{"gene":"ANXA2","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2015,"finding":"ANXA2 directly binds STAT3 and enhances its transcriptional activity, promoting EGF-induced epithelial-mesenchymal transition in breast cancer cells in a STAT3-dependent manner.","method":"Co-immunoprecipitation, knockdown (siRNA), in vitro migration/invasion assays, in vivo metastasis model","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP confirming direct binding, siRNA loss-of-function with specific EMT/metastasis phenotype, in vivo validation, single lab with multiple orthogonal methods","pmids":["26307676"],"is_preprint":false},{"year":2017,"finding":"Phosphorylation of ANXA2 at Tyr23 by SRC kinase drives its nuclear translocation; nuclear phospho-ANXA2(Tyr23) interacts with MYC, inhibiting MYC's ubiquitin-dependent proteasomal degradation, thereby stabilizing MYC which then activates HIF1A transcription and downstream VEGF expression to promote esophageal cancer metastasis.","method":"Co-immunoprecipitation, ubiquitination assay, ChIP, reporter assay, confocal immunofluorescence, siRNA knockdown, in vivo xenograft","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ubiquitination assay, ChIP, reporter, confocal), single lab with rigorous mechanistic dissection","pmids":["30081903"],"is_preprint":false},{"year":2017,"finding":"Tyr23 phosphorylation of ANXA2 is required for its interaction with STAT3 and for enhancing STAT3 sensitivity to IL-6 activation, leading to increased cyclin D1 and MMP2/9 expression and promoting breast cancer cell proliferation and invasion.","method":"Co-immunoprecipitation, phosphomutant constructs (Tyr23), Western blot, in vitro and in vivo functional assays","journal":"Breast cancer research and treatment","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP plus phosphomutant rescue experiments, consistent with prior STAT3 binding data from same group, two orthogonal methods","pmids":["28470457"],"is_preprint":false},{"year":2019,"finding":"RACK1 acts as a scaffold protein that mediates the interaction between SRC kinase and ANXA2, facilitating Src-dependent phosphorylation of ANXA2 at Tyr23, which is required for invasion and metastasis in multidrug-resistant breast cancer cells.","method":"Co-immunoprecipitation, siRNA knockdown, small molecule inhibitors, rescue experiments, in vivo metastasis model","journal":"Breast cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP of RACK1/Src/ANXA2 ternary complex, siRNA knockdown with specific phenotypic readout, in vivo validation, multiple orthogonal methods","pmids":["31113450"],"is_preprint":false},{"year":2021,"finding":"EphA2 activates YES1 kinase, which phosphorylates ANXA2 at Tyr24, leading to ANXA2 activation and increased nuclear localization; reexpression of wild-type but not Tyr24F mutant ANXA2 in ANXA2-KD cells restores YES1-induced invasion and migration in gastric cancer.","method":"Knockdown, overexpression, phosphomutant rescue (Tyr24F), in vitro invasion/migration assays, in vivo tumor growth models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — phosphomutant rescue establishes mechanistic specificity, in vitro and in vivo validation, multiple orthogonal methods in single study","pmids":["33941853"],"is_preprint":false},{"year":2016,"finding":"P-glycoprotein (P-gp) interacts with ANXA2 and promotes invasion of multidrug-resistant breast cancer cells by modulating Src-dependent tyrosine phosphorylation of ANXA2; P-gp also interacts with Src kinase upstream of ANXA2.","method":"Co-immunoprecipitation, co-localization, P-gp inhibitors and MDR1 knockdown, Western blot","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP interaction confirmed, multiple inhibitor approaches, but mechanism linking P-gp activity to ANXA2 phosphorylation is indirect; replicated across two publications from same group","pmids":["27754360","24239898"],"is_preprint":false},{"year":2000,"finding":"The ANXA2/S100A10 (p11) heterotetramer complex structure was modeled by docking algorithms against cryo-electron microscopy projected density maps, revealing that the interaction between the ANXA2 core and p11 is primarily electrostatic in character, stabilized through charged residues.","method":"Computational docking with validation against