{"gene":"ANGPTL2","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2014,"finding":"ANGPTL2 binds to LILRB2 (leukocyte immunoglobulin-like receptor B2) to activate downstream signaling; ligand multimerization is required for LILRB2 activation; the first and fourth Ig domains of LILRB2 contain a motif necessary for ANGPTL2 binding and activation; the fibronectin (FBN) domain at the C-terminus of ANGPTL2 is essential for LILRB2 stimulation.","method":"Co-immunoprecipitation, LILRB2 reporter activation assays, domain mutagenesis, ex vivo HSC expansion assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (binding assays, reporter activation, domain mutagenesis) in one rigorous study, replicated in follow-up work (PMID:35675737)","pmids":["24899623","35675737"],"is_preprint":false},{"year":2014,"finding":"Endothelial cell-derived ANGPTL2 activates proinflammatory NF-κB signaling in endothelial cells and increases monocyte/macrophage chemotaxis, leading to endothelial dysfunction and accelerated atherosclerosis progression.","method":"Angptl2 knockout in ApoE-deficient mice, Tie2-promoter-driven Angptl2 transgenic mice, bone marrow transplantation experiments, in vitro NF-κB signaling assays, monocyte chemotaxis assay","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic models (KO and transgenic), bone marrow transplantation for cell-type specificity, in vitro mechanistic confirmation","pmids":["24526691"],"is_preprint":false},{"year":2012,"finding":"Tumor cell-derived ANGPTL2 promotes tumor cell motility and invasion in an autocrine/paracrine manner, and accelerates metastasis in xenograft mouse models; transcription factors NFATc, ATF2, and c-Jun upregulate ANGPTL2 expression in aggressive tumor cells.","method":"In vitro motility and invasion assays, ANGPTL2 knockdown/overexpression, xenograft mouse models, transcription factor overexpression","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (in vitro functional assays and in vivo xenograft), replicated across subsequent cancer studies","pmids":["22345152"],"is_preprint":false},{"year":2014,"finding":"ANGPTL2 promotes osteosarcoma metastasis via integrin α5β1, p38 MAPK, and matrix metalloproteinases by promoting tumor cell intravasation; TLL1 (tolloid-like 1) protease cleaves ANGPTL2 into fragments in vitro that do not enhance tumor progression.","method":"Xenograft mouse models, integrin blocking, in vitro cleavage assays with TLL1 protease, ANGPTL2 overexpression and knockdown","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution of protease cleavage, in vivo xenograft validation, receptor pathway dissection with multiple orthogonal methods","pmids":["24448647"],"is_preprint":false},{"year":2016,"finding":"ANGPTL2 in the pathologically stressed heart inactivates AKT and SERCA2a signaling and decreases myocardial energy metabolism, causing cardiac dysfunction; Angptl2 knockout mice show increased left ventricular contractility and upregulated AKT-SERCA2a signaling.","method":"Cardiac-specific ANGPTL2 transgenic mice, Angptl2 knockout mice, pressure overload model, ANGPTL2 knockdown via siRNA, echocardiography, AKT/SERCA2a pathway analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic models (transgenic overexpression and KO), therapeutic knockdown experiment, multiple functional readouts","pmids":["27677409"],"is_preprint":false},{"year":2017,"finding":"ANGPTL2-mediated intestinal stromal cell (ISEMF) signaling maintains the intestinal stem cell niche by modulating competing BMP and β-catenin signaling; ANGPTL2 deficiency decreases Lgr5 expression and β-catenin transcriptional activity, and impairs epithelial regeneration after injury.","method":"Angptl2-deficient mice, intestinal injury model, Lgr5 expression analysis, β-catenin activity assay, cell-type-specific expression analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function mouse model with defined molecular pathway (BMP/β-catenin balance) and multiple phenotypic readouts","pmids":["28043948"],"is_preprint":false},{"year":2015,"finding":"ANGPTL2 binds LILRB2 to support the growth of lung cancer cells; the SHP2/CaMK1/CREB axis controls proliferation of lung cancer cell lines downstream of ANGPTL2-LILRB2 signaling.","method":"LILRB2 knockdown in NSCLC cell lines, proliferation and colony formation assays, migration assay, mechanistic pathway analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor knockdown with defined downstream pathway, single lab, limited orthogonal validation of ANGPTL2-LILRB2 binding in this context","pmids":["26056041"],"is_preprint":false},{"year":2015,"finding":"Tumor cell-derived ANGPTL2 increases CXCR4 expression in breast cancer cells, enhancing their responsiveness to CXCL12 and promoting bone metastasis; ANGPTL2 knockdown attenuates tumor cell responsiveness to CXCL12 by decreasing CXCR4 expression.","method":"ANGPTL2 knockdown in breast cancer cells, intracardiac injection xenograft model, CXCR4 expression analysis, CXCL12 migration assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo xenograft and in vitro mechanistic assays in single lab, defined molecular pathway","pmids":["25773070"],"is_preprint":false},{"year":2019,"finding":"ANGPTL2 signals through integrin α5β1 in chondrocytes to activate phosphorylation of ERK, JNK, p38, Akt, and NF-κB, inducing expression of inflammatory factors; inhibiting integrin α5β1 suppresses these inflammatory reactions.","method":"ANGPTL2 treatment of ATDC5 cells, anti-integrin α5β1 antibody blocking, western blotting for MAPK/Akt/NF-κB phosphorylation, RT-PCR for inflammatory markers","journal":"Cartilage","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-blocking experiment with defined downstream signaling cascade, single lab, in vitro only","pmids":["31581797"],"is_preprint":false},{"year":2016,"finding":"ANGPTL2 inflammatory signaling in macrophages is transduced through integrin α5β1 (not through paired immunoglobulin-like receptor B); ANGPTL2 promotes proinflammatory macrophage activity and nitric oxide production required for innate immune responses against bacterial infection.","method":"Angptl2-deficient mouse bone marrow-derived macrophages, integrin α5β1 pathway analysis, Salmonella infection model, NO production measurement, proinflammatory marker expression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — receptor pathway identified by genetic (KO) and functional (integrin signaling) approaches, in vivo infection model validation","pmids":["27402837"],"is_preprint":false},{"year":2021,"finding":"ANGPTL2 acts as a CD146 ligand on adipocytes; ANGPTL2 binds CD146 to activate CREB, which upregulates CD146 expression during adipogenesis and adipose inflammation; CD146 ablation suppresses adipogenesis and lipid accumulation; anti-CD146 antibodies inhibit obesity by disrupting CD146-ANGPTL2 interactions.","method":"Co-immunoprecipitation, CD146 knockout in preadipocytes and adipocytes, CREB signaling analysis, anti-CD146 antibody treatment, in vivo obesity model","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 / Strong — receptor identification with Co-IP, genetic ablation with defined signaling pathway (CREB), and in vivo antibody blockade","pmids":["33747748"],"is_preprint":false},{"year":2021,"finding":"Endothelial cell-derived small extracellular vesicles (SEVs) contain ANGPTL2, which accelerates AML leukemia progression via binding to the LILRB2 receptor; VPS33B governs the release of ANGPTL2-containing SEVs from endothelial cells.","method":"Cell-type-specific Vps33b conditional knockout (7 Cre lines), MLL-AF9 AML mouse model, protein analysis of SEV cargo, LILRB2 receptor binding assay, primary human AML cell maintenance assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional KO lines for cell-type specificity, mechanistic pathway (VPS33B→SEV→ANGPTL2→LILRB2) with functional validation in both mouse and human AML cells","pmids":["33108353"],"is_preprint":false},{"year":2021,"finding":"ANGPTL2 induces inflammatory factor expression via LILRB2 in human fibroblast-like synoviocytes, activating ERK, p38, JNK, NF-κB, and Akt phosphorylation; anti-LILRB2 antibody pretreatment inhibits these effects.","method":"Recombinant ANGPTL2 treatment of HFLS cells, anti-LILRB2 antibody blocking, RT-PCR, western blotting for MAPK/NF-κB/Akt