity, energy metabolism, and leptin signaling.","date":"2013","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/24035996","citation_count":35,"is_preprint":false},{"pmid":"25310770","id":"PMC_25310770","title":"Identification of PAQR3 as a new candidate tumor suppressor in hepatocellular carcinoma.","date":"2014","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/25310770","citation_count":34,"is_preprint":false},{"pmid":"19519172","id":"PMC_19519172","title":"Adiponectin identified as an agonist for PAQR3/RKTG using a yeast-based assay system.","date":"2009","source":"Journal of receptor and signal transduction research","url":"https://pubmed.ncbi.nlm.nih.gov/19519172","citation_count":29,"is_preprint":false},{"pmid":"26609468","id":"PMC_26609468","title":"PAQR3: a novel tumor suppressor gene.","date":"2015","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26609468","citation_count":28,"is_preprint":false},{"pmid":"25510670","id":"PMC_25510670","title":"The tumor suppressor role of PAQR3 in osteosarcoma.","date":"2014","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25510670","citation_count":26,"is_preprint":false},{"pmid":"26205499","id":"PMC_26205499","title":"DDB2 is involved in ubiquitination and degradation of PAQR3 and regulates tumorigenesis of gastric cancer cells.","date":"2015","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/26205499","citation_count":25,"is_preprint":false},{"pmid":"33123538","id":"PMC_33123538","title":"PAQR3 Inhibits Non-small Cell Lung Cancer Growth by Regulating the NF-κB/p53/Bax Axis.","date":"2020","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33123538","citation_count":24,"is_preprint":false},{"pmid":"33955706","id":"PMC_33955706","title":"PAQR3 inhibits proliferation and aggravates ferroptosis in acute lymphoblastic leukemia through modulation Nrf2 stability.","date":"2021","source":"Immunity, inflammation and disease","url":"https://pubmed.ncbi.nlm.nih.gov/33955706","citation_count":21,"is_preprint":false},{"pmid":"28903314","id":"PMC_28903314","title":"PAQR3 suppresses the proliferation, migration and tumorigenicity of human prostate cancer cells.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28903314","citation_count":21,"is_preprint":false},{"pmid":"33900016","id":"PMC_33900016","title":"Chromatin remodeller CHD7 is required for GABAergic neuron development by promoting PAQR3 expression.","date":"2021","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/33900016","citation_count":21,"is_preprint":false},{"pmid":"25900239","id":"PMC_25900239","title":"PAQR3 expression is downregulated in human breast cancers and correlated with HER2 expression.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25900239","citation_count":20,"is_preprint":false},{"pmid":"26232324","id":"PMC_26232324","title":"PAQR3 plays a suppressive role in laryngeal squamous cell carcinoma.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26232324","citation_count":20,"is_preprint":false},{"pmid":"30393483","id":"PMC_30393483","title":"PAQR3 inhibits proliferation via suppressing PI3K/AKT signaling pathway in non-small cell lung cancer.","date":"2017","source":"Archives of medical science : AMS","url":"https://pubmed.ncbi.nlm.nih.gov/30393483","citation_count":19,"is_preprint":false},{"pmid":"31095939","id":"PMC_31095939","title":"PAQR3 regulates phosphorylation of FoxO1 in insulin-resistant HepG2 cells via NF-κB signaling pathway.","date":"2019","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/31095939","citation_count":19,"is_preprint":false},{"pmid":"28548040","id":"PMC_28548040","title":"PAQR3 Inhibits the Proliferation and Tumorigenesis in Esophageal Cancer Cells.","date":"2017","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/28548040","citation_count":18,"is_preprint":false},{"pmid":"28802234","id":"PMC_28802234","title":"PAQR3 overexpression suppresses the aggressive phenotype of esophageal squamous cell carcinoma cells via inhibition of ERK signaling.","date":"2017","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/28802234","citation_count":18,"is_preprint":false},{"pmid":"30466064","id":"PMC_30466064","title":"PAQR3 Regulates Endoplasmic Reticulum-to-Golgi Trafficking of COPII Vesicle via Interaction with Sec13/Sec31 Coat Proteins.","date":"2018","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/30466064","citation_count":18,"is_preprint":false},{"pmid":"29787774","id":"PMC_29787774","title":"Silencing of PAQR3 suppresses extracellular matrix accumulation in high glucose-stimulated human glomerular mesangial cells via PI3K/AKT signaling pathway.","date":"2018","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29787774","citation_count":17,"is_preprint":false},{"pmid":"35710596","id":"PMC_35710596","title":"PAQR3 depletion accelerates diabetic wound healing by promoting angiogenesis through inhibiting STUB1-mediated PPARγ degradation.","date":"2022","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/35710596","citation_count":16,"is_preprint":false},{"pmid":"32016977","id":"PMC_32016977","title":"MiR-15b facilitates breast cancer progression via repressing tumor suppressor PAQR3.