cryo-EM projected density maps","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — structural modeling with cryo-EM density validation, but computational/modeling approach without mutagenesis confirmation in this paper","pmids":["11108962"],"is_preprint":false},{"year":2018,"finding":"TRIM65 E3 ubiquitin ligase ubiquitinates ANXA2, promoting its degradation and thereby modulating cytoskeleton rearrangement and EMT in bladder cancer cells.","method":"Ubiquitination assay, Co-IP, siRNA knockdown, in vitro and in vivo functional assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ubiquitination assay plus Co-IP confirm the TRIM65-ANXA2 ubiquitination relationship, single lab","pmids":["30075204"],"is_preprint":false},{"year":2022,"finding":"LINC00941 (lncRNA) directly binds the Annexin 1 domain of ANXA2 and acts as a decoy to prevent NEDD4L (E3 ligase) from binding the same domain, thereby suppressing NEDD4L-mediated ubiquitin-proteasomal degradation of ANXA2, leading to ANXA2 stabilization and FAK/AKT signaling activation in pancreatic cancer.","method":"RNA pulldown, mass spectrometry, RIP, Co-IP/MS, knockdown and rescue experiments","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RNA pulldown, mass spectrometry, Co-IP/MS collectively identify binding partners and mechanism; domain mapping and functional rescue experiments provide mechanistic specificity, single lab with multiple orthogonal methods","pmids":["35977942"],"is_preprint":false},{"year":2019,"finding":"Ahnak scaffolds a trimeric complex of Ahnak/p11(S100A10)/ANXA2 in hippocampal neurons; through its N-terminal region Ahnak binds the L-type VGCC pore-forming α1 subunit, and through its C-terminal region it bridges the β subunit and the p11/ANXA2 complex. Ahnak knockout reduces L-type calcium current and channel surface expression, and phenocopies p11 knockout depression-like behavior.","method":"Co-IP, knockout mouse models (constitutive and cell-type-specific), electrophysiology, behavioral assays, fractionation","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP defining ternary complex, multiple conditional KO models with specific cellular and behavioral phenotypes, electrophysiology validation; multiple orthogonal methods","pmids":["30760886"],"is_preprint":false},{"year":2009,"finding":"ANXA2 interacts with HIV-1 Gag at phosphatidylinositol (4,5) bisphosphate-containing lipid raft membrane domains where Gag mediates viral assembly; ANXA2 expression in 293T cells increases Gag processing and HIV-1 production.","method":"Bimolecular fluorescence complementation, overexpression, HIV-1 titer measurement","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — BiFC interaction at specific membrane microdomains, overexpression with viral output phenotype, single lab","pmids":["19325895"],"is_preprint":false},{"year":2015,"finding":"MIEN1 physically interacts with ANXA2 (confirmed by FRET); ITAM-phosphorylated MIEN1 enhances Tyr23 phosphorylation of ANXA2 and stimulates ANXA2 cell-surface translocation, increasing ANXA2 proteolytic activity and tumor cell motility.","method":"FRET, Co-immunoprecipitation, Western blot, wound healing assay, phosphomutant constructs","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET confirms physical interaction, phosphomutant analysis links Tyr23 phosphorylation to cell surface translocation; single lab with orthogonal methods","pmids":["26272794"],"is_preprint":false},{"year":2021,"finding":"ANXA2 interacts with EV71 3D polymerase (RNA-dependent RNA polymerase) via its annexin domain, localizes to viral replication organelles (ROs), and interacts with PI4KB; ANXA2 overexpression stimulates PI4P formation and promotes the PI4KB-3D interaction, facilitating EV71 RNA replication complex assembly and viral replication.","method":"Co-immunoprecipitation, knockout cell lines, confocal localization, PI4P quantification, overexpression","journal":"Virologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP defines interaction network, domain mapping, ANXA2-KO cells confirm functional requirement for PI4P production, single lab","pmids":["34196914"],"is_preprint":false},{"year":2017,"finding":"ANXA2 interacts with influenza NS1 protein in the cell cytoplasm; ANXA2 overexpression significantly