phosphorylation","journal":"Inflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-blocking experiment with defined downstream signaling, single lab, in vitro only","pmids":["33538932"],"is_preprint":false},{"year":2022,"finding":"Tumor cell-derived ANGPTL2 upregulates OB-cadherin expression, which interacts with β-catenin and blocks destruction complex-independent proteasomal degradation of β-catenin, thereby augmenting β-catenin pathway signaling and promoting colorectal cancer cell proliferation; increased ANGPTL2 in CRC cells is accompanied by decreased surface integrin α5β1 expression.","method":"ANGPTL2 deficiency in mouse intestinal tumor model, CRC cell overexpression/knockdown, OB-cadherin expression analysis, β-catenin interaction and degradation assays, integrin α5β1 surface expression analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse tumor model plus mechanistic in vitro pathway dissection, single lab","pmids":["35831580"],"is_preprint":false},{"year":2023,"finding":"ANGPTL2 binds MAG (myelin-associated glycoprotein) as a novel receptor, enhances MAG phosphorylation, recruits Fyn kinase, increases Fyn phosphorylation, and transactivates MYRF to promote oligodendrocyte differentiation and myelination; ANGPTL2-mediated remyelination depends on MAG receptor.","method":"Receptor identification and binding assay, Angptl2-null and Mag-null mice, cuprizone demyelination model, Angptl2-null/Mag-null double knockout, phosphorylation assays, HCN cell differentiation in vitro","journal":"Cell & bioscience","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — novel receptor identification with binding assay, epistatic double-KO showing pathway dependence, in vivo demyelination model, multiple orthogonal methods","pmids":["36855057"],"is_preprint":false},{"year":2023,"finding":"The ANGPTL2-α5β1 integrin pathway accelerates polycomb repressive complex 2 (PRC2)-mediated epigenetic repression of MHC-I expression in tumor cells, reducing susceptibility to CD8+ T-cell-mediated anti-tumor immune responses.","method":"ANGPTL2-deficient renal tubular epithelial cells in tRCC mouse model, IFN-γ-induced MHC-I expression assays, integrin α5β1 pathway blocking, PRC2 complex involvement analysis, CD8+ T-cell cytotoxicity assays","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined signaling pathway (ANGPTL2→integrin α5β1→PRC2→MHC-I repression) with functional immune readout, single lab","pmids":["37452654"],"is_preprint":false},{"year":2023,"finding":"Cardiac myofibroblast-derived ANGPTL2 enhances expression of chemoattractants via the NF-κB pathway, accelerating T cell recruitment into heart tissues during ICI-related autoimmune myocarditis.","method":"ANGPTL2-deficient mice in ICI-related autoimmune myocarditis model, cardiac fibroblast ANGPTL2 expression analysis, NF-κB pathway analysis, immune cell infiltration quantification","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function mouse model with cell-type identified source and defined NF-κB pathway, single lab","pmids":["37736764"],"is_preprint":false},{"year":2023,"finding":"ANGPTL2 promotes VEGF-A synthesis in lung cancer cells; integrin α5β1, p38, and NF-κB signaling mediate ANGPTL2-regulated lymphangiogenesis.","method":"ANGPTL2 overexpression in lung cancer cells, VEGF-A measurement, pathway inhibition (integrin α5β1, p38, NF-κB), LEC tube formation and migration assays, in vivo tumor growth and lymphangiogenesis model","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro pathway dissection with defined signaling components and in vivo validation, single lab","pmids":["36917086"],"is_preprint":false},{"year":2023,"finding":"ANGPTL2 activates NLRP3 inflammasome via suppressing DUSP1 signaling in cardiomyocytes, aggravating LPS-induced septic cardiomyopathy; DUSP1 overexpression inhibits ANGPTL2-mediated NLRP3 activation and improves cardiac dysfunction.","method":"Cardiac ANGPTL2 overexpression/knockdown (AAV vectors), NLRP3 knockdown, DUSP1 overexpression, LPS-induced cardiomyopathy model, echocardiography, pathway analysis","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic genetic dissection (ANGPTL2→DUSP1→NLRP3) with functional cardiac readout, single lab","pmids":["37531825"],"is_preprint":false},{"year":2022,"finding":"HIF1A transcriptionally activates ANGPTL2 expression (confirmed by luciferase reporter and ChIP assay); ANGPTL2 positively modulates HIF1A expression in cardiomyocytes; ANGPTL2 knockdown activates the Nrf2/HO-1 pathway to protect against hypoxia/reoxygenation injury.","method":"Luciferase reporter assay, ChIP assay, ANGPTL2 knockdown/overexpression in H9c2 cells, HIF1A knockdown, Nrf2/HO-1 pathway analysis","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct transcriptional regulation confirmed by luciferase and ChIP, but single lab, in vitro only","pmids":["34974813"],"is_preprint":false},{"year":2021,"finding":"CSN5 (COP9 signalosome subunit 5) directly binds ANGPTL2 protein, decreasing its ubiquitination and proteasomal degradation, thereby elevating ANGPTL2 protein levels in thyroid carcinoma cells.","method":"Co-immunoprecipitation, ubiquitination assay, CSN5 gain/loss of function, western blotting for ANGPTL2 protein levels, correlation analysis in patient tissues","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding by Co-IP with ubiquitination functional assay, single lab","pmids":["33508120"],"is_preprint":false},{"year":2020,"finding":"Stroma-derived ANGPTL2 drives generation of immunostimulatory macrophages via the NF-κB pathway, accelerating CD4+ T helper 1 cell activation and enhancing anti-tumor immune responses in intestinal tumorigenesis.","method":"ANGPTL2-deficient mice in colitis-associated colon cancer model, immune cell profiling, NF-κB pathway analysis, CD4+ and CD8+ T cell response measurement","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function mouse model with immune cell phenotyping and NF-κB pathway identification, single lab","pmids":["33051596"],"is_preprint":false},{"year":2016,"finding":"ANGPTL2 deficiency in lung epithelial cells and resident alveolar macrophages (not myeloid cells) causes more severe lung fibrosis following bleomycin treatment, indicating ANGPTL2 from these cell types plays a protective role against fibrosis; bone marrow transplant experiments excluded a myeloid cell contribution.","method":"Angptl2 KO mice, bleomycin-induced interstitial pneumonia model, bone marrow transplantation, rabbit monoclonal antibody generation for ANGPTL2 detection","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with bone marrow transplant to dissect cell-type specificity, single lab","pmids":["27542805"],"is_preprint":false},{"year":2018,"finding":"ANGPTL2 knockdown activates the MEK/ERK/Nrf-1 pathway in kidney cells, increasing autophagy and decreasing renal fibrosis markers; knockdown of MEK/ERK reverses these changes, placing ANGPTL2 upstream of this pathway.","method":"ANGPTL2 knockdown in high glucose-stimulated HK-2 cells, MEK/ERK pathway inhibition, western blotting for fibrosis and autophagy markers, in vivo STZ-induced diabetic rat model","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic pathway dissection (ANGPTL2→MEK/ERK→autophagy) in vitro and in vivo, single lab","pmids":["31632523"],"is_preprint":false},{"year":2024,"finding":"ANGPTL2 and NOX4 physically interact (co-immunoprecipitation in HEK293 cells); ANGPTL2 represses cardiac NOX4 activity, and ANGPTL2 knockdown upregulates cardiac NOX4, causing increased H2O2 production and left ventricular systolic dysfunction; AAV9-mediated NOX4 knockdown reverses LV dysfunction in ANGPTL2-knockdown mice.","method":"Co-immunoprecipitation in HEK293 cells, ANGPTL2 knockdown mice, AAV9-shRNA targeting NOX4, echocardiography, cardiac H2O2 measurement, immunofluorescence","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein interaction by Co-IP, epistatic rescue by NOX4 knockdown, single lab with multiple methods","pmids":["38426206"],"is_preprint":false},{"year":2022,"finding":"The fibronectin (FBN) domain at the C-terminus of ANGPTL2 is essential for LILRB2 signaling; membrane-anchored N-terminal ANGPTL2 (Nm-Angptl2) activates LILRB2 more potently than soluble ANGPTL2 and more efficiently expands mouse HSCs ex vivo.","method":"LILRB2 reporter