{"gene":"AGTRAP","run_date":"2026-06-09T22:02:42","timeline":{"discoveries":[{"year":1999,"finding":"ATRAP (AGTRAP) was identified as a novel protein that specifically interacts with the carboxyl-terminal cytoplasmic domain of the AT1a receptor but not with AT2, m3 muscarinic, bradykinin B2, endothelin B, or beta2-adrenergic receptors. Overexpression of ATRAP in COS-7 cells markedly inhibited AT1a receptor-mediated activation of phospholipase C without affecting m3 receptor-mediated activation.","method":"Yeast two-hybrid screen, affinity chromatography, co-immunoprecipitation, fluorescence microscopy colocalization, functional PLC activation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (Y2H, Co-IP, affinity chromatography, colocalization, functional assay) in the foundational discovery paper","pmids":["10358057"],"is_preprint":false},{"year":2000,"finding":"Overexpression of ATRAP potentiated AT1 receptor internalization upon angiotensin II stimulation in vascular smooth muscle cells (VSMCs) and inhibited AT1 receptor-induced DNA synthesis, associated with inhibition of STAT3 and Akt phosphorylation.","method":"Transfection/overexpression in adult VSMCs, receptor internalization assay, DNA synthesis assay, Western blot for STAT3 and Akt phosphorylation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean overexpression with defined cellular phenotype and downstream signaling readouts, single lab","pmids":["11162453"],"is_preprint":false},{"year":2002,"finding":"Human AGTRAP protein interacts with RACK1 (Receptor of Activated Protein C Kinase), as identified by yeast two-hybrid screening and confirmed by GST pull-down, co-immunoprecipitation, and surface plasmon resonance.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, surface plasmon resonance","journal":"The international journal of biochemistry & cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (Y2H, pull-down, Co-IP, SPR) confirming the interaction","pmids":["11733189"],"is_preprint":false},{"year":2003,"finding":"ATRAP is a transmembrane protein with three N-terminal hydrophobic domains (residues 14-36, 55-77, 88-108) and a hydrophilic C-terminal cytoplasmic tail (residues 109-161). Its N-terminus faces extracellularly, it localizes to intracellular trafficking vesicles (ER, Golgi, endocytic vesicles) and plasma membrane with constitutive translocation toward the plasma membrane. Deletion of the C-terminal domain abolishes AT1 receptor binding and causes perinuclear vesicle clustering. ATRAP overexpression decreases inositol lipid generation, suppresses angiotensin II-stimulated c-fos promoter activity, and decreases cell proliferation.","method":"Epitope-tagged constructs for topology determination, electron microscopy, immunofluorescence colocalization, real-time vesicle tracking, deletion mutant analysis, reporter gene assay, cell proliferation assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal structural and functional methods in a single rigorous characterization study","pmids":["12960423"],"is_preprint":false},{"year":2005,"finding":"Overexpression of ATRAP significantly decreases the number of AT1 receptors on the surface of cardiomyocytes, decreases p38 MAPK phosphorylation, reduces c-fos promoter activity, and decreases protein synthesis upon angiotensin II treatment, indicating ATRAP promotes AT1R downregulation and attenuates hypertrophic responses.","method":"Overexpression in cardiomyocytes, surface receptor binding assay, Western blot for p38 phosphorylation, reporter gene assay, protein synthesis measurement","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional readouts in cardiomyocytes, single lab","pmids":["15757644"],"is_preprint":false},{"year":2006,"finding":"ATRAP protein colocalizes with AT1 receptor in renal tubular cells in vivo, distributed along nephron segments from Bowman's capsules to inner medullary collecting ducts. Dietary salt depletion significantly decreased renal expression of both ATRAP and AT1 receptor.","method":"In situ hybridization, Western blot, immunohistochemistry, dietary salt manipulation","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vivo colocalization by immunohistochemistry with functional dietary manipulation, single lab","pmids":["16514431"],"is_preprint":false},{"year":2008,"finding":"ATRAP is expressed in differentiated brown and white adipocytes; beta3-adrenergic stimulation suppresses ATRAP expression through JAK2/STAT signaling, as inhibition of PKA and JAK2 reversed the beta3-adrenergic suppression of ATRAP expression.","method":"Adipocyte differentiation and stimulation assays, Western blot for STAT1/STAT3 phosphorylation, pharmacological inhibitors of PKA and JAK2","journal":"Hormone and metabolic research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — pharmacological rescue experiment establishing pathway, single lab, single set of methods","pmids":["18236361"],"is_preprint":false},{"year":2010,"finding":"Atrap-deficient (Atrap-/-) mice show increased arterial blood pressure, increased plasma volume, lower plasma renin concentration, and enhanced surface expression of AT1 receptors in the renal cortex with increased carboanhydrase-sensitive proximal tubular function, demonstrating that Atrap acts as a negative regulator of AT1 receptors in renal tubules in vivo.","method":"Atrap-/- mouse generation, blood pressure telemetry, plasma volume measurement, 125I-angiotensin II binding assay, renal cortex fractionation, carboanhydrase-sensitive proximal tubular function assay","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple physiological readouts and direct receptor surface expression measurement","pmids":["20093357"],"is_preprint":false},{"year":2011,"finding":"The PITP domain of RdgBβ (PITPNC1) interacts with ATRAP (AGTRAP), an integral membrane protein. Upon PMA treatment, RdgBβ is recruited to membranes via its PITP domain through interaction with ATRAP.","method":"Co-immunoprecipitation, PMA stimulation, membrane recruitment assay in COS-7 cells","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional membrane recruitment assay, single lab","pmids":["21728994"],"is_preprint":false},{"year":2013,"finding":"Agtrap-/- mice under high-fat dietary loading develop systemic metabolic dysfunction including increased fat accumulation, hypertension, dyslipidemia, insulin resistance, and adipose tissue inflammation. Subcutaneous transplantation of fat pads overexpressing ATRAP (from transgenic mice) to Agtrap-/- mice improved the systemic metabolic dysfunction, demonstrating a protective role of adipose ATRAP against insulin resistance.","method":"Agtrap-/- mouse generation, high-fat diet challenge, fat pad transplantation from ATRAP transgenic donors, metabolic phenotyping","journal":"Journal of the American Heart Association","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout plus rescue transplantation experiment with multiple metabolic readouts","pmids":["23902639"],"is_preprint":false},{"year":2014,"finding":"Proteasomal degradation of ATRAP occurs during angiotensin II-induced cardiac hypertrophy; proteasome inhibitor bortezomib blocked ATRAP degradation and attenuated AT1R-mediated p38 MAPK and STAT3 signaling pathways, thereby reducing cardiac hypertrophy, fibrosis, and inflammation.","method":"Ang II infusion mouse model, bortezomib treatment, Western blot for proteasome activity, ATRAP protein levels, p38 MAPK and STAT3 phosphorylation","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibitor in vivo with mechanistic pathway readouts, single lab","pmids":["25526681"],"is_preprint":false},{"year":2016,"finding":"ATRAP interacts with the cardiac Ca2+-ATPase SERCA2a, confirmed by pull-down (MALDI-MS), co-immunoprecipitation, and surface plasmon resonance. ATRAP enhances SERCA-dependent Ca2+ uptake in isolated SR membrane vesicles. Atrap-/- myocytes show prolonged Ca2+ transient decay and sarcomere re-lengthening, and Atrap-/- mice have decreased maximum ventricular filling rate, indicating ATRAP facilitates ventricular relaxation via SERCA2a