increases H5N1 HPAIV titer while siRNA-mediated knockdown inhibits viral protein expression and reduces progeny virus titer.","method":"Co-immunoprecipitation, confocal co-localization, siRNA knockdown, overexpression, viral titer assay","journal":"BMC microbiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and co-localization plus gain/loss-of-function with quantitative viral output, single lab","pmids":["28893180"],"is_preprint":false},{"year":2015,"finding":"ANXA2 depletion inhibits EGF-induced STAT3 phosphorylation and downstream cyclin D1 expression, decelerating G1-to-S phase transition and reducing breast cancer cell proliferation; the effect is mediated through STAT3 as a key transcriptional regulator of cyclin D1.","method":"siRNA knockdown, cell cycle analysis (flow cytometry), Western blot, qRT-PCR","journal":"Breast cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function with cell cycle phenotype and pathway analysis, single lab, consistent with multiple papers on ANXA2-STAT3 axis","pmids":["26253946"],"is_preprint":false},{"year":2012,"finding":"ANXA2 upregulation promotes breast cancer cell proliferation, migration, and invasion by increasing c-myc and cyclin D1 expression via activation of Erk1/2 signaling pathways.","method":"Overexpression, Western blot, in vitro migration/invasion assays, in vivo xenograft","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gain-of-function with defined pathway readout and in vivo validation, single lab","pmids":["22452352"],"is_preprint":false},{"year":2023,"finding":"FBXW10 promotes K63-linked polyubiquitination of ANXA2 in a process requiring S6K1-mediated phosphorylation; K63-ubiquitinated ANXA2 translocates from cytoplasm to cell membrane, binds KRAS, and activates the MEK/ERK pathway to drive hepatocellular carcinoma proliferation and metastasis.","method":"Ubiquitination assays (K63-linkage specific), Co-IP, subcellular fractionation, knockdown, in vitro and in vivo functional assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — K63-specific ubiquitination assay plus membrane translocation and KRAS binding by Co-IP, in vivo validation; single lab","pmids":["37277019"],"is_preprint":false},{"year":2014,"finding":"ERG oncoprotein directly binds the ANXA2 promoter and transcriptionally represses ANXA2 expression; ERG-mediated ANXA2 repression disrupts apical ANXA2 localization, actin bundling at cell-cell junctions, and epithelial cell polarity, promoting EMT through inhibition of CDC42/RHOA and cofilin activation.","method":"ERG siRNA, ChIP defining promoter binding, immunofluorescence for apical ANXA2 localization, gain- and loss-of-function, immunohistochemistry","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms ERG promoter binding for transcriptional repression, localization studies with functional consequences; single lab, multiple methods","pmids":["25344575"],"is_preprint":false},{"year":2018,"finding":"ANXA2 knockdown in obesity-induced insulin-resistant cells inhibits NF-κB p50 nuclear translocation, reduces pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) and SOCS3, and restores insulin signaling (IRS1 phosphorylation, glucose uptake), placing ANXA2 upstream of NF-κB in obesity-induced insulin resistance.","method":"siRNA knockdown in palmitic acid-induced IR cell model, high-fat diet mouse model, glucose tolerance test, Western blot, flow cytometry","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function with specific metabolic and signaling phenotypes in both cell and mouse models, single lab","pmids":["30462534"],"is_preprint":false},{"year":2019,"finding":"S100A11 interacts with ANXA2 and decreases ubiquitination and proteasomal degradation of ANXA2; this stabilizes ANXA2 which activates NF-κB signaling; NF-κB in turn transcriptionally activates S100A11, forming a positive feedback loop that promotes GBM progression.","method":"Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, in vivo orthotopic xenograft","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirms S100A11-ANXA2 interaction, ubiquitination assay supports mechanistic model, in vivo validation; single lab","pmids":["31430050"],"is_preprint":false},{"year":2022,"finding":"p-STAT3 (phospho-STAT3) binds to the Anxa2 promoter and drives its