activation assay, membrane-anchored ANGPTL2 constructs (C-terminal and N-terminal), HSC transplantation and limiting dilution assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain structure-function analysis with functional HSC expansion readout, single lab","pmids":["35675737"],"is_preprint":false},{"year":2024,"finding":"ANGPTL2 knockdown in alveolar macrophages reduces LILRB2 expression, thereby relieving LILRB2-mediated inhibition of TREM2, which enhances autophagy and reduces pyroptosis; TREM2 knockdown reverses the protective effects of ANGPTL2 silencing.","method":"ANGPTL2 knockdown in LPS-induced mouse ALI model and MH-S cells, LILRB2 overexpression rescue, TREM2 knockdown, autophagy flux detection, pyroptosis markers, western blot","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic pathway dissection (ANGPTL2→LILRB2→TREM2→autophagy/pyroptosis) with rescue experiments, single lab","pmids":["38758159"],"is_preprint":false},{"year":2025,"finding":"Adipocyte-secreted ANGPTL2 promotes hyperuricemia by inhibiting AKT/ABCG2 signaling in renal tubular cells, reducing uric acid excretion; Angptl2 knockout mice show decreased plasma uric acid and upregulated ABCG2, while adipocyte-specific ANGPTL2 overexpression increases plasma uric acid with decreased ABCG2.","method":"Angptl2 knockout mice, adipocyte-specific ANGPTL2 overexpression mice, HK-2 cells and primary RTECs treated with recombinant ANGPTL2, AKT/ABCG2 pathway analysis, DIA proteomics of human adipose tissue","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal genetic models (KO and overexpression) plus in vitro mechanistic pathway, single lab","pmids":["40180020"],"is_preprint":false},{"year":2016,"finding":"DNA methylation of specific CpGs in the ANGPTL2 promoter inhibits ANGPTL2 promoter activity, as demonstrated by in vitro luciferase assay; lower methylation in leukocytes is associated with higher ANGPTL2 expression in post-ACS patients.","method":"In vitro luciferase reporter assay with methylated DNA, bisulfite pyrosequencing of ANGPTL2 promoter CpGs, CRP and ANGPTL2 circulating level measurement","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct functional confirmation of methylation effect by luciferase assay, single lab","pmids":["27101308"],"is_preprint":false},{"year":2021,"finding":"ANGPTL2 induces MYELOID-derived suppressor cell (MDSC) generation in bone marrow by promoting pro-inflammatory cytokine production in adipose tissue, contributing to an immunosuppressive tumor microenvironment and resistance to ICI therapy in obese mice.","method":"Systemic ANGPTL2-deficient mice in syngeneic colorectal cancer model, high-fat diet obesity model, MDSC quantification in bone marrow, cytokine profiling in adipose tissue","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in two disease contexts with mechanistic pathway (ANGPTL2→adipose inflammation→MDSCs→immunosuppression), single lab","pmids":["39321028"],"is_preprint":false}],"current_model":"ANGPTL2 is a secreted glycoprotein that signals through multiple receptors—primarily integrin α5β1, LILRB2, CD146, and MAG—to activate downstream pathways including NF-κB, MAPKs (ERK/JNK/p38), AKT, and AKT-SERCA2a, thereby promoting chronic inflammation, tumor metastasis, macrophage activation, vascular remodeling, and oligodendrocyte differentiation, while its expression is transcriptionally activated by HIF1A and regulated epigenetically by promoter DNA methylation, and its protein stability is controlled by CSN5-mediated deubiquitination; context-dependent downstream effects include ANGPTL2-driven epigenetic repression of MHC-I via the PRC2 complex (promoting tumor immune evasion), activation of the NLRP3 inflammasome via DUSP1 suppression (cardiac inflammation), and inhibition of AKT/ABCG2 signaling in renal tubular cells (promoting hyperuricemia)."},"narrative":{"mechanistic_narrative":"ANGPTL2 is a secreted glycoprotein that functions as a multireceptor ligand coupling tissue stress and inflammation to cellular activation, vascular remodeling, tumor progression, and tissue regeneration [PMID:24526691, PMID:22345152, PMID:31581797]. It engages at least four distinct receptors with context-specific outputs: it binds LILRB2 through its C-terminal fibronectin domain, an interaction requiring ligand multimerization and the first and fourth Ig domains of the receptor, to drive proliferative and inflammatory signaling, while membrane-anchored N-terminal ANGPTL2 activates LILRB2 more potently than the soluble form [PMID:24899623, PMID:35675737]; it signals through integrin α5β1 to activate ERK, JNK, p38, AKT, and NF-κB in chondrocytes, macrophages, and tumor cells [PMID:31581797, PMID:27402837]; it acts as a CD146 ligand on adipocytes to activate CREB during adipogenesis and adipose inflammation [PMID:33747748]; and it binds the myelin-associated glycoprotein MAG to recruit Fyn kinase and transactivate MYRF, promoting oligodendrocyte differentiation and remyelination [PMID:36855057]. Through NF-κB activation in endothelial cells, macrophages, and fibroblasts, ANGPTL2 promotes chronic inflammation, monocyte chemotaxis, endothelial dysfunction, and accelerated atherosclerosis [PMID:24526691, PMID:37736764, PMID:33051596]. In cancer it acts in an autocrine/paracrine manner to enhance tumor cell motility, invasion, and metastasis via integrin α5β1/p38/MMP signaling, and promotes immune evasion by accelerating PRC2-mediated repression of MHC-I and by generating myeloid-derived suppressor cells [PMID:22345152, PMID:24448647, PMID:37452654, PMID:39321028]. Its activity is tuned at multiple levels: HIF1A transcriptionally activates ANGPTL2 in a positive feedback loop [PMID:34974813], promoter CpG methylation represses its expression [PMID:27101308], CSN5 binding stabilizes the protein by reducing its ubiquitination [PMID:33508120], and TLL1 protease cleaves ANGPTL2 into inactive fragments [PMID:24448647]. In the heart, ANGPTL2 has both injurious roles—inactivating AKT-SERCA2a signaling and activating the NLRP3 inflammasome via DUSP1 suppression—and protective roles, interacting with and repressing NOX4 to limit oxidative left ventricular dysfunction [PMID:27677409, PMID:37531825, PMID:38426206].","teleology":[{"year":2012,"claim":"Established that tumor-cell ANGPTL2 is functionally pro-metastatic and identified its transcriptional upstream regulators, framing it as an autocrine/paracrine driver of cancer aggressiveness.","evidence":"In vitro motility/invasion assays with knockdown/overexpression and xenograft models; NFATc/ATF2/c-Jun overexpression","pmids":["22345152"],"confidence":"High","gaps":["Receptor mediating these tumor cell effects not defined in this study","No structural basis for autocrine signaling"]},{"year":2014,"claim":"Identified LILRB2 as a direct ANGPTL2 receptor and mapped the binding determinants, defining the first molecular receptor interaction and the requirement for ligand multimerization.","evidence":"Co-IP, LILRB2 reporter activation assays, domain mutagenesis, ex vivo HSC expansion","pmids":["24899623","35675737"],"confidence":"High","gaps":["Downstream signaling cascade from LILRB2 not fully resolved here","In vivo relevance of HSC expansion to disease not addressed"]},{"year":2014,"claim":"Demonstrated that ANGPTL2 promotes metastasis through integrin α5β1/p38/MMP signaling and that TLL1 proteolytic cleavage inactivates it, revealing both a receptor pathway and a regulatory cleavage mechanism.","evidence":"Xenograft models, integrin blocking, in vitro TLL1 cleavage assays, overexpression/knockdown","pmids":["24448647"],"confidence":"High","gaps":["In vivo significance of TLL1 cleavage not established","Relationship between integrin and LILRB2 signaling unresolved"]},{"year":2014,"claim":"Showed that endothelial ANGPTL2 drives proinflammatory NF-κB signaling and atherosclerosis, linking the ligand to chronic vascular inflammation in vivo.","evidence":"Angptl2 KO in ApoE-null mice, Tie2-driven transgenics, bone marrow transplantation, in vitro NF-κB and chemotaxis assays","pmids":["24526691"],"confidence":"High","gaps":["Endothelial receptor mediating NF-κB activation not identified","Whether circulating vs. local ANGPTL2 drives the effect unclear"]},{"year":2016,"claim":"Distinguished integrin α5β1 (not PirB/LILRB) as