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32016977","citation_count":16,"is_preprint":false},{"pmid":"26327583","id":"PMC_26327583","title":"PAQR3 regulates Golgi vesicle fission and transport via the Gβγ-PKD signaling pathway.","date":"2015","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/26327583","citation_count":15,"is_preprint":false},{"pmid":"29122400","id":"PMC_29122400","title":"Aberrant promoter methylation of the PAQR3 gene is associated with prostate cancer.","date":"2017","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/29122400","citation_count":15,"is_preprint":false},{"pmid":"28528182","id":"PMC_28528182","title":"PAQR3 inhibits the proliferation, migration and invasion in human glioma cells.","date":"2017","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/28528182","citation_count":15,"is_preprint":false},{"pmid":"32021448","id":"PMC_32021448","title":"Characterization of the Golgi scaffold protein PAQR3, and its role in tumor suppression and metabolic pathway compartmentalization.","date":"2020","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/32021448","citation_count":14,"is_preprint":false},{"pmid":"33249098","id":"PMC_33249098","title":"Silencing PAQR3 protects against oxygen-glucose deprivation/reperfusion-induced neuronal apoptosis via activation of PI3K/AKT signaling in PC12 cells.","date":"2020","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33249098","citation_count":14,"is_preprint":false},{"pmid":"37690092","id":"PMC_37690092","title":"PAQR3 facilitates the ferroptosis of diffuse large B-cell lymphoma via the regulation of LDLR-mediated PI3K/AKT pathway.","date":"2023","source":"Hematological oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37690092","citation_count":12,"is_preprint":false},{"pmid":"39080055","id":"PMC_39080055","title":"METTL14 derived from exosomes of M1 macrophages promotes high glucose-induced apoptosis, inflammation and oxidative stress in glomerular endothelial cells by mediating PAQR3 m6A modification.","date":"2024","source":"Clinical and experimental nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/39080055","citation_count":12,"is_preprint":false},{"pmid":"30831144","id":"PMC_30831144","title":"PAQR3 modulates blood cholesterol level by facilitating interaction between LDLR and PCSK9.","date":"2019","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/30831144","citation_count":11,"is_preprint":false},{"pmid":"28214587","id":"PMC_28214587","title":"PAQR3 augments amino acid deprivation-induced autophagy by inhibiting mTORC1 signaling.","date":"2017","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/28214587","citation_count":9,"is_preprint":false},{"pmid":"25706881","id":"PMC_25706881","title":"PAQR3 modulates H3K4 trimethylation by spatial modulation of the regulatory subunits of COMPASS-like complexes in mammalian cells.","date":"2015","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/25706881","citation_count":9,"is_preprint":false},{"pmid":"35870178","id":"PMC_35870178","title":"Golgi scaffold protein PAQR3 as a candidate suppressor of gastric cardia adenocarcinoma via regulating TGF-β/Smad pathway.","date":"2022","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/35870178","citation_count":8,"is_preprint":false},{"pmid":"37017919","id":"PMC_37017919","title":"Hsa_circ_0003928 regulates the progression of diabetic nephropathy through miR-136-5p/PAQR3 axis.","date":"2023","source":"Journal of endocrinological investigation","url":"https://pubmed.ncbi.nlm.nih.gov/37017919","citation_count":8,"is_preprint":false},{"pmid":"32448978","id":"PMC_32448978","title":"PAQR3 protects against oxygen-glucose deprivation/reperfusion-induced injury through the ERK signaling pathway in N2A cells.","date":"2020","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/32448978","citation_count":7,"is_preprint":false},{"pmid":"27124708","id":"PMC_27124708","title":"Two-layer regulation of PAQR3 on ATG14-linked class III PtdIns3K activation upon glucose starvation.","date":"2016","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/27124708","citation_count":7,"is_preprint":false},{"pmid":"37767187","id":"PMC_37767187","title":"The Emerging Roles and Mechanisms of PAQR3 in Human Cancer: Pathophysiology and Therapeutic Implications.","date":"2023","source":"International journal of general medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37767187","citation_count":6,"is_preprint":false},{"pmid":"35232557","id":"PMC_35232557","title":"MiR-153-3p reduces extracellular matrix accumulation in high glucose-stimulated human glomerular mesangial cells via targeting PAQR3 in diabetic nephropathy.","date":"2022","source":"Endocrinologia, diabetes y nutricion","url":"https://pubmed.ncbi.nlm.nih.gov/35232557","citation_count":5,"is_preprint":false},{"pmid":"38321173","id":"PMC_38321173","title":"Systematic pan-cancer analyses of the potential function of the Golgi scaffold protein PAQR3.