transcription; elevated ANXA2 then promotes caspase-1-mediated hepatocyte pyroptosis and fibrosis in non-alcoholic steatohepatitis; inhibition of p-STAT3 suppresses pyroptosis which is rescued by ANXA2 overexpression.","method":"ChIP-seq, ChIP-qPCR, promoter reporter assay, siRNA knockdown, overexpression, NASH mouse model, in vitro NASH model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms transcription factor binding to promoter, rescue experiments establish pathway order; single lab, multiple orthogonal methods","pmids":["36324154"],"is_preprint":false},{"year":2024,"finding":"DBT (dihydrolipoamide branched chain transacylase E2) interacts with ANXA2 via its lipoyl-binding domain; the DBT-ANXA2 interaction activates Hippo signaling, decreasing nuclear YAP localization and repressing transcription of lipogenic genes in clear cell renal cell carcinoma.","method":"Co-immunoprecipitation, mass spectrometry, mutational studies, luciferase reporter assay, subcellular fractionation, in vitro and in vivo functional assays","journal":"Cancer communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain-mapping mutagenesis, reporter assay and YAP localization readout; single lab with multiple orthogonal methods","pmids":["36860124"],"is_preprint":false},{"year":2022,"finding":"USP4 deubiquitinase interacts with ANXA2, cleaving Lys48- and Lys63-linked polyubiquitin chains; Lys63-linked ubiquitination of ANXA2 at K28 specifically mediates Y24 phosphorylation; K10 acetylation of ANXA2 enhances its interaction with USP4. USP4-stabilized ANXA2 promotes GSC maintenance and radioresistance through BMX-mediated STAT3 activation.","method":"Co-IP, ubiquitination assays (linkage-specific), acetylation mutant constructs, phosphomutant (Y24), knockdown, in vivo models","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple PTM-specific assays (ubiquitination, acetylation, phosphorylation) with defined mechanistic connections, single lab","pmids":["40185997"],"is_preprint":false},{"year":2024,"finding":"HDAC9 interacts with ANXA2 (identified by IP-MS) and deacetylates it; this interaction inhibits ubiquitinated ANXA2 degradation, stabilizing ANXA2 and mediating depression-like behavior; HDAC9 knockdown/knockout in hippocampal neurons alleviates depression phenotypes.","method":"Immunoprecipitation-mass spectrometry, Co-IP, HDAC9 knockdown/knockout mouse model, behavioral assays","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS identifies interaction and deacetylation, in vivo behavioral phenotype with KO confirmation; single lab","pmids":["37690046"],"is_preprint":false},{"year":2018,"finding":"LUCAT1 lncRNA inhibits phosphorylation of ANXA2, which reduces degradation of the ANXA2-S100A10 heterotetramer (AIIt), resulting in accelerated conversion of plasminogen to plasmin and activation of metalloprotease proteins in hepatocellular carcinoma.","method":"RNA pulldown, Western blot, loss/gain-of-function experiments","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RNA pulldown confirms LUCAT1-ANXA2 interaction, Western blot tracks phosphorylation state and downstream plasmin pathway; single lab","pmids":["30588744"],"is_preprint":false},{"year":2024,"finding":"ANXA2 upregulates phosphorylation of HSF1, leading to transcriptional activation of ATG7; MTORC2 is required for ANXA2-mediated ATG7 transcription by HSF1 and contributes to ANXA2 protein stability; HSPA (Hsp70) interacts with ANXA2 and may protect it from lysosomal proteolysis. ANXA2-driven autophagy contributes to TNBC tumor aggressiveness.","method":"Bafilomycin A1 autophagic flux assay, ChIP, Western blot, Co-IP for ANXA2-HSPA interaction, siRNA knockdown, in vivo xenograft","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms transcriptional activation mechanism, autophagic flux assay validates functional output, Co-IP for binding; single lab, multiple methods","pmids":["38290972"],"is_preprint":false},{"year":2024,"finding":"Hspb1 directly interacts with Anxa2, decreasing Anxa2 aggregation and phosphorylation; Hspb1 also uses Anxa2 as an intermediary to interact with and maintain the antioxidative activity of Prdx1 by reducing Thr-90 phosphorylation of Prdx1; Hspb1 overexpression did not protect acinar-specific Prdx1-KO mice, establishing the