the macrophage receptor for ANGPTL2 inflammatory signaling and tied it to antibacterial innate immunity, establishing cell-type-specific receptor usage.","evidence":"Angptl2-deficient BMDMs, integrin pathway analysis, Salmonella infection model, NO measurement","pmids":["27402837"],"confidence":"High","gaps":["Molecular events downstream of integrin in macrophages not fully mapped","Reconciliation with LILRB2-dependent contexts not addressed"]},{"year":2016,"claim":"Defined cardiac ANGPTL2 as a suppressor of AKT-SERCA2a signaling and myocardial energetics, providing a mechanism for stress-induced cardiac dysfunction.","evidence":"Cardiac-specific transgenic and KO mice, pressure overload, siRNA knockdown, echocardiography","pmids":["27677409"],"confidence":"High","gaps":["Cardiac receptor mediating AKT-SERCA2a inactivation unidentified","Direct vs. indirect effect on SERCA2a unresolved"]},{"year":2016,"claim":"Revealed tissue-protective roles for ANGPTL2, with epithelial/alveolar macrophage-derived ANGPTL2 limiting lung fibrosis, and promoter DNA methylation controlling its expression, broadening the model beyond purely pathogenic signaling.","evidence":"Angptl2 KO mice with bleomycin and bone marrow transplant; luciferase assays with methylated promoter and bisulfite pyrosequencing","pmids":["27542805","27101308"],"confidence":"Medium","gaps":["Mechanism by which ANGPTL2 protects against fibrosis not defined","Single-lab findings for both protection and methylation"]},{"year":2017,"claim":"Showed ANGPTL2 from intestinal stromal cells maintains the stem cell niche via BMP/β-catenin balance, establishing a homeostatic developmental role in epithelial regeneration.","evidence":"Angptl2-deficient mice, intestinal injury model, Lgr5 and β-catenin activity assays","pmids":["28043948"],"confidence":"High","gaps":["Receptor transducing the niche signal not identified","Direct vs. indirect regulation of β-catenin unclear"]},{"year":2021,"claim":"Identified CD146 as a third ANGPTL2 receptor on adipocytes acting through CREB, and showed a VPS33B-controlled extracellular vesicle route delivering ANGPTL2 to LILRB2 in leukemia, diversifying both receptor repertoire and delivery mode.","evidence":"Co-IP, CD146 KO in adipocytes, anti-CD146 antibody obesity model; Vps33b conditional KO lines and MLL-AF9 AML model with SEV cargo analysis","pmids":["33747748","33108353"],"confidence":"High","gaps":["Structural basis of CD146 binding not defined","Whether SEV delivery operates in non-leukemic contexts unknown"]},{"year":2021,"claim":"Defined post-translational stabilization of ANGPTL2 by CSN5-mediated deubiquitination, adding protein-level control to its regulation.","evidence":"Co-IP and ubiquitination assays with CSN5 gain/loss in thyroid carcinoma cells","pmids":["33508120"],"confidence":"Medium","gaps":["E3 ligase opposing CSN5 not identified","Single-lab, single-tumor-type finding"]},{"year":2022,"claim":"Established a HIF1A-ANGPTL2 positive feedback loop, linking hypoxic stress responses to ANGPTL2 expression in cardiomyocytes.","evidence":"Luciferase reporter and ChIP assays, ANGPTL2 and HIF1A knockdown in H9c2 cells, Nrf2/HO-1 analysis","pmids":["34974813"],"confidence":"Medium","gaps":["In vivo confirmation lacking","Single-lab, in vitro only"]},{"year":2023,"claim":"Identified MAG as a novel ANGPTL2 receptor coupling to Fyn kinase and MYRF transactivation, revealing a regenerative role in oligodendrocyte differentiation and remyelination.","evidence":"Receptor binding assays, Angptl2-null/Mag-null single and double KO mice, cuprizone demyelination model, phosphorylation and differentiation assays","pmids":["36855057"],"confidence":"High","gaps":["How MAG binding relates to other ANGPTL2 receptors unknown","Direct vs. co-receptor role of MAG not resolved"]},{"year":2023,"claim":"Connected ANGPTL2-integrin α5β1 signaling to tumor immune evasion through PRC2-mediated MHC-I repression, extending its cancer role to adaptive immunity.","evidence":"ANGPTL2-deficient tubular cells in tRCC model, IFN-γ-induced MHC-I assays, integrin blocking, CD8+ T-cell cytotoxicity","pmids":["37452654"],"confidence":"Medium","gaps":["Link between integrin signaling and PRC2 recruitment not mechanistically defined","Single-lab finding"]},{"year":2023,"claim":"Defined context-dependent immune and cardiac mechanisms, including DUSP1-suppression-driven NLRP3 inflammasome activation and NF-κB-driven chemoattractant production, sharpening ANGPTL2's role in inflammatory disease.","evidence":"Cardiac AAV overexpression/knockdown with DUSP1 and NLRP3 manipulation in septic cardiomyopathy; ANGPTL2-deficient mice in ICI myocarditis with NF-κB analysis","pmids":["37531825","37736764"],"confidence":"Medium","gaps":["Receptors upstream of DUSP1 suppression not identified","Single-lab findings"]},{"year":2024,"claim":"Revealed an ANGPTL2-NOX4 physical interaction that restrains cardiac oxidative stress, identifying a protective, redox-regulatory function distinct from its inflammatory roles.","evidence":"Co-IP in HEK293, ANGPTL2 knockdown mice with AAV9-shRNA NOX4 rescue, echocardiography, H2O2 measurement","pmids":["38426206"],"confidence":"Medium","gaps":["Whether intracellular vs. secreted ANGPTL2 binds NOX4 unclear","Single-lab finding"]},{"year":2025,"claim":"Extended ANGPTL2 signaling to metabolic disease, showing adipocyte-secreted ANGPTL2 inhibits renal AKT/ABCG2 signaling to promote hyperuricemia.","evidence":"Angptl2 KO and adipocyte-specific overexpression mice, recombinant ANGPTL2 in HK-2/RTEC cells, AKT/ABCG2 analysis, adipose proteomics","pmids":["40180020"],"confidence":"Medium","gaps":["Renal receptor for ANGPTL2 not identified","Single-lab finding"]},{"year":null,"claim":"How a single secreted ligand selects among integrin α5β1, LILRB2, CD146, and MAG to produce opposing pro-inflammatory, pro-tumor, protective, and regenerative outcomes in different tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model of receptor selection","Roles of multimerization, membrane anchoring, and proteolytic cleavage in directing receptor choice not integrated","Conditions favoring protective vs. pathogenic signaling not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,8,10,14]},{"term_id":"GO:0060089","term_label":"molecular transducer 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Japanese journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21226278","citation_count":1,"is_preprint":false},{"pmid":"30655796","id":"PMC_30655796","title":"Use of ANGPTL2 mRNA levels in formalin-fixed paraffin-embedded tissues as a biomarker to diagnose gastric cancer and to evaluate the extent of vascular invasion.","date":"2018","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/30655796","citation_count":1,"is_preprint":false},{"pmid":"40196450","id":"PMC_40196450","title":"Serum Angptl2 and CyPA Levels in Acute Myocardial Infarction and In-Stent Restenosis After Percutaneous Coronary Intervention: A Single-Center Retrospective Case-Control Study.","date":"2025","source":"Vascular health and risk management","url":"https://pubmed.ncbi.nlm.nih.gov/40196450","citation_count":0,"is_preprint":false},{"pmid":"41347835","id":"PMC_41347835","title":"[Retracted] GDC‑0152 attenuates the malignant progression of osteosarcoma promoted by ANGPTL2 via PI3K/AKT but not p38MAPK signaling pathway.","date":"2025","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41347835","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.15.680997","title":"Decoding Chromatin Dynamics in Cardiac Organoids Reveals Genetic Drivers of Human Heart Development and Disease","date":"2025-10-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.15.680997","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.09.663949","title":"Human Decidual RUNX1 Promotes Angiogenesis and Trophoblast Differentiation by Regulating Extracellular Vesicle Signaling","date":"2025-07-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.09.663949","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":40933,"output_tokens":7520,"usd":0.1178,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17054,"output_tokens":5327,"usd":0.109223,"stage2_stop_reason":"end_turn"},"total_usd":0.227023,"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\": 2014,\n      \"finding\": \"ANGPTL2 binds to LILRB2 (leukocyte immunoglobulin-like receptor B2) to activate downstream signaling; ligand multimerization is required for LILRB2 activation; the first and fourth Ig domains of LILRB2 contain a motif necessary for ANGPTL2 binding and activation; the fibronectin (FBN) domain at the C-terminus of ANGPTL2 is essential for LILRB2 stimulation.