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38321173","citation_count":4,"is_preprint":false},{"pmid":"35833812","id":"PMC_35833812","title":"Platelet rich plasma alleviates OGD/R injury in N2a cell by enhancing autophagy through the miR‑223/PAQR3 pathway.","date":"2022","source":"Acta neurobiologiae experimentalis","url":"https://pubmed.ncbi.nlm.nih.gov/35833812","citation_count":2,"is_preprint":false},{"pmid":"40723340","id":"PMC_40723340","title":"Transcriptomic and Functional Validation Reveals PAQR3/P6-55 as Potential Therapeutic Targets in Colon Cancer.","date":"2025","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/40723340","citation_count":0,"is_preprint":false},{"pmid":"41609065","id":"PMC_41609065","title":"The role of PAQR3 in cancer progression - Molecular regulation, signaling pathways, and clinical implications: A review.","date":"2026","source":"Biomolecules & biomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/41609065","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":29972,"output_tokens":6543,"usd":0.094031,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15460,"output_tokens":4709,"usd":0.097513,"stage2_stop_reason":"end_turn"},"total_usd":0.191544,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"PAQR3 is exclusively localized in the Golgi apparatus and negatively regulates insulin signaling by physically interacting with the p110α catalytic subunit of PI3K, shunting cytosolic p110α to the Golgi apparatus. PAQR3 also competes with the p85 regulatory subunit for binding p110α, thereby reducing PI3K complex formation and downstream AKT/GSK3β phosphorylation in response to insulin.\",\n      \"method\": \"Co-immunoprecipitation, PAQR3 overexpression/deletion in hepatocytes and mouse liver, PI3K activity assay, PIP3 production measurement, AKT/GSK3β phosphorylation, GLUT4 translocation assay\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, deletion/overexpression, enzymatic activity, downstream readouts) in one rigorous study with in vitro and in vivo validation\",\n      \"pmids\": [\"23086038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PAQR3 suppresses Ras/Raf/MEK/ERK signaling and inhibits EGF-stimulated ERK phosphorylation and EGF-induced nuclear accumulation of β-catenin in colorectal cancer cells; Paqr3 deletion in ApcMin/+ mice accelerates tumor development in the small intestine.\",\n      \"method\": \"Paqr3-deleted mouse model crossed with ApcMin/+ mice, PAQR3 overexpression/knockdown in SW-480 cells, ERK phosphorylation assay, β-catenin nuclear localization assay, proliferation and anchorage-independent growth assays\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in vivo plus orthogonal cellular assays with clear pathway placement\",\n      \"pmids\": [\"22828136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PAQR3, localized in the Golgi apparatus, acts as an anchor protein for the Scap/SREBP complex at the Golgi. PAQR3 interacts with both Scap and SREBP, promotes Scap/SREBP complex formation, potentiates SREBP processing and lipid synthesis. The interaction of Scap with PAQR3 vs. Insig-1 is mutually exclusive and regulated by cholesterol level. PAQR3 knockdown in liver blunts the SREBP pathway and decreases hepatic cholesterol content. A synthetic peptide disrupting PAQR3–Scap/SREBP interaction inhibits SREBP processing.\",\n      \"method\": \"Co-immunoprecipitation, PAQR3 knockdown in mouse liver, SREBP processing assay, lipid synthesis assay, cholesterol measurement, synthetic peptide competition assay, Golgi co-localization\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vivo liver knockdown, functional SREBP processing assay, mechanistic peptide competition, multiple orthogonal methods\",\n      \"pmids\": [\"26311497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PAQR3 functions as a scaffold protein at the Golgi that preferentially facilitates formation of the ATG14L-linked VPS34/PI3K complex (for autophagy initiation) over the UVRAG-linked complex, leading to elevated PI(3)P generation. Upon glucose starvation, AMPK directly phosphorylates PAQR3 at threonine 32, switching on PI(3)P production and autophagosome formation. Paqr3-deleted mice show reduced exercise-induced autophagy and disaggregation of the ATG14L-associated VPS34 complex.\",\n      \"method\": \"Co-immunoprecipitation, PAQR3 deletion in mice, in vitro AMPK phosphorylation assay, PI(3)P production assay, autophagy flux assays, exercise-induced autophagy in vivo\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay identifying phosphorylation site, Co-IP for complex formation, in vivo mouse KO with exercise autophagy phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"26834238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PAQR3 promotes proteasomal degradation of Twist1 by forming a ternary complex with Twist1 and the E3 ubiquitin ligase BTRC, enhancing Twist1–BTRC interaction and Twist1 polyubiquitination. PAQR3 overexpression mobilizes Twist1 from the nucleus to a cytoplasmic proteasome-containing structure. The Twist1-box domain is required for