Hspb1/Anxa2/Prdx1 axis for ROS control in acute pancreatitis.","method":"Co-IP, Hspb1 KO and Anxa2 KO mice, AAV8-Hspb1 overexpression, acinar-specific Prdx1 KO mice, ROS measurements, phosphorylation analysis","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple KO mouse models establish epistasis, Co-IP identifies direct interactions, genetic rescue (AAV8-Hspb1) and Prdx1-KO epistasis rigorously validate the three-protein axis","pmids":["38481805"],"is_preprint":false},{"year":2017,"finding":"SMN depletion reduces axonal transport of ANXA2 mRNA in motor neuron-like cells; a G-rich motif near the 3'UTR of Anxa2 mRNA is required for its axonal localization; mutations in this motif abolish targeting of Anxa2 reporter mRNAs to axon-like structures in SMN-sufficient cells, and localization is restricted to cell body in SMN-depleted cells.","method":"SMN depletion, reporter mRNA localization assays, site-directed mutagenesis of 3'UTR G-rich motif, fluorescence imaging in differentiated NSC-34 cells","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of cis-acting element confirms necessity for axonal localization; SMN depletion epistasis links localization to SMN complex; single lab, two orthogonal approaches","pmids":["28258160"],"is_preprint":false},{"year":2022,"finding":"ANXA2 knockdown in renal tubular epithelial cells globally alters transcription and alternative splicing of inflammatory response genes, including chemokine CCL5, interferon-regulating genes (ISG15, IFI6, IFI44, IFITM1, IRF7), and alternative splicing of UBA52, RBCK1, and LITAF, indicating ANXA2 regulates inflammatory signaling at the level of gene expression and RNA processing.","method":"RNA-sequencing of ANXA2-knockdown HK2 cells, qRT-PCR validation, bioinformatics pathway analysis","journal":"BMC genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — transcriptomic loss-of-function identifies specific downstream genes and pathways; single lab, two methods (RNA-seq + qRT-PCR validation)","pmids":["35906541"],"is_preprint":false},{"year":2021,"finding":"The ANXA2/S100A10 heterotetramer (AIIt) functions as a cell surface plasminogen receptor that both promotes plasmin formation at the cell surface and regulates plasmin destruction; AIIt is activated by oncogenes including SRC, RAS, HIF1α, and PML-RAR and is epigenetically regulated by DNA methylation.","method":"Review synthesizing biochemical reconstitution, Co-IP, and genetic studies from multiple labs (cited primary literature)","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — established from multiple primary experiments across labs as summarized; review paper itself does not add new experiments, but underlying evidence is strong","pmids":["34944416"],"is_preprint":false},{"year":2022,"finding":"FOXD1 transcriptionally induces RalA expression; RalA forms a complex with ANXA2 and Src, enhancing the ANXA2-Src interaction and increasing Tyr23 phosphorylation of ANXA2, which activates ERK1/2 signaling to promote circulating tumor cell formation and breast cancer metastasis; inhibiting RalA-GTP form attenuates ANXA2-Src interaction.","method":"GST-pulldown, Co-IP, ChIP-seq, CUT&Tag-seq, in vivo CTC models, ERK1/2 inhibitor treatment","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GST-pulldown and Co-IP define the RalA-ANXA2-Src complex; ChIP establishes FOXD1-RalA transcriptional link; in vivo CTC validation; single lab with multiple methods","pmids":["36229838"],"is_preprint":false},{"year":2024,"finding":"PFN1 (profilin-1) interacts with phospho-ANXA2 by recruiting Src kinase to phosphorylate ANXA2, which promotes STAT3 phosphorylation and transcriptional activity, driving VSMC phenotype switching and neointimal hyperplasia.","method":"Co-IP, single-cell RNA sequencing, SMC-specific PFN1 knockout mice, Western blot, wire-injury neointimal hyperplasia model","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP defines PFN1-ANXA2-Src complex, SMC-specific KO with defined phenotype; single lab, multiple orthogonal methods","pmids":["39508106"],"is_preprint":false},{"year":2024,"finding":"ADAM8 metalloproteinase binds ANXA2 and promotes phosphorylation of ANXA2 at Ser26; ADAM8 knockout impedes ANXA2 Ser26 phosphorylation, which in turn inhibits mTOR Ser2448 phosphorylation