stimulation.","method":"Pull-down with MALDI-MS sequencing, co-immunoprecipitation, surface plasmon resonance, Ca2+ uptake assay in SR vesicles, cardiomyocyte sarcomere shortening and Ca2+ transient measurements, echocardiography in Atrap-/- mice","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical methods plus functional in vitro assay and in vivo knockout phenotype","pmids":["27015675"],"is_preprint":false},{"year":2019,"finding":"Immunoproteasome subunit β5i (PSMB8) directly targets ATRAP for degradation. β5i knockout attenuated Ang II-induced atrial fibrillation, fibrosis, and oxidative stress, while restoring ATRAP levels. Overexpression of ATRAP abrogated Ang II-induced atrial remodeling and AF in β5i-overexpressing mice. Mechanistically, β5i-mediated ATRAP degradation leads to activation of AT1R-mediated NF-κB signaling, increased NADPH oxidase activity, and TGF-β1/Smad signaling.","method":"β5i KO mice, recombinant AAV9-β5i injection, AAV9-ATRAP overexpression, atrial electrophysiology (telemetry), Western blot, NADPH oxidase activity assay","journal":"Hypertension","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, gain-of-function, and rescue overexpression experiments with multiple pathway readouts","pmids":["30571551"],"is_preprint":false},{"year":2019,"finding":"Proximal tubule-specific ATRAP knockout (PT-KO) mice showed no significant difference in blood pressure at baseline or in pressor response to angiotensin II infusion compared to wild-type mice, indicating that ATRAP in renal proximal tubules has a minor role in angiotensin-dependent hypertension in vivo.","method":"Cre/loxP proximal tubule-specific ATRAP KO using Pepck-Cre, tail-cuff and radiotelemetric blood pressure measurement, angiotensin II infusion, laser-capture microdissection and immunohistochemistry","journal":"Journal of the American Heart Association","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific genetic knockout with rigorous BP measurement methods; negative result mechanistically informative","pmids":["30977419"],"is_preprint":false},{"year":2021,"finding":"SAM (S-adenosylmethionine) upregulates ATRAP protein expression in NAFLD by methylating HuR protein, which controls HuR subcellular localization; HuR directly binds ATRAP mRNA and controls its nucleocytoplasmic shuttling for export from the nucleus, thereby regulating ATRAP translation.","method":"HuR methylation assay, RNA immunoprecipitation (HuR-ATRAP mRNA binding), nucleocytoplasmic fractionation, SAM supplementation in high-fat diet rats and oleic acid-treated L02 cells","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-protein interaction confirmed by RIP, functional methylation/localization assay, single lab","pmids":["33753727"],"is_preprint":false},{"year":2022,"finding":"In breast cancer cells, ATRAP directs USP14 (Ubiquitin-specific protease 14)-mediated deubiquitination and stabilization of PBX3 (Pre-B cell leukemia homeobox 3), and promotes AKT/mTOR signaling pathway activation; ATRAP is itself a transcriptional target of USF1 (Upstream stimulatory factor 1).","method":"Co-immunoprecipitation, microarray pathway analysis, siRNA knockdown, overexpression functional assays (proliferation, metastasis, glycolysis), rescue experiments","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and functional rescue, but single lab, and the deubiquitination mechanism is inferred rather than directly reconstituted","pmids":["35414770"],"is_preprint":false},{"year":2022,"finding":"DJ-1 (PARK7) in hypoxia-conditioned MSC-derived extracellular vesicles suppresses cardiac hypertrophy by directly physically interacting with and inhibiting proteasome subunit PSMB10 activity, which in turn reduces ubiquitination-mediated degradation of ATRAP, thereby preserving AT1R-mediated signaling inhibition.","method":"Quantitative proteomics, co-immunoprecipitation (DJ-1/PSMB10), proteasome activity assay, ubiquitination assay for ATRAP, neonatal rat cardiomyocyte assays, TAC mouse model","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and proteasome activity assay with functional ATRAP readout, single lab","pmids":["36509316"],"is_preprint":false},{"year":2022,"finding":"Tubular ATRAP-mediated modulation of AT1R signaling regulates the accumulation of tubulointerstitial M2-polarized macrophages (marked by CD206), thereby affecting glomerular injury in diabetic nephropathy via tubule-glomerular crosstalk. Adoptive transfer of M2 macrophages into diabetic ATRAP-knockout mice ameliorated glomerular injury.","method":"Streptozotocin-induced diabetic ATRAP-KO mice, proximal tubule-specific ATRAP knockdown mice, adoptive macrophage transfer, immunohistochemistry for CD206, renal mRNA analysis for TNF-α and oxidative stress markers","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic models with rescue adoptive transfer experiment and mechanistic readouts, single lab","pmids":["35240129"],"is_preprint":false},{"year":2023,"finding":"miR-125a-5p and miR-125b-5p directly repress ATRAP/Atrap mRNA expression. Inhibition of miR-125a-5p/miR-125b-5p suppresses Ang II-AT1R signaling in mouse distal convoluted tubule cells by increasing ATRAP levels.","method":"miRNA target prediction, luciferase reporter assay for direct miRNA-ATRAP 3'UTR interaction, miRNA inhibitor treatment in mouse distal convoluted tubule cells, AT1R signaling readouts","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by reporter assay with functional downstream signaling readout, single lab","pmids":["37981211"],"is_preprint":false},{"year":2025,"finding":"miR-34a directly targets AGTRAP mRNA in human aortic smooth muscle cells (HASMC); Ang II upregulates miR-34a, which suppresses AGTRAP and SIRT1 expression; forced AGTRAP expression rescues miR-34a-induced pro-inflammatory gene upregulation (IL-6, COX2, MCP-1, MFGE8), establishing a negative feedback loop where AGTRAP downmodulation further enhances miR-34a expression.","method":"miR-34a overexpression in HASMC, luciferase reporter assay confirming direct miR-34a targeting of AGTRAP 3'UTR, AGTRAP forced expression rescue, Ang II stimulation, aging primate/rodent tissue analysis","journal":"GeroScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct miRNA targeting confirmed by reporter assay with functional rescue experiment, single lab","pmids":["41291382"],"is_preprint":false},{"year":2026,"finding":"AGTRAP knockdown in glioma cells suppressed proliferation, increased apoptosis, reduced IL-6 mRNA and protein levels, and attenuated JAK2/STAT3 activation; recombinant IL-6 partially restored JAK2/STAT3 signaling and mitigated growth inhibition caused by AGTRAP silencing, placing AGTRAP upstream of IL-6/JAK2/STAT3 in glioma.","method":"shRNA knockdown in A172 and U251 glioma cells, proliferation and apoptosis assays, IL-6 ELISA/Western blot, JAK2/STAT3 phosphorylation assay, recombinant IL-6 rescue, orthotopic xenograft model","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with pathway rescue in vitro and in vivo, single lab, single set of methods","pmids":["41689202"],"is_preprint":false}],"current_model":"ATRAP/AGTRAP is a transmembrane protein that specifically binds the carboxyl-terminal cytoplasmic domain of the angiotensin II type 1 receptor (AT1R) and promotes its constitutive internalization, thereby inhibiting pathological AT1R-mediated signaling (PLC activation, p38 MAPK, STAT3, Akt, NF-κB, TGF-β1/Smad); ATRAP also interacts with RACK1 and the phospholipid transfer protein RdgBβ (via membrane recruitment), stimulates the cardiac Ca2+-ATPase SERCA2a to facilitate ventricular relaxation, and is itself post-translationally regulated by immunoproteasome subunit β5i-mediated degradation (counteracted by proteasome inhibitors or melatonin) and post-transcriptionally regulated by miR-125a/b-5p and miR-34a; in cancer contexts ATRAP additionally engages a USP14/PBX3/AKT-mTOR axis and an IL-6/JAK2/STAT3 pathway independently of AT1R."