interaction with both PAQR3 and BTRC. This mechanism suppresses EMT and metastasis of gastric cancer cells in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, protein stability assay, domain deletion/mutagenesis, PAQR3/BTRC overexpression, in vivo metastasis model\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP showing ternary complex, ubiquitination assay, domain mapping, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"26905590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PAQR3 directly interacts with PPARα and promotes its polyubiquitination and proteasome-mediated degradation through the E3 ubiquitin ligase HUWE1. PAQR3 enhances the interaction between HUWE1 and PPARα. Paqr3 knockdown/deletion in mouse liver reduces hepatic triglyceride levels and increases fatty acid oxidation and ketogenesis upon fasting via increased PPARα activity.\",\n      \"method\": \"Co-immunoprecipitation, in vivo and in vitro ubiquitination assay, adenovirus-mediated knockdown, liver-specific Paqr3 knockout mouse, PPARα target gene expression, fatty acid oxidation and ketogenesis measurements\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP for ternary complex, ubiquitination assay, in vivo liver-specific KO, multiple metabolic readouts\",\n      \"pmids\": [\"29331071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PAQR3 regulates ER-to-Golgi anterograde transport by interacting with the WD domains of Sec13 and Sec31A (COPII outer coat proteins) via its N-terminal end, enhancing Golgi localization of Sec13 and Sec31A and facilitating tethering of COPII vesicles to the Golgi. PAQR3 is localized in ERGIC and cis-Golgi structures. PAQR3 deletion delays ER-to-Golgi trafficking of N-acetylgalactosaminyltransferase-2 and affects cargo transport in RUSH assay.\",\n      \"method\": \"APEX2 proximity labeling, Co-immunoprecipitation, RUSH assay, brefeldin A washout assay, domain interaction mapping, subcellular fractionation/immunofluorescence\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity labeling plus Co-IP plus functional trafficking assays with domain mapping in one study, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"30466064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PAQR3 negatively modulates H3K4 trimethylation (H3K4me3) in mammalian cells by interacting with the WRAD sub-complex (WDR5, ASH2, RBBP5, DPY30) regulatory subunits of COMPASS-like complexes and tethering them to the Golgi apparatus, thereby reducing histone methyltransferase activity in the nucleus. PAQR3 also interferes with the interaction of WDR5 with the C-terminus of MLL1. PAQR3 negatively regulates HOXC8 and HOXA9 gene expression.\",\n      \"method\": \"Co-immunoprecipitation, histone methyltransferase activity assay, subcellular fractionation, PAQR3 overexpression/knockdown, gene expression analysis, hypoxia-induced H3K4me3 measurement\",\n      \"journal\": \"The Biochemical Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for complex interactions, enzymatic activity assay, functional gene expression readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25706881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DDB2 interacts with PAQR3 in vivo and in vitro and promotes PAQR3 ubiquitination and proteasomal degradation, targeting lysine 61 of PAQR3. DDB2 overexpression reduces PAQR3 protein stability and polyubiquitination; knockdown has the opposite effect. The effect of DDB2 on gastric cancer cell proliferation and migration is mediated by PAQR3.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay, ubiquitination assay, protein stability assay (cycloheximide chase), site-directed mutagenesis (K61), DDB2 knockdown/overexpression, rescue experiments\",\n      \"journal\": \"The Biochemical Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro binding, ubiquitination assay with mutagenesis identifying K61 site, rescue experiments, multiple orthogonal methods in one study\",\n      \"pmids\": [\"26205499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PAQR3 negatively regulates amino acid-induced mTORC1 activation by directly interacting (via its N-terminal end) with the WD domains of Raptor and mLST8, disrupting intact mTORC1 complex formation. PAQR3 reduces the interaction of mTOR with Raptor and mLST8, modulates leucine-induced cell size changes, and knockdown of PAQR3 reduces amino acid deprivation-induced autophagy in a rapamycin-reversible manner.\",\n      \"method\": \"Co-immunoprecipitation, domain interaction mapping, cell size measurement, PAQR3 knockdown, autophagy flux assay, rapamycin rescue\",\n      \"journal\": \"Cellular Signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, functional autophagy assay with pharmacological rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28214587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Paqr3-deleted mice are resistant to high-fat diet-induced obesity and hepatic steatosis, with improved insulin resistance and insulin signaling. PAQR3 modulates leptin signaling in the hypothalamus: PAQR3 overexpression reduces leptin signaling whereas Paqr3 deletion enhances it. Paqr3-deleted mice show increased energy expenditure and physical activity.