\",\n      \"method\": \"Co-immunoprecipitation, LILRB2 reporter activation assays, domain mutagenesis, ex vivo HSC expansion assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (binding assays, reporter activation, domain mutagenesis) in one rigorous study, replicated in follow-up work (PMID:35675737)\",\n      \"pmids\": [\"24899623\", \"35675737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Endothelial cell-derived ANGPTL2 activates proinflammatory NF-κB signaling in endothelial cells and increases monocyte/macrophage chemotaxis, leading to endothelial dysfunction and accelerated atherosclerosis progression.\",\n      \"method\": \"Angptl2 knockout in ApoE-deficient mice, Tie2-promoter-driven Angptl2 transgenic mice, bone marrow transplantation experiments, in vitro NF-κB signaling assays, monocyte chemotaxis assay\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic models (KO and transgenic), bone marrow transplantation for cell-type specificity, in vitro mechanistic confirmation\",\n      \"pmids\": [\"24526691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Tumor cell-derived ANGPTL2 promotes tumor cell motility and invasion in an autocrine/paracrine manner, and accelerates metastasis in xenograft mouse models; transcription factors NFATc, ATF2, and c-Jun upregulate ANGPTL2 expression in aggressive tumor cells.\",\n      \"method\": \"In vitro motility and invasion assays, ANGPTL2 knockdown/overexpression, xenograft mouse models, transcription factor overexpression\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (in vitro functional assays and in vivo xenograft), replicated across subsequent cancer studies\",\n      \"pmids\": [\"22345152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ANGPTL2 promotes osteosarcoma metastasis via integrin α5β1, p38 MAPK, and matrix metalloproteinases by promoting tumor cell intravasation; TLL1 (tolloid-like 1) protease cleaves ANGPTL2 into fragments in vitro that do not enhance tumor progression.\",\n      \"method\": \"Xenograft mouse models, integrin blocking, in vitro cleavage assays with TLL1 protease, ANGPTL2 overexpression and knockdown\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution of protease cleavage, in vivo xenograft validation, receptor pathway dissection with multiple orthogonal methods\",\n      \"pmids\": [\"24448647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ANGPTL2 in the pathologically stressed heart inactivates AKT and SERCA2a signaling and decreases myocardial energy metabolism, causing cardiac dysfunction; Angptl2 knockout mice show increased left ventricular contractility and upregulated AKT-SERCA2a signaling.\",\n      \"method\": \"Cardiac-specific ANGPTL2 transgenic mice, Angptl2 knockout mice, pressure overload model, ANGPTL2 knockdown via siRNA, echocardiography, AKT/SERCA2a pathway analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic models (transgenic overexpression and KO), therapeutic knockdown experiment, multiple functional readouts\",\n      \"pmids\": [\"27677409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ANGPTL2-mediated intestinal stromal cell (ISEMF) signaling maintains the intestinal stem cell niche by modulating competing BMP and β-catenin signaling; ANGPTL2 deficiency decreases Lgr5 expression and β-catenin transcriptional activity, and impairs epithelial regeneration after injury.\",\n      \"method\": \"Angptl2-deficient mice, intestinal injury model, Lgr5 expression analysis, β-catenin activity assay, cell-type-specific expression analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function mouse model with defined molecular pathway (BMP/β-catenin balance) and multiple phenotypic readouts\",\n      \"pmids\": [\"28043948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ANGPTL2 binds LILRB2 to support the growth of lung cancer cells; the SHP2/CaMK1/CREB axis controls proliferation of lung cancer cell lines downstream of ANGPTL2-LILRB2 signaling.\",\n      \"method\": \"LILRB2 knockdown in NSCLC cell lines, proliferation and colony formation assays, migration assay, mechanistic pathway analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor knockdown with defined downstream pathway, single lab, limited orthogonal validation of ANGPTL2-LILRB2 binding in this context\",\n      \"pmids\": [\"26056041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Tumor cell-derived ANGPTL2 increases CXCR4 expression in breast cancer cells, enhancing their responsiveness to CXCL12 and promoting bone metastasis; ANGPTL2 knockdown attenuates tumor cell responsiveness to CXCL12 by decreasing CXCR4 expression.\",\n      \"method\": \"ANGPTL2 knockdown in breast cancer cells, intracardiac injection xenograft model, CXCR4 expression analysis, CXCL12 migration assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo xenograft and in vitro mechanistic assays in single lab, defined molecular pathway\",\n      \"pmids\": [\"25773070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ANGPTL2 signals through integrin α5β1 in chondrocytes to activate phosphorylation of ERK, JNK, p38, Akt, and NF-κB, inducing expression of inflammatory factors; inhibiting integrin α5β1 suppresses these inflammatory reactions.\",\n      \"method\": \"ANGPTL2 treatment of ATDC5 cells, anti-integrin α5β1 antibody blocking, western blotting for MAPK/Akt/NF-κB phosphorylation, RT-PCR for inflammatory markers\",\n      \"journal\": \"Cartilage\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-blocking experiment with defined downstream signaling cascade, single lab, in vitro only\",\n      \"pmids\": [\"31581797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ANGPTL2 inflammatory signaling in macrophages is transduced through integrin α5β1 (not through paired immunoglobulin-like receptor B); ANGPTL2 promotes proinflammatory macrophage activity and nitric oxide production required for innate immune responses against bacterial infection.\",\n      \"method\": \"Angptl2-deficient mouse bone marrow-derived macrophages, integrin α5β1 pathway analysis, Salmonella infection model, NO production measurement, proinflammatory marker expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — receptor pathway identified by genetic (KO) and functional (integrin signaling) approaches, in vivo infection model validation\",\n      \"pmids\": [\"27402837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ANGPTL2 acts as a CD146 ligand on adipocytes; ANGPTL2 binds CD146 to activate CREB, which upregulates CD146 expression during adipogenesis and adipose inflammation; CD146 ablation suppresses adipogenesis and lipid accumulation; anti-CD146 antibodies inhibit obesity by disrupting CD146-ANGPTL2 interactions.\",\n      \"method\": \"Co-immunoprecipitation, CD146 knockout in preadipocytes and adipocytes, CREB signaling analysis, anti-CD146 antibody treatment, in vivo obesity model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — receptor identification with Co-IP, genetic ablation with defined signaling pathway (CREB), and in vivo antibody blockade\",\n      \"pmids\": [\"33747748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Endothelial cell-derived small extracellular vesicles (SEVs) contain ANGPTL2, which accelerates AML leukemia progression via binding to the LILRB2 receptor; VPS33B governs the release of ANGPTL2-containing SEVs from endothelial cells.\",\n      \"method\": \"Cell-type-specific Vps33b conditional knockout (7 Cre lines), MLL-AF9 AML mouse model, protein analysis of SEV cargo, LILRB2 receptor binding assay, primary human AML cell maintenance assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional KO lines for cell-type specificity, mechanistic pathway (VPS33B→SEV→ANGPTL2→LILRB2) with functional validation in both mouse and human AML cells\",\n      \"pmids\": [\"33108353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ANGPTL2 induces inflammatory factor expression via LILRB2 in human fibroblast-like synoviocytes, activating ERK, p38, JNK, NF-κB, and Akt phosphorylation; anti-LILRB2 antibody pretreatment inhibits these effects.