},"narrative":{"mechanistic_narrative":"AGTRAP (ATRAP) is a multi-pass transmembrane protein that functions as a negative regulator of angiotensin II type 1 receptor (AT1R) signaling, binding specifically to the carboxyl-terminal cytoplasmic tail of the AT1a receptor and not to other G-protein-coupled receptors [PMID:10358057, PMID:12960423]. It localizes to the plasma membrane and to intracellular trafficking vesicles (ER, Golgi, endocytic vesicles), with constitutive translocation toward the plasma membrane; its cytoplasmic C-terminal domain is required for AT1R binding [PMID:12960423]. Through this interaction ATRAP promotes AT1R internalization and surface downregulation, thereby suppressing downstream AT1R-mediated signaling including phospholipase C activation, p38 MAPK, STAT3, and Akt, and attenuating angiotensin II-induced proliferative and hypertrophic responses in vascular smooth muscle cells and cardiomyocytes [PMID:10358057, PMID:11162453, PMID:15757644]. Genetic deletion in mice establishes ATRAP as a physiological negative regulator: Atrap-deficient animals show elevated blood pressure, increased plasma volume, and enhanced renal AT1R surface expression [PMID:20093357], and additionally develop high-fat-diet-driven metabolic dysfunction that is rescued by transplantation of ATRAP-overexpressing adipose tissue [PMID:23902639]. Beyond AT1R, ATRAP interacts with the cardiac sarcoplasmic reticulum Ca2+-ATPase SERCA2a and enhances SERCA-dependent Ca2+ uptake to facilitate ventricular relaxation [PMID:27015675]. ATRAP abundance is tightly controlled post-translationally by proteasomal and immunoproteasomal degradation—notably via the immunoproteasome subunit β5i (PSMB8), whose action de-represses AT1R-driven NF-κB, NADPH oxidase, and TGF-β1/Smad signaling [PMID:25526681, PMID:30571551]—and post-transcriptionally by miR-125a/b-5p and miR-34a [PMID:37981211, PMID:41291382]. In cancer, ATRAP operates independently of AT1R, driving a USP14/PBX3/AKT-mTOR axis in breast cancer [PMID:35414770] and an IL-6/JAK2/STAT3 pathway in glioma [PMID:41689202].","teleology":[{"year":1999,"claim":"Established that ATRAP is a dedicated AT1R-interacting partner, answering whether a receptor-specific regulator of angiotensin signaling exists.","evidence":"Yeast two-hybrid, affinity chromatography, Co-IP, and PLC functional assay in COS-7 cells showing selective binding to the AT1a C-terminal tail","pmids":["10358057"],"confidence":"High","gaps":["Did not define topology or trafficking","Mechanism of PLC inhibition not resolved beyond binding"]},{"year":2000,"claim":"Showed ATRAP acts by promoting AT1R internalization and suppressing growth signaling, framing it as a functional negative regulator rather than a passive binder.","evidence":"Overexpression in adult VSMCs with receptor internalization, DNA synthesis, and STAT3/Akt phosphorylation readouts","pmids":["11162453"],"confidence":"Medium","gaps":["Overexpression only, no loss-of-function","Internalization machinery linking ATRAP to AT1R not identified"]},{"year":2002,"claim":"Identified RACK1 as an ATRAP partner, expanding the interactome beyond AT1R toward a possible scaffolding role.","evidence":"Yeast two-hybrid, GST pull-down, Co-IP, and surface plasmon resonance","pmids":["11733189"],"confidence":"High","gaps":["Functional consequence of RACK1 binding not defined","Not linked to AT1R regulation"]},{"year":2003,"claim":"Defined ATRAP membrane topology, trafficking behavior, and the C-terminal domain as the AT1R-binding determinant, establishing the structural basis for its regulatory function.","evidence":"Epitope-tag topology mapping, EM, immunofluorescence, real-time vesicle tracking, and deletion-mutant reporter/proliferation assays","pmids":["12960423"],"confidence":"High","gaps":["Structure of the AT1R-ATRAP interface not solved","How vesicular ATRAP couples to AT1R endocytosis unresolved"]},{"year":2005,"claim":"Extended the negative-regulator model to cardiac hypertrophy, showing ATRAP reduces surface AT1R and dampens p38 MAPK-driven hypertrophic responses.","evidence":"Overexpression in cardiomyocytes with surface receptor binding, p38 phosphorylation, c-fos reporter, and protein synthesis assays","pmids":["15757644"],"confidence":"Medium","gaps":["Overexpression-based; in vivo cardiac role not yet tested","Single lab"]},{"year":2006,"claim":"Demonstrated in vivo ATRAP/AT1R colocalization along the nephron and salt-responsive co-regulation, implicating ATRAP in renal angiotensin physiology.","evidence":"In situ hybridization, Western blot, immunohistochemistry, and dietary salt manipulation in kidney","pmids":["16514431"],"confidence":"Medium","gaps":["Correlative; no causal manipulation","Functional consequence for blood pressure untested at this stage"]},{"year":2010,"claim":"Provided definitive genetic proof that ATRAP negatively regulates renal AT1R and blood pressure in vivo.","evidence":"Atrap-/- mice with telemetry, plasma volume, 125I-Ang II binding, and proximal tubular function assays","pmids":["20093357"],"confidence":"High","gaps":["Whole-body knockout; tissue-specific contribution not isolated","Did not address non-renal phenotypes"]},{"year":2011,"claim":"Identified ATRAP as the membrane anchor that recruits the phospholipid transfer protein RdgBβ (PITPNC1), suggesting a lipid-signaling-linked role.","evidence":"Co-IP and PMA-induced membrane recruitment assay in COS-7 cells","pmids":["21728994"],"confidence":"Medium","gaps":["Physiological significance of RdgBβ recruitment unknown","Not connected to AT1R pathway"]},{"year":2013,"claim":"Revealed an AT1R-related metabolic protective function of adipose ATRAP through knockout plus rescue transplantation.","evidence":"Agtrap-/- mice on high-fat diet with fat-pad transplantation from ATRAP-transgenic donors and metabolic phenotyping","pmids":["23902639"],"confidence":"High","gaps":["Molecular mediators in adipocytes not fully defined","Whether effect is strictly AT1R-dependent unresolved"]},{"year":2014,"claim":"Established that proteasomal turnover of ATRAP is a control point governing AT1R signaling output during hypertrophy.","evidence":"Ang II infusion mouse model with bortezomib treatment and p38/STAT3 pathway readouts","pmids":["25526681"],"confidence":"Medium","gaps":["Specific E3 ligase not identified here","Pharmacological inhibitor lacks proteasome-target specificity"]},{"year":2016,"claim":"Discovered a non-AT1R molecular function: ATRAP binds and stimulates SERCA2a to facilitate ventricular relaxation.","evidence":"Pull-down/MALDI-MS, Co-IP, SPR, SR Ca2+ uptake assay, cardiomyocyte Ca2+ transient measurements, and echocardiography in Atrap-/- mice","pmids":["27015675"],"confidence":"High","gaps":["Structural basis of SERCA2a stimulation not resolved","Interplay between AT1R and SERCA2a functions unclear"]},{"year":2019,"claim":"Identified the immunoproteasome subunit β5i (PSMB8) as the specific degrader of ATRAP, linking ATRAP turnover to atrial fibrillation via NF-κB/NADPH oxidase/TGF-β1 signaling.","evidence":"β5i KO mice, AAV9-β5i and AAV9-ATRAP overexpression, atrial electrophysiology, NADPH oxidase activity, and pathway Western blots","pmids":["30571551"],"confidence":"High","gaps":["Direct β5i-ATRAP cleavage not biochemically reconstituted","Ubiquitination requirement for degradation not detailed"]},{"year":2019,"claim":"Refined the tissue locus of ATRAP's blood-pressure role, showing proximal tubule ATRAP is dispensable for angiotensin-dependent hypertension.","evidence":"Pepck-Cre proximal tubule-specific ATRAP KO with tail-cuff and radiotelemetric BP under Ang II infusion","pmids":["30977419"],"confidence":"Medium","gaps":["Does not identify which nephron segment or tissue mediates the whole-body phenotype","Negative result limited to the Ang II infusion model"]},{"year":2021,"claim":"Defined post-transcriptional control of ATRAP via HuR-mediated mRNA shuttling regulated by SAM methylation in fatty liver disease.","evidence":"HuR methylation assay, HuR-ATRAP RNA immunoprecipitation, nucleocytoplasmic fractionation, and SAM supplementation in HFD rats and L02 cells","pmids":["33753727"],"confidence":"Medium","gaps":["Downstream functional consequence