\",\n      \"method\": \"Paqr3 knockout mouse model, high-fat diet feeding, metabolic rate measurement, leptin signaling assay in hypothalamus, insulin tolerance test, hepatic steatosis analysis\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic KO with multiple metabolic phenotypes and defined pathway (leptin signaling), single lab with multiple orthogonal physiological readouts\",\n      \"pmids\": [\"24035996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Using a yeast-based functional assay, adiponectin was identified as an agonist of PAQR3, consistent with PAQR3's close homology to AdipoR1 (PAQR1) and AdipoR2 (PAQR2).\",\n      \"method\": \"Yeast-based receptor activity assay with adiponectin as ligand\",\n      \"journal\": \"Journal of Receptor and Signal Transduction Research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single yeast-based assay in one study, heterologous system with no mammalian cell validation\",\n      \"pmids\": [\"19519172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PAQR3 promotes Gβγ signaling specifically at the Golgi apparatus to regulate Golgi vesicle fission and Golgi-to-plasma membrane protein transport via the Gβγ–PKD signaling pathway. PAQR3 expression causes Golgi fragmentation dependent on its Gβ binding; a Gβ binding-deficient PAQR3 mutant fails to cause fragmentation and acts as a dominant negative to inhibit Golgi-to-PM transport of VSV-G cargo.\",\n      \"method\": \"PAQR3 overexpression/mutagenesis, Golgi fragmentation assay, VSV-G Golgi-to-PM transport assay, Gβγ inhibitor (gallein) and GRK2ct, PKD dominant-negative and inhibitor (Gö6976)\",\n      \"journal\": \"Cellular Signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis, pharmacological inhibitors, and cargo transport assay in one study, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26327583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PAQR3 modulates blood LDL-C and cholesterol levels by interacting with both LDLR (via its β-sheet domain) and PCSK9 (via its P-domain) and enhancing LDLR–PCSK9 interaction, thereby accelerating LDLR degradation. PAQR3 co-localizes with LDLR, PCSK9, and LDL in early endosomes. Paqr3 hepatic deletion reduces blood LDL-C and increases LDLR half-life.\",\n      \"method\": \"Co-immunoprecipitation, domain interaction mapping, LDLR half-life assay (cycloheximide chase), Paqr3 liver-specific knockout mouse, blood cholesterol measurement, immunofluorescent co-localization\",\n      \"journal\": \"Metabolism: Clinical and Experimental\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, in vivo hepatic KO, LDLR half-life measurement, co-localization, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30831144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PAQR3 suppresses tumor growth in NSCLC by potentiating autophagy induced by the EGFR inhibitor erlotinib. PAQR3 blocks the interaction of BECN1 with activated EGFR, inhibits tyrosine phosphorylation of BECN1, and abrogates BECN1 interaction with autophagy inhibitory proteins RUBCN/Rubicon and BCL2. Knockdown of ATG7 abolishes the tumor suppressive activity of PAQR3.\",\n      \"method\": \"Co-immunoprecipitation, BECN1 tyrosine phosphorylation assay, ATG7 knockdown rescue, erlotinib treatment, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP showing PAQR3 disrupts EGFR–BECN1 interaction, phosphorylation assay, genetic epistasis with ATG7 KD, single lab\",\n      \"pmids\": [\"31448672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GPS (gentiopicroside) directly binds to the NH2-terminus of PAQR3 (residues Leu40, Asp42, Glu69, Tyr125, Ser129), spatially inhibiting the interaction between PAQR3 and PI3K p110α and restoring PI3K/AKT signaling. GPS also promotes DDB2-mediated ubiquitinated degradation of PAQR3.\",\n      \"method\": \"Surface plasmon resonance (SPR), microscale thermophoresis (MST), thermal shift assay (TSA), cellular thermal shift assay (CETSA), molecular docking, PAQR3–p110α Co-IP competition assay, DDB2-mediated ubiquitination assay\",\n      \"journal\": \"Acta Pharmaceutica Sinica B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple direct binding assays (SPR, MST, TSA, CETSA) with site identification, Co-IP competition, single lab\",\n      \"pmids\": [\"35755276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PAQR3 overexpression promotes BTRC-mediated ubiquitin degradation of the transcription factor Twist1 in endothelial progenitor cells, reducing Twist1 protein level and impairing angiogenesis. This is consistent with the mechanism established in gastric cancer cells (PMID:26905590).