and activates autophagy in macrophages, promoting cardiac repair after myocardial infarction.","method":"COIP/mass spectrometry, macrophage-specific ADAM8 KO mice, AAV6-overexpression, phosphorylation analysis, autophagy markers","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — COIP/MS identifies direct ADAM8-ANXA2 binding, KO mice establish in vivo epistasis through defined phosphorylation-autophagy axis; single lab","pmids":["39097092"],"is_preprint":false},{"year":2021,"finding":"The S100A10/ANXA2 complex facilitates exocytosis of HBV virions across trophoblast cells; HBV virions co-localize with S100A10/ANXA2 and the autophagosome marker LC3; knockdown of either AnxA2 or S100A10 reduces the amount of exo-virus in Transwell assays.","method":"Co-localization (confocal), knockdown, Transwell exocytosis assay, immunohistochemistry of placental tissues","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function for both complex partners with quantitative exocytosis readout; co-localization with functional validation; single lab","pmids":["34645932"],"is_preprint":false},{"year":2024,"finding":"ANXA2 mediates endocytosis of microplastics into breast cancer cells; once internalized, MPs bound to ANXA2 regulate mitophagy by inhibiting IL-17 exocytosis, causing mitochondrial damage.","method":"MPs pulldown experiments, mass spectrometry, endocytosis/mitophagy assays, Western blot","journal":"Environmental pollution","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pulldown/MS identifies ANXA2-MP binding but the downstream mechanism (ANXA2-IL-17-mitophagy) is supported only by correlative data in a single study","pmids":["39557355"],"is_preprint":false},{"year":2017,"finding":"ANXA2 promotes LDL receptor availability and thereby regulates LDL-C levels by serving as an endogenous inhibitor of PCSK9; the ANXA2 repeat-1 (R1) domain binds PCSK9 and blocks its ability to promote LDL-R degradation; the coding SNP V98L in ANXA2-R1 is associated with higher LDL-C and CHD risk.","method":"SNP genotype-phenotype association, allele-specific protein binding assay, reporter gene assay, eQTL analysis in human cohorts","journal":"Atherosclerosis","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — allele-specific binding assay and reporter gene assay establish functional SNP effects on ANXA2 expression; LDL-C association replicated in two independent cohorts; mechanistic claim of ANXA2-R1 binding PCSK9 based on prior mouse-model literature","pmids":["28456096"],"is_preprint":false},{"year":2019,"finding":"HE4 interacts with ANXA2 and MMP2 to form a trimeric HE4-ANXA2-MMP2 protein complex; ANXA2 acts as a bridge mediating HE4 regulation of MMP2 expression and promoting cancer cell migration.","method":"Co-immunoprecipitation, double-labeling immunofluorescence, siRNA knockdown, migration/invasion assays","journal":"Cancer cell international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and co-localization identify the complex but the mechanistic link between HE4-ANXA2-MMP2 is not deeply dissected; single lab, single method (Co-IP)","pmids":["31210752"],"is_preprint":false},{"year":2021,"finding":"FLNA (filamin A) interacts with ANXA2 (confirmed by Co-IP) and together they activate the Wnt/β-catenin pathway, contributing to gefitinib resistance in NSCLC; SP1 transcriptionally activates FLNA to regulate this resistance pathway.","method":"Co-immunoprecipitation, ChIP for SP1-FLNA promoter binding, siRNA knockdown, overexpression, in vivo mouse models","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and ChIP establish the interaction and upstream regulation, in vivo validation; single lab","pmids":["34018148"],"is_preprint":false},{"year":2022,"finding":"SRF (serum response factor) transcription factor binds the ANXA2 promoter and represses its expression; ANXA2 activates NF-κB signaling by inducing nuclear translocation of p50; thus SRF-mediated repression of ANXA2 protects against pancreatitis-associated NF-κB activation.","method":"Dual luciferase reporter assay, ChIP, Co-IP, siRNA knockdown, in vivo AP mouse model","journal":"Inflammation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms SRF promoter binding, Co-IP confirms molecular interactions, in vivo disease model validation; single lab