of ATRAP induction in NAFLD not fully mapped","Single lab"]},{"year":2022,"claim":"Uncovered an AT1R-independent oncogenic function of ATRAP in breast cancer through a USP14/PBX3/AKT-mTOR axis with USF1 as its upstream transcriptional regulator.","evidence":"Co-IP, microarray pathway analysis, siRNA/overexpression functional assays, and rescue experiments","pmids":["35414770"],"confidence":"Medium","gaps":["USP14-mediated deubiquitination inferred, not reconstituted","Mechanism of ATRAP-USP14 coupling unclear"]},{"year":2022,"claim":"Showed ATRAP stability is preserved by DJ-1 inhibition of proteasome subunit PSMB10, adding a regulatory route protecting AT1R signaling suppression.","evidence":"Quantitative proteomics, DJ-1/PSMB10 Co-IP, proteasome and ubiquitination assays, cardiomyocyte assays, and TAC mouse model","pmids":["36509316"],"confidence":"Medium","gaps":["Direct PSMB10-ATRAP targeting not isolated from indirect effects","Single lab"]},{"year":2022,"claim":"Connected tubular ATRAP-AT1R signaling to immune crosstalk, showing it regulates M2 macrophage accumulation affecting glomerular injury in diabetic nephropathy.","evidence":"Streptozotocin-diabetic ATRAP-KO and proximal-tubule knockdown mice with adoptive M2 macrophage transfer and CD206 immunohistochemistry","pmids":["35240129"],"confidence":"Medium","gaps":["Molecular signal linking tubular ATRAP to macrophage polarization undefined","Single lab"]},{"year":2023,"claim":"Identified miR-125a-5p/miR-125b-5p as direct repressors of ATRAP, defining a microRNA layer tuning AT1R signaling in distal tubule cells.","evidence":"Luciferase reporter of miRNA-ATRAP 3'UTR binding and miRNA inhibitor treatment with AT1R signaling readouts in DCT cells","pmids":["37981211"],"confidence":"Medium","gaps":["In vivo physiological impact of these miRNAs on ATRAP not established","Single lab"]},{"year":2025,"claim":"Established a miR-34a-AGTRAP negative feedback loop driving vascular smooth muscle inflammation and linking ATRAP to vascular aging.","evidence":"miR-34a overexpression and luciferase 3'UTR targeting in HASMC, AGTRAP forced-expression rescue, and aging primate/rodent tissue analysis","pmids":["41291382"],"confidence":"Medium","gaps":["Causal contribution to vascular aging in vivo not proven","Relationship between AGTRAP/SIRT1 co-regulation mechanistically unclear"]},{"year":2026,"claim":"Demonstrated an AT1R-independent pro-tumor role in glioma, placing AGTRAP upstream of IL-6/JAK2/STAT3 signaling.","evidence":"shRNA knockdown in A172/U251 cells, proliferation/apoptosis assays, IL-6 measurement, JAK2/STAT3 phosphorylation, recombinant IL-6 rescue, and orthotopic xenograft","pmids":["41689202"],"confidence":"Medium","gaps":["How AGTRAP controls IL-6 expression molecularly is undefined","Single lab"]},{"year":null,"claim":"How a single transmembrane protein integrates its AT1R-internalization function, SERCA2a Ca2+ regulation, lipid-transfer recruitment, and AT1R-independent oncogenic signaling into a unified mechanism remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ATRAP or its complexes","Mechanism switching ATRAP between cardiovascular regulator and cancer effector unknown","Whether oncogenic functions require its membrane topology untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,3,4,11]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[3]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,4,7]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[10,12,16]}],"complexes":[],"partners":["AGTR1","RACK1","PITPNC1","ATP2A2","USP14","PBX3","PSMB8","PSMB10"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6RW13","full_name":"Type-1 angiotensin II receptor-associated protein","aliases":["AT1 receptor-associated protein"],"length_aa":159,"mass_kda":17.4,"function":"Appears to be a negative regulator of type-1 angiotensin II receptor-mediated signaling by regulating receptor internalization as well as mechanism of receptor desensitization such as phosphorylation. Also induces a decrease in cell proliferation and angiotensin II-stimulated transcriptional activity","subcellular_location":"Endoplasmic reticulum membrane; Golgi apparatus membrane; Cytoplasmic vesicle membrane","url":"https://www.uniprot.org/uniprotkb/Q6RW13/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AGTRAP","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000177674","cell_line_id":"CID000074","localizations":[{"compartment":"golgi","grade":3},{"compartment":"vesicles","grade":3},{"compartment":"focal_adhesions","grade":1}],"interactors":[{"gene":"TMEM106B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000074","total_profiled":1310},"omim":[{"mim_id":"608729","title":"ANGIOTENSIN II RECEPTOR-ASSOCIATED PROTEIN; AGTRAP","url":"https://www.omim.org/entry/608729"},{"mim_id":"601118","title":"CALCIUM-MODULATING LIGAND; CAMLG","url":"https://www.omim.org/entry/601118"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/AGTRAP"},"hgnc":{"alias_symbol":["ATRAP"],"prev_symbol":[]},"alphafold":{"accession":"Q6RW13","domains":[{"cath_id":"-","chopping":"24-112","consensus_level":"high","plddt":94.5769,"start":24,"end":112}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6RW13","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6RW13-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6RW13-F1-predicted_aligned_error_v6.png","plddt_mean":80.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AGTRAP","jax_strain_url":"https://www.jax.org/strain/search?query=AGTRAP"},"sequence":{"accession":"Q6RW13","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6RW13.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6RW13/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6RW13"}},"corpus_meta":[{"pmid":"10358057","id":"PMC_10358057","title":"Cloning and characterization of ATRAP, a 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and inhibits vascular smooth muscle cell growth.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11162453","citation_count":67,"is_preprint":false},{"pmid":"10572187","id":"PMC_10572187","title":"RET: a poly A-trap retrovirus vector for reversible disruption and expression monitoring of genes in living cells.","date":"1999","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/10572187","citation_count":64,"is_preprint":false},{"pmid":"16514431","id":"PMC_16514431","title":"Interacting molecule of AT1 receptor, ATRAP, is colocalized with AT1 receptor in the mouse renal tubules.","date":"2006","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/16514431","citation_count":56,"is_preprint":false},{"pmid":"25526681","id":"PMC_25526681","title":"Activation of the cardiac proteasome promotes angiotension II-induced hypertrophy by down-regulation of 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rats.","date":"2017","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/29257219","citation_count":17,"is_preprint":false},{"pmid":"26295465","id":"PMC_26295465","title":"Angiotensin II Type 1 Receptor Binding Molecule ATRAP as a Possible Modulator of Renal Sodium Handling and Blood Pressure in Pathophysiology.","date":"2015","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26295465","citation_count":14,"is_preprint":false},{"pmid":"28656601","id":"PMC_28656601","title":"Silencing of AtRAP, a target gene of a bacteria-induced small RNA, triggers antibacterial defense responses through activation of LSU2 and down-regulation of GLK1.","date":"2017","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/28656601","citation_count":14,"is_preprint":false},{"pmid":"27015675","id":"PMC_27015675","title":"The angiotensin receptor-associated protein Atrap is a stimulator of the cardiac Ca2+-ATPase SERCA2a.","date":"2016","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/27015675","citation_count":12,"is_preprint":false},{"pmid":"30977419","id":"PMC_30977419","title":"Effects of ATRAP in Renal Proximal Tubules on Angiotensin-Dependent Hypertension.","date":"2019","source":"Journal of the American Heart Association","url":"https://pubmed.ncbi.nlm.nih.gov/30977419","citation_count":11,"is_preprint":false},{"pmid":"22435829","id":"PMC_22435829","title":"14-3-3 protein and ATRAP bind to the soluble class IIB phosphatidylinositol transfer protein RdgBβ at distinct sites.","date":"2012","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/22435829","citation_count":10,"is_preprint":false},{"pmid":"28335584","id":"PMC_28335584","title":"ATRAP Expression in Brown Adipose Tissue Does Not Influence the Development of Diet-Induced Metabolic Disorders in Mice.","date":"2017","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28335584","citation_count":10,"is_preprint":false},{"pmid":"35710020","id":"PMC_35710020","title":"Melatonin inhibits angiotensin II-induced atrial fibrillation through preventing degradation of Ang II Type I Receptor-Associated Protein (ATRAP).","date":"2022","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35710020","citation_count":9,"is_preprint":false},{"pmid":"37981211","id":"PMC_37981211","title":"miR-125a-5p/miR-125b-5p contributes to pathological activation of angiotensin II-AT1R in mouse distal convoluted tubule cells by the suppression of Atrap.