\",\n      \"method\": \"PAQR3 overexpression, ubiquitination assay for Twist1, BTRC knockdown/overexpression, protein level measurement, angiogenesis (tube formation) assay\",\n      \"journal\": \"Diabetes Research and Clinical Practice\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mechanistic detail relies on prior gastric cancer study; limited new in vitro evidence for this cell type\",\n      \"pmids\": [\"34461141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PAQR3 silencing in macrophages inhibits STUB1-mediated PPARγ ubiquitination and degradation, thereby increasing PPARγ protein level and promoting M2 macrophage polarization, which accelerates diabetic wound healing and angiogenesis.\",\n      \"method\": \"PAQR3 knockdown in macrophages, ubiquitination assay for PPARγ, Co-IP of STUB1 with PPARγ, PPARγ inhibitor rescue, STUB1 overexpression rescue, in vivo diabetic wound healing model\",\n      \"journal\": \"Laboratory Investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP showing STUB1–PPARγ interaction altered by PAQR3 KD, ubiquitination assay, rescue experiments, in vivo model, single lab\",\n      \"pmids\": [\"35710596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PAQR3 binds Nrf2 (as shown by pull-down assay) and modulates Nrf2 stability through ubiquitination in acute lymphoblastic leukemia cells, promoting ferroptosis. Nrf2 overexpression reverses the anti-proliferative and pro-ferroptotic effects of PAQR3.\",\n      \"method\": \"Pull-down assay, ubiquitination assay, PAQR3 overexpression, Nrf2 overexpression rescue, ferroptosis markers (MDA, ROS, Fe2+), proliferation assay\",\n      \"journal\": \"Immunity, Inflammation and Disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pulldown, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"33955706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL14 (delivered via M1 macrophage-derived exosomes) induces m6A modification of PAQR3 mRNA, increasing PAQR3 expression in glomerular endothelial cells under high glucose conditions. Elevated PAQR3 promotes apoptosis, inflammation, and oxidative stress; METTL14 knockdown in exosomes reverses these effects by reducing PAQR3.\",\n      \"method\": \"Methylated RNA immunoprecipitation (MeRIP) assay, dual-luciferase reporter assay, exosome isolation and co-culture, METTL14 knockdown in M1 macrophages, PAQR3 knockdown/overexpression, cell function assays\",\n      \"journal\": \"Clinical and Experimental Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP assay demonstrating m6A modification, dual-luciferase validation, exosome mechanistic model, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39080055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CHD7 directly transcriptionally activates paqr3b expression in zebrafish; loss of CHD7 downregulates paqr3b, leading to upregulation of MAPK/ERK signaling and defective GABAergic neuron development. This was confirmed in CHD7-mutant human cells. Restoration of paqr3b or pharmacological reduction of ERK signaling rescues GABAergic defects.\",\n      \"method\": \"chd7 knockout zebrafish model, paqr3b expression analysis (ChIP/reporter implied), MAPK/ERK signaling measurement, GABAergic neuron quantification, behavioral assay, rescue experiments with ephedrine, CHD7 mutant human cell validation\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in zebrafish KO, human cell validation, behavioral and neuronal phenotypes with pathway placement, single lab\",\n      \"pmids\": [\"33900016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PAQR3 reduces LDLR mRNA stability (as shown by RIP assay and pull-down) to suppress LDLR expression in diffuse large B-cell lymphoma cells, thereby inhibiting PI3K/AKT signaling and promoting ferroptosis.\",\n      \"method\": \"RIP (RNA immunoprecipitation) assay, pull-down assay, PAQR3 overexpression, LDLR knockdown/overexpression, ferroptosis markers, PI3K/AKT inhibitor rescue, in vivo xenograft\",\n      \"journal\": \"Hematological Oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RIP and pulldown for RNA binding are unusual for a membrane protein; single lab, mechanism not fully validated\",\n      \"pmids\": [\"37690092\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PAQR3 is a Golgi-resident seven-transmembrane scaffold protein that negatively regulates multiple oncogenic signaling pathways by spatially sequestering key signaling components to the Golgi: it sequesters PI3K p110α to the Golgi (blocking insulin/PI3K/AKT signaling), anchors the Scap/SREBP complex at the Golgi (regulating cholesterol biosynthesis), scaffolds the ATG14L–VPS34 autophagy-initiating complex (with AMPK-mediated phosphorylation at T32 as a switch), disrupts mTORC1 assembly by binding Raptor/mLST8, promotes proteasomal degradation of PPARα (via HUWE1) and Twist1 (via BTRC), facilitates tethering of COPII vesicles to the Golgi via Sec13/Sec31A interaction, modulates LDLR degradation by enhancing LDLR–PCSK9 interaction, sequesters WRAD sub-complex components to suppress nuclear H3K4me3, and promotes Gβγ–PKD-mediated Golgi vesicle fission; PAQR3 protein stability is itself regulated by DDB2-mediated ubiquitination at K61.