with multiple methods","pmids":["35900381"],"is_preprint":false},{"year":2024,"finding":"MOF histone acetyltransferase (KAT8), stabilized by USP10 deubiquitination at K410, promotes H4K16 acetylation at the ANXA2 promoter in a JUN-dependent manner to transcriptionally activate ANXA2, which subsequently activates Wnt/β-catenin signaling to drive ESCC progression; catalytically inactive MOF fails to promote ANXA2 transcription.","method":"ChIP-seq, Co-IP, siRNA/overexpression with catalytic mutant (MOF-E350Q), in vitro and in vivo functional assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq establishes H4K16ac enrichment at ANXA2 promoter, catalytic mutant confirms acetyltransferase dependence, Co-IP for USP10-MOF interaction; single lab, multiple orthogonal methods","pmids":["38317006"],"is_preprint":false},{"year":2025,"finding":"USP10 nuclear expression increases upon oxaliplatin treatment, binds XAB2, and deubiquitinates K48-linked polyubiquitination at K593 of XAB2 to stabilize it; XAB2 then binds the ANXA2 promoter (by ChIP) to transcriptionally upregulate ANXA2, promoting DNA damage repair and oxaliplatin resistance in CRC.","method":"Co-IP, mass spectrometry for ubiquitination sites, ChIP-seq, ChIP-qPCR, dual-luciferase reporter, ubiquitin assay, functional assays","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR and reporter assay establish XAB2-ANXA2 transcriptional regulation; ubiquitination site MS identifies K593; single lab with multiple orthogonal methods","pmids":["40069750"],"is_preprint":false},{"year":2024,"finding":"m7G-modified tsRNA (mtiRL), catalyzed by METTL1, specifically binds ANXA2 and promotes its Tyr24 phosphorylation by enhancing the interaction between ANXA2 and YES1 kinase, leading to increased nuclear localization of p-ANXA2-Y24 and bladder cancer malignancy.","method":"RNA-protein binding assays, small RNA sequencing, m7G modification chip, Co-IP for ANXA2-YES1 interaction, knockdown/overexpression, in vitro and in vivo models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-protein binding and Co-IP establish mechanism, m7G modification confirmed biochemically, in vivo validation; single lab with multiple methods","pmids":["38894581"],"is_preprint":false},{"year":2023,"finding":"NINJ1 competitively binds ANXA2, an inhibitory interacting protein of TLR4, thereby blocking the ANXA2-TLR4 interaction and activating TLR4 signaling; macrophage-specific NINJ1 deficiency inhibits AAA formation and reduces macrophage infiltration via the TLR4/NF-κB/CCR2 pathway.","method":"Protein-protein interaction analysis, Co-IP, macrophage-specific KO mice (Ninj1flox/flox Lyz2-Cre), RNA-sequencing, in vitro and in vivo functional assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and competitive binding establish NINJ1-ANXA2-TLR4 relationship, conditional KO mice with specific macrophage phenotype; single lab","pmids":["38922800"],"is_preprint":false},{"year":2024,"finding":"ANXA2 promotes TIM-4-induced mitochondrial fusion by interacting with TIM-4 to promote PI3K/AKT pathway activation, which increases L-OPA1 protein expression and oxidative phosphorylation in lung cancer cells.","method":"Co-IP, siRNA knockdown, PI3K inhibitor treatment, Western blot for OPA1/mitochondrial fusion markers, proliferation assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP confirms TIM-4-ANXA2 interaction, pharmacological and genetic perturbations define signaling axis; single lab","pmids":["36806050"],"is_preprint":false},{"year":2024,"finding":"ANXA2 promotes GBM progression by activating BMX-mediated STAT3 activation; USP4-mediated stabilization of ANXA2 (through deubiquitination) and its K10 acetylation enhance this pathway to support GSC maintenance and radioresistance.","method":"Co-IP, knockdown, overexpression, GSC functional assays, in vivo models (cited in same paper as USP4 findings)","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and functional assays, but the specific BMX-STAT3 link downstream of ANXA2 lacks deep mechanistic dissection; single lab","pmids":["40185997"],"is_preprint":false},{"year":2015,"finding":"ANXA2 knockdown in prostate epithelial cells (via ERG siRNA) enhances apical ANXA2 localization, promotes bundling of actin filaments at cell-cell junctions, and