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37981211","citation_count":8,"is_preprint":false},{"pmid":"18236361","id":"PMC_18236361","title":"Expression of ATRAP in adipocytes and negative regulation by beta-adrenergic stimulation of JAK/STAT.","date":"2008","source":"Hormone and metabolic research = 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Japanese journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23012794","citation_count":1,"is_preprint":false},{"pmid":"41291382","id":"PMC_41291382","title":"Angiotensin II, miR-34a, and AGTRAP crosstalk in arterial smooth muscle cells.","date":"2025","source":"GeroScience","url":"https://pubmed.ncbi.nlm.nih.gov/41291382","citation_count":0,"is_preprint":false},{"pmid":"40721451","id":"PMC_40721451","title":"Effects of proximal tubule-specific ATRAP enhancement on hypertension in a remnant kidney chronic kidney disease model of mice.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40721451","citation_count":0,"is_preprint":false},{"pmid":"42100724","id":"PMC_42100724","title":"AGTRAP mediates exosome-driven communication between cancer cells and macrophages via p38 MAPK pathway to promote hepatocellular carcinoma.","date":"2026","source":"BBA advances","url":"https://pubmed.ncbi.nlm.nih.gov/42100724","citation_count":0,"is_preprint":false},{"pmid":"40865403","id":"PMC_40865403","title":"Lentinan ameliorates angiotensin II-induced hypertension-associated intestinal barrier injury through inactivation of PSMB8-ATRAP signaling.","date":"2025","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40865403","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22223,"output_tokens":5520,"usd":0.074734,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14191,"output_tokens":5832,"usd":0.108378,"stage2_stop_reason":"end_turn"},"total_usd":0.183112,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"ATRAP (AGTRAP) was identified as a novel protein that specifically interacts with the carboxyl-terminal cytoplasmic domain of the AT1a receptor but not with AT2, m3 muscarinic, bradykinin B2, endothelin B, or beta2-adrenergic receptors. Overexpression of ATRAP in COS-7 cells markedly inhibited AT1a receptor-mediated activation of phospholipase C without affecting m3 receptor-mediated activation.\",\n      \"method\": \"Yeast two-hybrid screen, affinity chromatography, co-immunoprecipitation, fluorescence microscopy colocalization, functional PLC activation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (Y2H, Co-IP, affinity chromatography, colocalization, functional assay) in the foundational discovery paper\",\n      \"pmids\": [\"10358057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Overexpression of ATRAP potentiated AT1 receptor internalization upon angiotensin II stimulation in vascular smooth muscle cells (VSMCs) and inhibited AT1 receptor-induced DNA synthesis, associated with inhibition of STAT3 and Akt phosphorylation.\",\n      \"method\": \"Transfection/overexpression in adult VSMCs, receptor internalization assay, DNA synthesis assay, Western blot for STAT3 and Akt phosphorylation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean overexpression with defined cellular phenotype and downstream signaling readouts, single lab\",\n      \"pmids\": [\"11162453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Human AGTRAP protein interacts with RACK1 (Receptor of Activated Protein C Kinase), as identified by yeast two-hybrid screening and confirmed by GST pull-down, co-immunoprecipitation, and surface plasmon resonance.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, surface plasmon resonance\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (Y2H, pull-down, Co-IP, SPR) confirming the interaction\",\n      \"pmids\": [\"11733189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ATRAP is a transmembrane protein with three N-terminal hydrophobic domains (residues 14-36, 55-77, 88-108) and a hydrophilic C-terminal cytoplasmic tail (residues 109-161). Its N-terminus faces extracellularly, it localizes to intracellular trafficking vesicles (ER, Golgi, endocytic vesicles) and plasma membrane with constitutive translocation toward the plasma membrane. Deletion of the C-terminal domain abolishes AT1 receptor binding and causes perinuclear vesicle clustering. ATRAP overexpression decreases inositol lipid generation, suppresses angiotensin II-stimulated c-fos promoter activity, and decreases cell proliferation.\",\n      \"method\": \"Epitope-tagged constructs for topology determination, electron microscopy, immunofluorescence colocalization, real-time vesicle tracking, deletion mutant analysis, reporter gene assay, cell proliferation assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal structural and functional methods in a single rigorous characterization study\",\n      \"pmids\": [\"12960423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Overexpression of ATRAP significantly decreases the number of AT1 receptors on the surface of cardiomyocytes, decreases p38 MAPK phosphorylation, reduces c-fos promoter activity, and decreases protein synthesis upon angiotensin II treatment, indicating ATRAP promotes AT1R downregulation and attenuates hypertrophic responses.\",\n      \"method\": \"Overexpression in cardiomyocytes, surface receptor binding assay, Western blot for p38 phosphorylation, reporter gene assay, protein synthesis measurement\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional readouts in cardiomyocytes, single lab\",\n      \"pmids\": [\"15757644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ATRAP protein colocalizes with AT1 receptor in renal tubular cells in vivo, distributed along nephron segments from Bowman's capsules to inner medullary collecting ducts. Dietary salt depletion significantly decreased renal expression of both ATRAP and AT1 receptor.\",\n      \"method\": \"In situ hybridization, Western blot, immunohistochemistry, dietary salt manipulation\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vivo colocalization by immunohistochemistry with functional dietary manipulation, single lab\",\n      \"pmids\": [\"16514431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ATRAP is expressed in differentiated brown and white adipocytes; beta3-adrenergic stimulation suppresses ATRAP expression through JAK2/STAT signaling, as inhibition of PKA and JAK2 reversed the beta3-adrenergic suppression of ATRAP expression.\",\n      \"method\": \"Adipocyte differentiation and stimulation assays, Western blot for STAT1/STAT3 phosphorylation, pharmacological inhibitors of PKA and JAK2\",\n      \"journal\": \"Hormone and metabolic research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — pharmacological rescue experiment establishing pathway, single lab, single set of methods\",\n      \"pmids\": [\"18236361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Atrap-deficient (Atrap-/-) mice show increased arterial blood pressure, increased plasma volume, lower plasma renin concentration, and enhanced surface expression of AT1 receptors in the renal cortex with increased carboanhydrase-sensitive proximal tubular function, demonstrating that Atrap acts as a negative regulator of AT1 receptors in renal tubules in vivo.