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PAQR3 is a Golgi-resident seven-transmembrane scaffold that acts as a spatial regulator of signaling by sequestering or assembling pathway components at the Golgi apparatus, thereby restraining several growth- and metabolism-promoting programs [#0, #2]. In insulin signaling it physically captures the PI3K catalytic subunit p110\\u03b1, shunting it to the Golgi and competing with the p85 regulatory subunit to suppress PIP3 production and AKT/GSK3\\u03b2 activation, and it parallels this by dampening Ras/Raf/MEK/ERK output and \\u03b2-catenin nuclear accumulation \\u2014 an activity that is tumor-suppressive in vivo, since Paqr3 loss accelerates intestinal tumorigenesis in ApcMin/+ mice [#0, #1]. The same scaffold logic recurs across distinct pathways: PAQR3 anchors the Scap/SREBP complex at the Golgi to potentiate SREBP processing and cholesterol synthesis in a cholesterol-sensitive, Insig-1-competitive manner [#2]; it preferentially nucleates the ATG14L\\u2013VPS34 autophagy-initiating complex to drive PI(3)P generation, a function switched on by direct AMPK phosphorylation at threonine 32 during glucose starvation and exercise [#3]; and it disrupts mTORC1 assembly by binding the WD domains of Raptor and mLST8 [#9]. PAQR3 additionally serves as an adaptor that delivers substrates to E3 ligases, forming ternary complexes that promote proteasomal degradation of Twist1 (via BTRC, suppressing EMT and metastasis) and PPAR\\u03b1 (via HUWE1, restraining hepatic fatty-acid oxidation) [#4, #5]. At the membrane-trafficking level it tethers COPII vesicles to the cis-Golgi/ERGIC through its N-terminus binding the WD domains of Sec13 and Sec31A, and it promotes G\\u03b2\\u03b3\\u2013PKD-mediated Golgi vesicle fission [#6, #12]. PAQR3 also enhances LDLR\\u2013PCSK9 interaction to accelerate LDLR degradation and modulate blood LDL-C [#13], and tethers the WRAD/COMPASS-like regulatory subunits to the Golgi to suppress nuclear H3K4 trimethylation [#7]. Consistent with these molecular roles, Paqr3-null mice resist high-fat-diet obesity and hepatic steatosis with improved insulin signaling [#10]. PAQR3 protein stability is itself controlled by DDB2-mediated ubiquitination at lysine 61 [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"An early question was whether PAQR3, by homology to the adiponectin receptors, functions as a ligand-activated receptor, addressed by testing adiponectin as an agonist.\",\n      \"evidence\": \"Yeast-based receptor activity assay with adiponectin\",\n      \"pmids\": [\"19519172\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Heterologous yeast system with no mammalian validation\", \"No demonstration of adiponectin-dependent signaling output in cells\", \"Receptor function not reconciled with later scaffold/sequestration roles\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that PAQR3 is a Golgi-localized negative regulator of growth signaling, defining its core mechanism as spatial sequestration of signaling enzymes (p110\\u03b1) and suppression of Ras/ERK output.\",\n      \"evidence\": \"Co-IP, p85 competition, PI3K/PIP3 assays in hepatocytes and liver, plus ApcMin/+ genetic epistasis and cellular ERK/\\u03b2-catenin assays\",\n      \"pmids\": [\"23086038\", \"22828136\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of p110\\u03b1 capture not resolved\", \"How Golgi anchoring is reconciled with cytosolic p110\\u03b1 pool kinetics unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed the organismal consequence of PAQR3 loss \\u2014 resistance to diet-induced obesity and steatosis with enhanced leptin signaling \\u2014 linking the molecular scaffold to whole-body energy metabolism.\",\n      \"evidence\": \"Paqr3 knockout mice, high-fat-diet feeding, metabolic rate and hypothalamic leptin signaling assays\",\n      \"pmids\": [\"24035996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific contributions to the phenotype not dissected\", \"Molecular target of PAQR3 in hypothalamic leptin signaling not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended the scaffold paradigm beyond signaling kinases to cholesterol biosynthesis and chromatin, showing PAQR3 anchors Scap/SREBP at the Golgi and tethers WRAD subunits away from nuclear COMPASS-like complexes.\",\n      \"evidence\": \"Reciprocal Co-IP, in vivo liver knockdown, SREBP processing and peptide competition assays; HMT activity assay and H3K4me3 measurement\",\n      \"pmids\": [\"26311497\", \"25706881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"WRAD tethering shown at Medium confidence with single-lab Co-IP\", \"How a Golgi protein accesses nuclear chromatin regulators mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined how PAQR3 abundance is controlled, identifying DDB2 as an E3-associated factor that ubiquitinates PAQR3 at K61 to drive its degradation.\",\n      \"evidence\": \"Co-IP, in vitro binding, ubiquitination and cycloheximide-chase assays with K61 mutagenesis and rescue in gastric cancer cells\",\n      \"pmids\": [\"26205499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DDB2 acts as the direct ligase or an adaptor not fully defined\", \"Physiological signals controlling DDB2\\u2013PAQR3 axis unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved how PAQR3 acts on autophagy and as an E3-ligase adaptor, showing AMPK-T32 phosphorylation switches PAQR3 to favor the ATG14L\\u2013VPS34 complex, and that PAQR3 bridges Twist1 to BTRC for degradation.