\",\n      \"method\": \"Recombinant ANGPTL2 treatment of HFLS cells, anti-LILRB2 antibody blocking, RT-PCR, western blotting for MAPK/NF-κB/Akt phosphorylation\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-blocking experiment with defined downstream signaling, single lab, in vitro only\",\n      \"pmids\": [\"33538932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Tumor cell-derived ANGPTL2 upregulates OB-cadherin expression, which interacts with β-catenin and blocks destruction complex-independent proteasomal degradation of β-catenin, thereby augmenting β-catenin pathway signaling and promoting colorectal cancer cell proliferation; increased ANGPTL2 in CRC cells is accompanied by decreased surface integrin α5β1 expression.\",\n      \"method\": \"ANGPTL2 deficiency in mouse intestinal tumor model, CRC cell overexpression/knockdown, OB-cadherin expression analysis, β-catenin interaction and degradation assays, integrin α5β1 surface expression analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse tumor model plus mechanistic in vitro pathway dissection, single lab\",\n      \"pmids\": [\"35831580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ANGPTL2 binds MAG (myelin-associated glycoprotein) as a novel receptor, enhances MAG phosphorylation, recruits Fyn kinase, increases Fyn phosphorylation, and transactivates MYRF to promote oligodendrocyte differentiation and myelination; ANGPTL2-mediated remyelination depends on MAG receptor.\",\n      \"method\": \"Receptor identification and binding assay, Angptl2-null and Mag-null mice, cuprizone demyelination model, Angptl2-null/Mag-null double knockout, phosphorylation assays, HCN cell differentiation in vitro\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — novel receptor identification with binding assay, epistatic double-KO showing pathway dependence, in vivo demyelination model, multiple orthogonal methods\",\n      \"pmids\": [\"36855057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The ANGPTL2-α5β1 integrin pathway accelerates polycomb repressive complex 2 (PRC2)-mediated epigenetic repression of MHC-I expression in tumor cells, reducing susceptibility to CD8+ T-cell-mediated anti-tumor immune responses.\",\n      \"method\": \"ANGPTL2-deficient renal tubular epithelial cells in tRCC mouse model, IFN-γ-induced MHC-I expression assays, integrin α5β1 pathway blocking, PRC2 complex involvement analysis, CD8+ T-cell cytotoxicity assays\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined signaling pathway (ANGPTL2→integrin α5β1→PRC2→MHC-I repression) with functional immune readout, single lab\",\n      \"pmids\": [\"37452654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cardiac myofibroblast-derived ANGPTL2 enhances expression of chemoattractants via the NF-κB pathway, accelerating T cell recruitment into heart tissues during ICI-related autoimmune myocarditis.\",\n      \"method\": \"ANGPTL2-deficient mice in ICI-related autoimmune myocarditis model, cardiac fibroblast ANGPTL2 expression analysis, NF-κB pathway analysis, immune cell infiltration quantification\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function mouse model with cell-type identified source and defined NF-κB pathway, single lab\",\n      \"pmids\": [\"37736764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ANGPTL2 promotes VEGF-A synthesis in lung cancer cells; integrin α5β1, p38, and NF-κB signaling mediate ANGPTL2-regulated lymphangiogenesis.\",\n      \"method\": \"ANGPTL2 overexpression in lung cancer cells, VEGF-A measurement, pathway inhibition (integrin α5β1, p38, NF-κB), LEC tube formation and migration assays, in vivo tumor growth and lymphangiogenesis model\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro pathway dissection with defined signaling components and in vivo validation, single lab\",\n      \"pmids\": [\"36917086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ANGPTL2 activates NLRP3 inflammasome via suppressing DUSP1 signaling in cardiomyocytes, aggravating LPS-induced septic cardiomyopathy; DUSP1 overexpression inhibits ANGPTL2-mediated NLRP3 activation and improves cardiac dysfunction.\",\n      \"method\": \"Cardiac ANGPTL2 overexpression/knockdown (AAV vectors), NLRP3 knockdown, DUSP1 overexpression, LPS-induced cardiomyopathy model, echocardiography, pathway analysis\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic genetic dissection (ANGPTL2→DUSP1→NLRP3) with functional cardiac readout, single lab\",\n      \"pmids\": [\"37531825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HIF1A transcriptionally activates ANGPTL2 expression (confirmed by luciferase reporter and ChIP assay); ANGPTL2 positively modulates HIF1A expression in cardiomyocytes; ANGPTL2 knockdown activates the Nrf2/HO-1 pathway to protect against hypoxia/reoxygenation injury.\",\n      \"method\": \"Luciferase reporter assay, ChIP assay, ANGPTL2 knockdown/overexpression in H9c2 cells, HIF1A knockdown, Nrf2/HO-1 pathway analysis\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct transcriptional regulation confirmed by luciferase and ChIP, but single lab, in vitro only\",\n      \"pmids\": [\"34974813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CSN5 (COP9 signalosome subunit 5) directly binds ANGPTL2 protein, decreasing its ubiquitination and proteasomal degradation, thereby elevating ANGPTL2 protein levels in thyroid carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, CSN5 gain/loss of function, western blotting for ANGPTL2 protein levels, correlation analysis in patient tissues\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding by Co-IP with ubiquitination functional assay, single lab\",\n      \"pmids\": [\"33508120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Stroma-derived ANGPTL2 drives generation of immunostimulatory macrophages via the NF-κB pathway, accelerating CD4+ T helper 1 cell activation and enhancing anti-tumor immune responses in intestinal tumorigenesis.\",\n      \"method\": \"ANGPTL2-deficient mice in colitis-associated colon cancer model, immune cell profiling, NF-κB pathway analysis, CD4+ and CD8+ T cell response measurement\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function mouse model with immune cell phenotyping and NF-κB pathway identification, single lab\",\n      \"pmids\": [\"33051596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ANGPTL2 deficiency in lung epithelial cells and resident alveolar macrophages (not myeloid cells) causes more severe lung fibrosis following bleomycin treatment, indicating ANGPTL2 from these cell types plays a protective role against fibrosis; bone marrow transplant experiments excluded a myeloid cell contribution.\",\n      \"method\": \"Angptl2 KO mice, bleomycin-induced interstitial pneumonia model, bone marrow transplantation, rabbit monoclonal antibody generation for ANGPTL2 detection\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with bone marrow transplant to dissect cell-type specificity, single lab\",\n      \"pmids\": [\"27542805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ANGPTL2 knockdown activates the MEK/ERK/Nrf-1 pathway in kidney cells, increasing autophagy and decreasing renal fibrosis markers; knockdown of MEK/ERK reverses these changes, placing ANGPTL2 upstream of this pathway.\",\n      \"method\": \"ANGPTL2 knockdown in high glucose-stimulated HK-2 cells, MEK/ERK pathway inhibition, western blotting for fibrosis and autophagy markers, in vivo STZ-induced diabetic rat model\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic pathway dissection (ANGPTL2→MEK/ERK→autophagy) in vitro and in vivo, single lab\",\n      \"pmids\": [\"31632523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANGPTL2 and NOX4 physically interact (co-immunoprecipitation in HEK293 cells); ANGPTL2 represses cardiac NOX4 activity, and ANGPTL2 knockdown upregulates cardiac NOX4, causing increased H2O2 production and left ventricular systolic dysfunction; AAV9-mediated NOX4 knockdown reverses LV dysfunction in ANGPTL2-knockdown mice.