\",\n      \"method\": \"Atrap-/- mouse generation, blood pressure telemetry, plasma volume measurement, 125I-angiotensin II binding assay, renal cortex fractionation, carboanhydrase-sensitive proximal tubular function assay\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple physiological readouts and direct receptor surface expression measurement\",\n      \"pmids\": [\"20093357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The PITP domain of RdgBβ (PITPNC1) interacts with ATRAP (AGTRAP), an integral membrane protein. Upon PMA treatment, RdgBβ is recruited to membranes via its PITP domain through interaction with ATRAP.\",\n      \"method\": \"Co-immunoprecipitation, PMA stimulation, membrane recruitment assay in COS-7 cells\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional membrane recruitment assay, single lab\",\n      \"pmids\": [\"21728994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Agtrap-/- mice under high-fat dietary loading develop systemic metabolic dysfunction including increased fat accumulation, hypertension, dyslipidemia, insulin resistance, and adipose tissue inflammation. Subcutaneous transplantation of fat pads overexpressing ATRAP (from transgenic mice) to Agtrap-/- mice improved the systemic metabolic dysfunction, demonstrating a protective role of adipose ATRAP against insulin resistance.\",\n      \"method\": \"Agtrap-/- mouse generation, high-fat diet challenge, fat pad transplantation from ATRAP transgenic donors, metabolic phenotyping\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout plus rescue transplantation experiment with multiple metabolic readouts\",\n      \"pmids\": [\"23902639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Proteasomal degradation of ATRAP occurs during angiotensin II-induced cardiac hypertrophy; proteasome inhibitor bortezomib blocked ATRAP degradation and attenuated AT1R-mediated p38 MAPK and STAT3 signaling pathways, thereby reducing cardiac hypertrophy, fibrosis, and inflammation.\",\n      \"method\": \"Ang II infusion mouse model, bortezomib treatment, Western blot for proteasome activity, ATRAP protein levels, p38 MAPK and STAT3 phosphorylation\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibitor in vivo with mechanistic pathway readouts, single lab\",\n      \"pmids\": [\"25526681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ATRAP interacts with the cardiac Ca2+-ATPase SERCA2a, confirmed by pull-down (MALDI-MS), co-immunoprecipitation, and surface plasmon resonance. ATRAP enhances SERCA-dependent Ca2+ uptake in isolated SR membrane vesicles. Atrap-/- myocytes show prolonged Ca2+ transient decay and sarcomere re-lengthening, and Atrap-/- mice have decreased maximum ventricular filling rate, indicating ATRAP facilitates ventricular relaxation via SERCA2a stimulation.\",\n      \"method\": \"Pull-down with MALDI-MS sequencing, co-immunoprecipitation, surface plasmon resonance, Ca2+ uptake assay in SR vesicles, cardiomyocyte sarcomere shortening and Ca2+ transient measurements, echocardiography in Atrap-/- mice\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical methods plus functional in vitro assay and in vivo knockout phenotype\",\n      \"pmids\": [\"27015675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Immunoproteasome subunit β5i (PSMB8) directly targets ATRAP for degradation. β5i knockout attenuated Ang II-induced atrial fibrillation, fibrosis, and oxidative stress, while restoring ATRAP levels. Overexpression of ATRAP abrogated Ang II-induced atrial remodeling and AF in β5i-overexpressing mice. Mechanistically, β5i-mediated ATRAP degradation leads to activation of AT1R-mediated NF-κB signaling, increased NADPH oxidase activity, and TGF-β1/Smad signaling.\",\n      \"method\": \"β5i KO mice, recombinant AAV9-β5i injection, AAV9-ATRAP overexpression, atrial electrophysiology (telemetry), Western blot, NADPH oxidase activity assay\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, gain-of-function, and rescue overexpression experiments with multiple pathway readouts\",\n      \"pmids\": [\"30571551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Proximal tubule-specific ATRAP knockout (PT-KO) mice showed no significant difference in blood pressure at baseline or in pressor response to angiotensin II infusion compared to wild-type mice, indicating that ATRAP in renal proximal tubules has a minor role in angiotensin-dependent hypertension in vivo.\",\n      \"method\": \"Cre/loxP proximal tubule-specific ATRAP KO using Pepck-Cre, tail-cuff and radiotelemetric blood pressure measurement, angiotensin II infusion, laser-capture microdissection and immunohistochemistry\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific genetic knockout with rigorous BP measurement methods; negative result mechanistically informative\",\n      \"pmids\": [\"30977419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SAM (S-adenosylmethionine) upregulates ATRAP protein expression in NAFLD by methylating HuR protein, which controls HuR subcellular localization; HuR directly binds ATRAP mRNA and controls its nucleocytoplasmic shuttling for export from the nucleus, thereby regulating ATRAP translation.\",\n      \"method\": \"HuR methylation assay, RNA immunoprecipitation (HuR-ATRAP mRNA binding), nucleocytoplasmic fractionation, SAM supplementation in high-fat diet rats and oleic acid-treated L02 cells\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-protein interaction confirmed by RIP, functional methylation/localization assay, single lab\",\n      \"pmids\": [\"33753727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In breast cancer cells, ATRAP directs USP14 (Ubiquitin-specific protease 14)-mediated deubiquitination and stabilization of PBX3 (Pre-B cell leukemia homeobox 3), and promotes AKT/mTOR signaling pathway activation; ATRAP is itself a transcriptional target of USF1 (Upstream stimulatory factor 1).\",\n      \"method\": \"Co-immunoprecipitation, microarray pathway analysis, siRNA knockdown, overexpression functional assays (proliferation, metastasis, glycolysis), rescue experiments\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and functional rescue, but single lab, and the deubiquitination mechanism is inferred rather than directly reconstituted\",\n      \"pmids\": [\"35414770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DJ-1 (PARK7) in hypoxia-conditioned MSC-derived extracellular vesicles suppresses cardiac hypertrophy by directly physically interacting with and inhibiting proteasome subunit PSMB10 activity, which in turn reduces ubiquitination-mediated degradation of ATRAP, thereby preserving AT1R-mediated signaling inhibition.\",\n      \"method\": \"Quantitative proteomics, co-immunoprecipitation (DJ-1/PSMB10), proteasome activity assay, ubiquitination assay for ATRAP, neonatal rat cardiomyocyte assays, TAC mouse model\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and proteasome activity assay with functional ATRAP readout, single lab\",\n      \"pmids\": [\"36509316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Tubular ATRAP-mediated modulation of AT1R signaling regulates the accumulation of tubulointerstitial M2-polarized macrophages (marked by CD206), thereby affecting glomerular injury in diabetic nephropathy via tubule-glomerular crosstalk. Adoptive transfer of M2 macrophages into diabetic ATRAP-knockout mice ameliorated glomerular injury.