\",\n      \"evidence\": \"In vitro AMPK kinase assay, Co-IP for complex composition, PI(3)P and exercise-autophagy in KO mice; ternary-complex Co-IP, ubiquitination and domain mapping with in vivo metastasis model\",\n      \"pmids\": [\"26834238\", \"26905590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism of preferential ATG14L vs UVRAG selection unknown\", \"Whether BTRC and ATG14L scaffolding use distinct PAQR3 surfaces unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed PAQR3 antagonizes mTORC1 by binding the WD domains of Raptor and mLST8 to block complex assembly, placing it as a brake on amino-acid-driven growth.\",\n      \"evidence\": \"Co-IP with N-terminal domain mapping, cell-size and rapamycin-reversible autophagy assays\",\n      \"pmids\": [\"28214587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab evidence without in vivo validation\", \"Whether Golgi localization is required for mTORC1 disruption not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established two further mechanistic roles: PAQR3 as a HUWE1-adaptor degrading PPAR\\u03b1 to restrain hepatic lipid oxidation, and as a COPII-tethering factor binding Sec13/Sec31A WD domains to control ER-to-Golgi transport.\",\n      \"evidence\": \"Co-IP, in vivo/in vitro ubiquitination and liver-specific KO metabolic readouts; APEX2 proximity labeling, RUSH and brefeldin-A washout trafficking assays with domain mapping\",\n      \"pmids\": [\"29331071\", \"30466064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"COPII work is single-lab Medium-strength\", \"How substrate-adaptor specificity (PPAR\\u03b1/HUWE1) is achieved structurally unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected PAQR3 to cholesterol clearance and to EGFR-inhibitor-induced autophagy, showing it enhances LDLR\\u2013PCSK9 interaction to accelerate LDLR degradation and blocks EGFR\\u2013BECN1 association to relieve autophagy inhibition.\",\n      \"evidence\": \"Co-IP with domain mapping, LDLR half-life and hepatic KO LDL-C measurements; BECN1 phosphorylation and ATG7-KD epistasis with erlotinib tumor assays\",\n      \"pmids\": [\"30831144\", \"31448672\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"BECN1/EGFR work at Medium confidence single-lab\", \"How endosomal LDLR/PCSK9 role relates to Golgi residence unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated PAQR3 promotes G\\u03b2\\u03b3\\u2013PKD signaling at the Golgi to drive vesicle fission and Golgi-to-plasma-membrane cargo transport, with G\\u03b2 binding required.\",\n      \"evidence\": \"Mutagenesis, Golgi fragmentation and VSV-G transport assays with gallein/GRK2ct and PKD inhibition\",\n      \"pmids\": [\"26327583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Endogenous physiological context of Golgi fission role not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Recent work explored disease-context regulation and additional effectors of PAQR3, including m6A-dependent induction by METTL14, pharmacological disruption by gentiopicroside, and roles in macrophage PPAR\\u03b3, Nrf2/ferroptosis, LDLR mRNA, angiogenesis, and CHD7-dependent neuronal development.\",\n      \"evidence\": \"MeRIP/luciferase exosome model, SPR/MST/CETSA binding with site mapping, ubiquitination/RIP/pull-down assays, and zebrafish chd7-KO genetic epistasis\",\n      \"pmids\": [\"39080055\", \"35755276\", \"35710596\", \"33955706\", \"37690092\", \"34461141\", \"33900016\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Several findings (Nrf2 binding, LDLR-mRNA binding, angiogenesis) are single low-confidence reports\", \"RNA-binding claims unusual for a transmembrane protein and not reconciled with its scaffold mechanism\", \"Direct vs indirect effects in disease models not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single Golgi-anchored multipass scaffold selects among its many partners (PI3K, SREBP, ATG14L, Raptor, COPII, E3 ligases) in a cell- and signal-specific manner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of PAQR3 with any partner\", \"No unified accounting of how localization, phosphorylation, and ligand state route PAQR3 toward distinct complexes\", \"Whether reported nuclear/chromatin and RNA-level activities reflect a common mechanism is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 3, 4, 5, 9, 6, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 2, 3, 6, 12]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3, 14]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 5, 10, 13]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [6, 12]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 5, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PIK3CA\", \"SCAP\", \"ATG14\", \"RPTOR\", \"MLST8\", \"BTRC\", \"HUWE1\", \"SEC31A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}