\",\n      \"method\": \"Co-immunoprecipitation in HEK293 cells, ANGPTL2 knockdown mice, AAV9-shRNA targeting NOX4, echocardiography, cardiac H2O2 measurement, immunofluorescence\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein interaction by Co-IP, epistatic rescue by NOX4 knockdown, single lab with multiple methods\",\n      \"pmids\": [\"38426206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The fibronectin (FBN) domain at the C-terminus of ANGPTL2 is essential for LILRB2 signaling; membrane-anchored N-terminal ANGPTL2 (Nm-Angptl2) activates LILRB2 more potently than soluble ANGPTL2 and more efficiently expands mouse HSCs ex vivo.\",\n      \"method\": \"LILRB2 reporter activation assay, membrane-anchored ANGPTL2 constructs (C-terminal and N-terminal), HSC transplantation and limiting dilution assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain structure-function analysis with functional HSC expansion readout, single lab\",\n      \"pmids\": [\"35675737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANGPTL2 knockdown in alveolar macrophages reduces LILRB2 expression, thereby relieving LILRB2-mediated inhibition of TREM2, which enhances autophagy and reduces pyroptosis; TREM2 knockdown reverses the protective effects of ANGPTL2 silencing.\",\n      \"method\": \"ANGPTL2 knockdown in LPS-induced mouse ALI model and MH-S cells, LILRB2 overexpression rescue, TREM2 knockdown, autophagy flux detection, pyroptosis markers, western blot\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic pathway dissection (ANGPTL2→LILRB2→TREM2→autophagy/pyroptosis) with rescue experiments, single lab\",\n      \"pmids\": [\"38758159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Adipocyte-secreted ANGPTL2 promotes hyperuricemia by inhibiting AKT/ABCG2 signaling in renal tubular cells, reducing uric acid excretion; Angptl2 knockout mice show decreased plasma uric acid and upregulated ABCG2, while adipocyte-specific ANGPTL2 overexpression increases plasma uric acid with decreased ABCG2.\",\n      \"method\": \"Angptl2 knockout mice, adipocyte-specific ANGPTL2 overexpression mice, HK-2 cells and primary RTECs treated with recombinant ANGPTL2, AKT/ABCG2 pathway analysis, DIA proteomics of human adipose tissue\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal genetic models (KO and overexpression) plus in vitro mechanistic pathway, single lab\",\n      \"pmids\": [\"40180020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DNA methylation of specific CpGs in the ANGPTL2 promoter inhibits ANGPTL2 promoter activity, as demonstrated by in vitro luciferase assay; lower methylation in leukocytes is associated with higher ANGPTL2 expression in post-ACS patients.\",\n      \"method\": \"In vitro luciferase reporter assay with methylated DNA, bisulfite pyrosequencing of ANGPTL2 promoter CpGs, CRP and ANGPTL2 circulating level measurement\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct functional confirmation of methylation effect by luciferase assay, single lab\",\n      \"pmids\": [\"27101308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ANGPTL2 induces MYELOID-derived suppressor cell (MDSC) generation in bone marrow by promoting pro-inflammatory cytokine production in adipose tissue, contributing to an immunosuppressive tumor microenvironment and resistance to ICI therapy in obese mice.\",\n      \"method\": \"Systemic ANGPTL2-deficient mice in syngeneic colorectal cancer model, high-fat diet obesity model, MDSC quantification in bone marrow, cytokine profiling in adipose tissue\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in two disease contexts with mechanistic pathway (ANGPTL2→adipose inflammation→MDSCs→immunosuppression), single lab\",\n      \"pmids\": [\"39321028\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANGPTL2 is a secreted glycoprotein that signals through multiple receptors—primarily integrin α5β1, LILRB2, CD146, and MAG—to activate downstream pathways including NF-κB, MAPKs (ERK/JNK/p38), AKT, and AKT-SERCA2a, thereby promoting chronic inflammation, tumor metastasis, macrophage activation, vascular remodeling, and oligodendrocyte differentiation, while its expression is transcriptionally activated by HIF1A and regulated epigenetically by promoter DNA methylation, and its protein stability is controlled by CSN5-mediated deubiquitination; context-dependent downstream effects include ANGPTL2-driven epigenetic repression of MHC-I via the PRC2 complex (promoting tumor immune evasion), activation of the NLRP3 inflammasome via DUSP1 suppression (cardiac inflammation), and inhibition of AKT/ABCG2 signaling in renal tubular cells (promoting hyperuricemia).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ANGPTL2 is a secreted glycoprotein that functions as a multireceptor ligand coupling tissue stress and inflammation to cellular activation, vascular remodeling, tumor progression, and tissue regeneration [#1, #2, #8]. It engages at least four distinct receptors with context-specific outputs: it binds LILRB2 through its C-terminal fibronectin domain, an interaction requiring ligand multimerization and the first and fourth Ig domains of the receptor, to drive proliferative and inflammatory signaling, while membrane-anchored N-terminal ANGPTL2 activates LILRB2 more potently than the soluble form [#0, #25]; it signals through integrin \\u03b15\\u03b21 to activate ERK, JNK, p38, AKT, and NF-\\u03baB in chondrocytes, macrophages, and tumor cells [#8, #9]; it acts as a CD146 ligand on adipocytes to activate CREB during adipogenesis and adipose inflammation [#10]; and it binds the myelin-associated glycoprotein MAG to recruit Fyn kinase and transactivate MYRF, promoting oligodendrocyte differentiation and remyelination [#14]. Through NF-\\u03baB activation in endothelial cells, macrophages, and fibroblasts, ANGPTL2 promotes chronic inflammation, monocyte chemotaxis, endothelial dysfunction, and accelerated atherosclerosis [#1, #16, #21]. In cancer it acts in an autocrine/paracrine manner to enhance tumor cell motility, invasion, and metastasis via integrin \\u03b15\\u03b21/p38/MMP signaling, and promotes immune evasion by accelerating PRC2-mediated repression of MHC-I and by generating myeloid-derived suppressor cells [#2, #3, #15, #29]. Its activity is tuned at multiple levels: HIF1A transcriptionally activates ANGPTL2 in a positive feedback loop [#19], promoter CpG methylation represses its expression [#28], CSN5 binding stabilizes the protein by reducing its ubiquitination [#20], and TLL1 protease cleaves ANGPTL2 into inactive fragments [#3]. In the heart, ANGPTL2 has both injurious roles\\u2014inactivating AKT-SERCA2a signaling and activating the NLRP3 inflammasome via DUSP1 suppression\\u2014and protective roles, interacting with and repressing NOX4 to limit oxidative left ventricular dysfunction [#4, #18, #24].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that tumor-cell ANGPTL2 is functionally pro-metastatic and identified its transcriptional upstream regulators, framing it as an autocrine/paracrine driver of cancer aggressiveness.\",\n      \"evidence\": \"In vitro motility/invasion assays with knockdown/overexpression and xenograft models; NFATc/ATF2/c-Jun overexpression\",\n      \"pmids\": [\"22345152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating these tumor cell effects not defined in this study\", \"No structural basis for autocrine signaling\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified LILRB2 as a direct ANGPTL2 receptor and mapped the binding determinants, defining the first molecular receptor interaction and the requirement for ligand multimerization.\",\n      \"evidence\": \"Co-IP, LILRB2 reporter activation assays, domain mutagenesis, ex vivo HSC expansion\",\n      \"pmids\": [\"24899623\", \"35675737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling cascade from LILRB2 not fully resolved here\", \"In vivo relevance of HSC expansion to disease not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated that ANGPTL2 promotes metastasis through integrin \\u03b15\\u03b21/p38/MMP signaling and that TLL1 proteolytic cleavage inactivates it, revealing both a receptor pathway and a regulatory cleavage mechanism.