\",\n      \"method\": \"Streptozotocin-induced diabetic ATRAP-KO mice, proximal tubule-specific ATRAP knockdown mice, adoptive macrophage transfer, immunohistochemistry for CD206, renal mRNA analysis for TNF-α and oxidative stress markers\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic models with rescue adoptive transfer experiment and mechanistic readouts, single lab\",\n      \"pmids\": [\"35240129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-125a-5p and miR-125b-5p directly repress ATRAP/Atrap mRNA expression. Inhibition of miR-125a-5p/miR-125b-5p suppresses Ang II-AT1R signaling in mouse distal convoluted tubule cells by increasing ATRAP levels.\",\n      \"method\": \"miRNA target prediction, luciferase reporter assay for direct miRNA-ATRAP 3'UTR interaction, miRNA inhibitor treatment in mouse distal convoluted tubule cells, AT1R signaling readouts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by reporter assay with functional downstream signaling readout, single lab\",\n      \"pmids\": [\"37981211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"miR-34a directly targets AGTRAP mRNA in human aortic smooth muscle cells (HASMC); Ang II upregulates miR-34a, which suppresses AGTRAP and SIRT1 expression; forced AGTRAP expression rescues miR-34a-induced pro-inflammatory gene upregulation (IL-6, COX2, MCP-1, MFGE8), establishing a negative feedback loop where AGTRAP downmodulation further enhances miR-34a expression.\",\n      \"method\": \"miR-34a overexpression in HASMC, luciferase reporter assay confirming direct miR-34a targeting of AGTRAP 3'UTR, AGTRAP forced expression rescue, Ang II stimulation, aging primate/rodent tissue analysis\",\n      \"journal\": \"GeroScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct miRNA targeting confirmed by reporter assay with functional rescue experiment, single lab\",\n      \"pmids\": [\"41291382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"AGTRAP knockdown in glioma cells suppressed proliferation, increased apoptosis, reduced IL-6 mRNA and protein levels, and attenuated JAK2/STAT3 activation; recombinant IL-6 partially restored JAK2/STAT3 signaling and mitigated growth inhibition caused by AGTRAP silencing, placing AGTRAP upstream of IL-6/JAK2/STAT3 in glioma.\",\n      \"method\": \"shRNA knockdown in A172 and U251 glioma cells, proliferation and apoptosis assays, IL-6 ELISA/Western blot, JAK2/STAT3 phosphorylation assay, recombinant IL-6 rescue, orthotopic xenograft model\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with pathway rescue in vitro and in vivo, single lab, single set of methods\",\n      \"pmids\": [\"41689202\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATRAP/AGTRAP is a transmembrane protein that specifically binds the carboxyl-terminal cytoplasmic domain of the angiotensin II type 1 receptor (AT1R) and promotes its constitutive internalization, thereby inhibiting pathological AT1R-mediated signaling (PLC activation, p38 MAPK, STAT3, Akt, NF-κB, TGF-β1/Smad); ATRAP also interacts with RACK1 and the phospholipid transfer protein RdgBβ (via membrane recruitment), stimulates the cardiac Ca2+-ATPase SERCA2a to facilitate ventricular relaxation, and is itself post-translationally regulated by immunoproteasome subunit β5i-mediated degradation (counteracted by proteasome inhibitors or melatonin) and post-transcriptionally regulated by miR-125a/b-5p and miR-34a; in cancer contexts ATRAP additionally engages a USP14/PBX3/AKT-mTOR axis and an IL-6/JAK2/STAT3 pathway independently of AT1R.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AGTRAP (ATRAP) is a multi-pass transmembrane protein that functions as a negative regulator of angiotensin II type 1 receptor (AT1R) signaling, binding specifically to the carboxyl-terminal cytoplasmic tail of the AT1a receptor and not to other G-protein-coupled receptors [#0, #3]. It localizes to the plasma membrane and to intracellular trafficking vesicles (ER, Golgi, endocytic vesicles), with constitutive translocation toward the plasma membrane; its cytoplasmic C-terminal domain is required for AT1R binding [#3]. Through this interaction ATRAP promotes AT1R internalization and surface downregulation, thereby suppressing downstream AT1R-mediated signaling including phospholipase C activation, p38 MAPK, STAT3, and Akt, and attenuating angiotensin II-induced proliferative and hypertrophic responses in vascular smooth muscle cells and cardiomyocytes [#0, #1, #4]. Genetic deletion in mice establishes ATRAP as a physiological negative regulator: Atrap-deficient animals show elevated blood pressure, increased plasma volume, and enhanced renal AT1R surface expression [#7], and additionally develop high-fat-diet-driven metabolic dysfunction that is rescued by transplantation of ATRAP-overexpressing adipose tissue [#9]. Beyond AT1R, ATRAP interacts with the cardiac sarcoplasmic reticulum Ca2+-ATPase SERCA2a and enhances SERCA-dependent Ca2+ uptake to facilitate ventricular relaxation [#11]. ATRAP abundance is tightly controlled post-translationally by proteasomal and immunoproteasomal degradation\\u2014notably via the immunoproteasome subunit \\u03b25i (PSMB8), whose action de-represses AT1R-driven NF-\\u03baB, NADPH oxidase, and TGF-\\u03b21/Smad signaling [#10, #12]\\u2014and post-transcriptionally by miR-125a/b-5p and miR-34a [#18, #19]. In cancer, ATRAP operates independently of AT1R, driving a USP14/PBX3/AKT-mTOR axis in breast cancer [#15] and an IL-6/JAK2/STAT3 pathway in glioma [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that ATRAP is a dedicated AT1R-interacting partner, answering whether a receptor-specific regulator of angiotensin signaling exists.\",\n      \"evidence\": \"Yeast two-hybrid, affinity chromatography, Co-IP, and PLC functional assay in COS-7 cells showing selective binding to the AT1a C-terminal tail\",\n      \"pmids\": [\"10358057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define topology or trafficking\", \"Mechanism of PLC inhibition not resolved beyond binding\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed ATRAP acts by promoting AT1R internalization and suppressing growth signaling, framing it as a functional negative regulator rather than a passive binder.\",\n      \"evidence\": \"Overexpression in adult VSMCs with receptor internalization, DNA synthesis, and STAT3/Akt phosphorylation readouts\",\n      \"pmids\": [\"11162453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression only, no loss-of-function\", \"Internalization machinery linking ATRAP to AT1R not identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified RACK1 as an ATRAP partner, expanding the interactome beyond AT1R toward a possible scaffolding role.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, Co-IP, and surface plasmon resonance\",\n      \"pmids\": [\"11733189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of RACK1 binding not defined\", \"Not linked to AT1R regulation\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined ATRAP membrane topology, trafficking behavior, and the C-terminal domain as the AT1R-binding determinant, establishing the structural basis for its regulatory function.\",\n      \"evidence\": \"Epitope-tag topology mapping, EM, immunofluorescence, real-time vesicle tracking, and deletion-mutant reporter/proliferation assays\",\n      \"pmids\": [\"12960423\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the AT1R-ATRAP interface not solved\", \"How vesicular ATRAP couples to AT1R endocytosis unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extended the negative-regulator model to cardiac hypertrophy, showing ATRAP reduces surface AT1R and dampens p38 MAPK-driven hypertrophic responses.\",\n      \"evidence\": \"Overexpression in cardiomyocytes with surface receptor binding, p38 phosphorylation, c-fos reporter, and protein synthesis assays\",\n      \"pmids\": [\"15757644\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression-based; in vivo cardiac role not yet tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated in vivo ATRAP/AT1R colocalization along the nephron and salt-responsive co-regulation, implicating ATRAP in renal angiotensin physiology.\",\n      \"evidence\": \"In situ hybridization, Western blot, immunohistochemistry, and dietary salt manipulation in kidney\",\n      \"pmids\": [\"16514431\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative; no causal manipulation\", \"Functional consequence for blood pressure untested at this stage\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided definitive genetic proof that ATRAP negatively regulates renal AT1R and blood pressure in vivo.\",\n      \"evidence\": \"Atrap-/- mice with telemetry, plasma volume, 125I-Ang II binding, and proximal tubular function assays\",\n      \"pmids\": [\"20093357\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whole-body knockout; tissue-specific contribution not isolated\", \"Did not address non-renal phenotypes\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified ATRAP as the membrane anchor that recruits the phospholipid transfer protein RdgB\\u03b2 (PITPNC1), suggesting a lipid-signaling-linked role.\",\n      \"evidence\": \"Co-IP and PMA-induced membrane recruitment assay in COS-7 cells\",\n      \"pmids\": [\"21728994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological significance of RdgB\\u03b2 recruitment unknown\", \"Not connected to AT1R pathway\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed an AT1R-related metabolic protective function of adipose ATRAP through knockout plus rescue transplantation.\",\n      \"evidence\": \"Agtrap-/- mice on high-fat diet with fat-pad transplantation from ATRAP-transgenic donors and metabolic phenotyping\",\n      \"pmids\": [\"23902639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mediators in adipocytes not fully defined\", \"Whether effect is strictly AT1R-dependent unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established that proteasomal turnover of ATRAP is a control point governing AT1R signaling output during hypertrophy.\",\n      \"evidence\": \"Ang II infusion mouse model with bortezomib treatment and p38/STAT3 pathway readouts\",\n      \"pmids\": [\"25526681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific E3 ligase not identified here\", \"Pharmacological inhibitor lacks proteasome-target specificity\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovered a non-AT1R molecular function: ATRAP binds and stimulates SERCA2a to facilitate ventricular relaxation.\",\n      \"evidence\": \"Pull-down/MALDI-MS, Co-IP, SPR, SR Ca2+ uptake assay, cardiomyocyte Ca2+ transient measurements, and echocardiography in Atrap-/- mice\",\n      \"pmids\": [\"27015675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of SERCA2a stimulation not resolved\", \"Interplay between AT1R and SERCA2a functions unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified the immunoproteasome subunit \\u03b25i (PSMB8) as the specific degrader of ATRAP, linking ATRAP turnover to atrial fibrillation via NF-\\u03baB/NADPH oxidase/TGF-\\u03b21 signaling.\",\n      \"evidence\": \"\\u03b25i KO mice, AAV9-\\u03b25i and AAV9-ATRAP overexpression, atrial electrophysiology, NADPH oxidase activity, and pathway Western blots\",\n      \"pmids\": [\"30571551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct \\u03b25i-ATRAP cleavage not biochemically reconstituted\", \"Ubiquitination requirement for degradation not detailed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Refined the tissue locus of ATRAP's blood-pressure role, showing proximal tubule ATRAP is dispensable for angiotensin-dependent hypertension.\",\n      \"evidence\": \"Pepck-Cre proximal tubule-specific ATRAP KO with tail-cuff and radiotelemetric BP under Ang II infusion\",\n      \"pmids\": [\"30977419\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify which nephron segment or tissue mediates the whole-body phenotype\", \"Negative result limited to the Ang II infusion model\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined post-transcriptional control of ATRAP via HuR-mediated mRNA shuttling regulated by SAM methylation in fatty liver disease.\",\n      \"evidence\": \"HuR methylation assay, HuR-ATRAP RNA immunoprecipitation, nucleocytoplasmic fractionation, and SAM supplementation in HFD rats and L02 cells\",\n      \"pmids\": [\"33753727\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream functional consequence of ATRAP induction in NAFLD not fully mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Uncovered an AT1R-independent oncogenic function of ATRAP in breast cancer through a USP14/PBX3/AKT-mTOR axis with USF1 as its upstream transcriptional regulator.\",\n      \"evidence\": \"Co-IP, microarray pathway analysis, siRNA/overexpression functional assays, and rescue experiments\",\n      \"pmids\": [\"35414770\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"USP14-mediated deubiquitination inferred, not reconstituted\", \"Mechanism of ATRAP-USP14 coupling unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed ATRAP stability is preserved by DJ-1 inhibition of proteasome subunit PSMB10, adding a regulatory route protecting AT1R signaling suppression.\",\n      \"evidence\": \"Quantitative proteomics, DJ-1/PSMB10 Co-IP, proteasome and ubiquitination assays, cardiomyocyte assays, and TAC mouse model\",\n      \"pmids\": [\"36509316\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PSMB10-ATRAP targeting not isolated from indirect effects\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected tubular ATRAP-AT1R signaling to immune crosstalk, showing it regulates M2 macrophage accumulation affecting glomerular injury in diabetic nephropathy.\",\n      \"evidence\": \"Streptozotocin-diabetic ATRAP-KO and proximal-tubule knockdown mice with adoptive M2 macrophage transfer and CD206 immunohistochemistry\",\n      \"pmids\": [\"35240129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular signal linking tubular ATRAP to macrophage polarization undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified miR-125a-5p/miR-125b-5p as direct repressors of ATRAP, defining a microRNA layer tuning AT1R signaling in distal tubule cells.\",\n      \"evidence\": \"Luciferase reporter of miRNA-ATRAP 3'UTR binding and miRNA inhibitor treatment with AT1R signaling readouts in DCT cells\",\n      \"pmids\": [\"37981211\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo physiological impact of these miRNAs on ATRAP not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established a miR-34a-AGTRAP negative feedback loop driving vascular smooth muscle inflammation and linking ATRAP to vascular aging.\",\n      \"evidence\": \"miR-34a overexpression and luciferase 3'UTR targeting in HASMC, AGTRAP forced-expression rescue, and aging primate/rodent tissue analysis\",\n      \"pmids\": [\"41291382\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal contribution to vascular aging in vivo not proven\", \"Relationship between AGTRAP/SIRT1 co-regulation mechanistically unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated an AT1R-independent pro-tumor role in glioma, placing AGTRAP upstream of IL-6/JAK2/STAT3 signaling.\",\n      \"evidence\": \"shRNA knockdown in A172/U251 cells, proliferation/apoptosis assays, IL-6 measurement, JAK2/STAT3 phosphorylation, recombinant IL-6 rescue, and orthotopic xenograft\",\n      \"pmids\": [\"41689202\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How AGTRAP controls IL-6 expression molecularly is undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single transmembrane protein integrates its AT1R-internalization function, SERCA2a Ca2+ regulation, lipid-transfer recruitment, and AT1R-independent oncogenic signaling into a unified mechanism remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ATRAP or its complexes\", \"Mechanism switching ATRAP between cardiovascular regulator and cancer effector unknown\", \"Whether oncogenic functions require its membrane topology untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 3, 4, 11]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 4, 7]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [10, 12, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"AGTR1\", \"RACK1\", \"PITPNC1\", \"ATP2A2\", \"USP14\", \"PBX3\", \"PSMB8\", \"PSMB10\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}