\",\n      \"evidence\": \"Xenograft models, integrin blocking, in vitro TLL1 cleavage assays, overexpression/knockdown\",\n      \"pmids\": [\"24448647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance of TLL1 cleavage not established\", \"Relationship between integrin and LILRB2 signaling unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed that endothelial ANGPTL2 drives proinflammatory NF-\\u03baB signaling and atherosclerosis, linking the ligand to chronic vascular inflammation in vivo.\",\n      \"evidence\": \"Angptl2 KO in ApoE-null mice, Tie2-driven transgenics, bone marrow transplantation, in vitro NF-\\u03baB and chemotaxis assays\",\n      \"pmids\": [\"24526691\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endothelial receptor mediating NF-\\u03baB activation not identified\", \"Whether circulating vs. local ANGPTL2 drives the effect unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Distinguished integrin \\u03b15\\u03b21 (not PirB/LILRB) as the macrophage receptor for ANGPTL2 inflammatory signaling and tied it to antibacterial innate immunity, establishing cell-type-specific receptor usage.\",\n      \"evidence\": \"Angptl2-deficient BMDMs, integrin pathway analysis, Salmonella infection model, NO measurement\",\n      \"pmids\": [\"27402837\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular events downstream of integrin in macrophages not fully mapped\", \"Reconciliation with LILRB2-dependent contexts not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined cardiac ANGPTL2 as a suppressor of AKT-SERCA2a signaling and myocardial energetics, providing a mechanism for stress-induced cardiac dysfunction.\",\n      \"evidence\": \"Cardiac-specific transgenic and KO mice, pressure overload, siRNA knockdown, echocardiography\",\n      \"pmids\": [\"27677409\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cardiac receptor mediating AKT-SERCA2a inactivation unidentified\", \"Direct vs. indirect effect on SERCA2a unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed tissue-protective roles for ANGPTL2, with epithelial/alveolar macrophage-derived ANGPTL2 limiting lung fibrosis, and promoter DNA methylation controlling its expression, broadening the model beyond purely pathogenic signaling.\",\n      \"evidence\": \"Angptl2 KO mice with bleomycin and bone marrow transplant; luciferase assays with methylated promoter and bisulfite pyrosequencing\",\n      \"pmids\": [\"27542805\", \"27101308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ANGPTL2 protects against fibrosis not defined\", \"Single-lab findings for both protection and methylation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed ANGPTL2 from intestinal stromal cells maintains the stem cell niche via BMP/\\u03b2-catenin balance, establishing a homeostatic developmental role in epithelial regeneration.\",\n      \"evidence\": \"Angptl2-deficient mice, intestinal injury model, Lgr5 and \\u03b2-catenin activity assays\",\n      \"pmids\": [\"28043948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor transducing the niche signal not identified\", \"Direct vs. indirect regulation of \\u03b2-catenin unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified CD146 as a third ANGPTL2 receptor on adipocytes acting through CREB, and showed a VPS33B-controlled extracellular vesicle route delivering ANGPTL2 to LILRB2 in leukemia, diversifying both receptor repertoire and delivery mode.\",\n      \"evidence\": \"Co-IP, CD146 KO in adipocytes, anti-CD146 antibody obesity model; Vps33b conditional KO lines and MLL-AF9 AML model with SEV cargo analysis\",\n      \"pmids\": [\"33747748\", \"33108353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CD146 binding not defined\", \"Whether SEV delivery operates in non-leukemic contexts unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined post-translational stabilization of ANGPTL2 by CSN5-mediated deubiquitination, adding protein-level control to its regulation.\",\n      \"evidence\": \"Co-IP and ubiquitination assays with CSN5 gain/loss in thyroid carcinoma cells\",\n      \"pmids\": [\"33508120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase opposing CSN5 not identified\", \"Single-lab, single-tumor-type finding\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a HIF1A-ANGPTL2 positive feedback loop, linking hypoxic stress responses to ANGPTL2 expression in cardiomyocytes.\",\n      \"evidence\": \"Luciferase reporter and ChIP assays, ANGPTL2 and HIF1A knockdown in H9c2 cells, Nrf2/HO-1 analysis\",\n      \"pmids\": [\"34974813\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo confirmation lacking\", \"Single-lab, in vitro only\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified MAG as a novel ANGPTL2 receptor coupling to Fyn kinase and MYRF transactivation, revealing a regenerative role in oligodendrocyte differentiation and remyelination.\",\n      \"evidence\": \"Receptor binding assays, Angptl2-null/Mag-null single and double KO mice, cuprizone demyelination model, phosphorylation and differentiation assays\",\n      \"pmids\": [\"36855057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How MAG binding relates to other ANGPTL2 receptors unknown\", \"Direct vs. co-receptor role of MAG not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected ANGPTL2-integrin \\u03b15\\u03b21 signaling to tumor immune evasion through PRC2-mediated MHC-I repression, extending its cancer role to adaptive immunity.\",\n      \"evidence\": \"ANGPTL2-deficient tubular cells in tRCC model, IFN-\\u03b3-induced MHC-I assays, integrin blocking, CD8+ T-cell cytotoxicity\",\n      \"pmids\": [\"37452654\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between integrin signaling and PRC2 recruitment not mechanistically defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined context-dependent immune and cardiac mechanisms, including DUSP1-suppression-driven NLRP3 inflammasome activation and NF-\\u03baB-driven chemoattractant production, sharpening ANGPTL2's role in inflammatory disease.\",\n      \"evidence\": \"Cardiac AAV overexpression/knockdown with DUSP1 and NLRP3 manipulation in septic cardiomyopathy; ANGPTL2-deficient mice in ICI myocarditis with NF-\\u03baB analysis\",\n      \"pmids\": [\"37531825\", \"37736764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptors upstream of DUSP1 suppression not identified\", \"Single-lab findings\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed an ANGPTL2-NOX4 physical interaction that restrains cardiac oxidative stress, identifying a protective, redox-regulatory function distinct from its inflammatory roles.\",\n      \"evidence\": \"Co-IP in HEK293, ANGPTL2 knockdown mice with AAV9-shRNA NOX4 rescue, echocardiography, H2O2 measurement\",\n      \"pmids\": [\"38426206\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether intracellular vs. secreted ANGPTL2 binds NOX4 unclear\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended ANGPTL2 signaling to metabolic disease, showing adipocyte-secreted ANGPTL2 inhibits renal AKT/ABCG2 signaling to promote hyperuricemia.\",\n      \"evidence\": \"Angptl2 KO and adipocyte-specific overexpression mice, recombinant ANGPTL2 in HK-2/RTEC cells, AKT/ABCG2 analysis, adipose proteomics\",\n      \"pmids\": [\"40180020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Renal receptor for ANGPTL2 not identified\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single secreted ligand selects among integrin \\u03b15\\u03b21, LILRB2, CD146, and MAG to produce opposing pro-inflammatory, pro-tumor, protective, and regenerative outcomes in different tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model of receptor selection\", \"Roles of multimerization, membrane anchoring, and proteolytic cleavage in directing receptor choice not integrated\", \"Conditions favoring protective vs. pathogenic signaling not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 8, 10, 14]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 8, 10, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 2, 11, 27]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 8, 10, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 9, 16, 21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 4, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LILRB2\", \"ITGA5\", \"ITGB1\", \"CD146\", \"MAG\", \"CSN5\", \"NOX4\", \"TLL1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}