maintains epithelial polarity; conversely, ERG-driven transcriptional repression of ANXA2 disrupts ANXA2-mediated polarity by inhibiting CDC42 and RHOA and activating cofilin, promoting EMT.","method":"ERG siRNA, immunofluorescence for apical ANXA2 localization and actin, Western blot for CDC42/RHOA/cofilin, ChIP for ERG promoter binding","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization experiments directly linked to functional polarity consequences, ChIP establishes upstream transcriptional mechanism; single lab","pmids":["25344575"],"is_preprint":false},{"year":2024,"finding":"Exosomal ANXA2 secreted by ovarian cancer cells binds TLR2 on human peritoneal mesothelial cells (HPMCs), activating HPMCs and shifting their phenotype toward mesenchymal cells, increasing LCN2 expression, which in turn promotes ovarian cancer cell adhesion, proliferation, motility, and lipid metabolism reprogramming.","method":"ANXA2 inhibitor (LCKLSL) and TLR2 inhibitor (C29) co-culture experiments, RNA-seq of HPMCs, Co-IP, in vivo OvCa xenograft models","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — ligand-receptor interaction supported by inhibitor rescue experiments and transcriptomic output; in vivo validation; single lab","pmids":["39709496"],"is_preprint":false},{"year":2021,"finding":"ANXA2 knockdown in acute pancreatitis model cells reduces NF-κB activation (p50 nuclear translocation), inflammation, and apoptosis; the ANXA2 promoter is bound and repressed by SRF, and ANXA2 directly interacts with the NF-κB pathway.","method":"siRNA knockdown, AP model (cerulein/LPS), dual luciferase reporter, ChIP, Co-IP, flow cytometry","journal":"Inflammation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms SRF binding to ANXA2 promoter, Co-IP identifies ANXA2 interactions in NF-κB pathway, functional assays in disease model; single lab","pmids":["35900381"],"is_preprint":false}],"current_model":"ANXA2 is a calcium-dependent phospholipid-binding protein that functions as a multifunctional signaling scaffold: its Tyr23/Tyr24 phosphorylation by SRC (or YES1/MIEN1) drives nuclear translocation and enhanced interactions with partners including STAT3, MYC, and KRAS to promote proliferation and invasion; at the cell surface it forms the ANXA2/S100A10 (AIIt) heterotetramer that serves as an oncogenic plasminogen receptor, while RACK1 and RalA organize a ternary complex with Src to amplify phosphorylation; its stability is regulated by competing ubiquitination (by NEDD4L, TRIM65, TRIM21; reversed by USP4, USP10, NUSAP1) and deacetylation (HDAC9), and its transcription is activated by p-STAT3/ERG repression axis; in neurons, Ahnak scaffolds the ANXA2/p11 complex to the L-type voltage-gated calcium channel, linking ANXA2 to calcium signaling and depressive behavior."},"narrative":{"mechanistic_narrative":"ANXA2 is a calcium- and phospholipid-binding scaffold protein that integrates membrane biology, tyrosine-kinase signaling, and transcriptional control to drive cell proliferation, migration, invasion, and inflammatory responses [PMID:30081903, PMID:34944416]. Its central regulatory event is tyrosine phosphorylation in its N-terminal tail (Tyr23/Tyr24) by Src-family kinases, which is organized by scaffolds and adaptors: RACK1 bridges Src to ANXA2 [PMID:31113450], FOXD1-induced RalA forms a ternary RalA/ANXA2/Src complex that amplifies Tyr23 phosphorylation and ERK1/2 signaling [PMID:36229838], and PFN1 recruits Src to phosphorylate ANXA2 [PMID:39508106]; EphA2-activated YES1 phosphorylates Tyr24 [PMID:33941853], and MIEN1 further promotes Tyr23 phosphorylation and cell-surface translocation [PMID:26272794]. Phosphorylation drives nuclear translocation, where ANXA2 binds STAT3 to enhance IL-6/EGF-responsive transcription of cyclin D1 and MMP2/9 [PMID:26307676, PMID:28470457, PMID:26253946], and binds and stabilizes MYC to activate HIF1A/VEGF [PMID:30081903]; ANXA2 also engages KRAS at the membrane to activate MEK/ERK [PMID:37277019] and promotes Wnt/β-catenin signaling [PMID:38317006]. At the cell surface ANXA2 forms the ANXA2/S100A10 (p11) heterotetramer (AIIt), an electrostatically stabilized complex [PMID:11108962] that acts as a plasminogen receptor regulating plasmin generation [PMID:30588744, PMID:34944416]. ANXA2 abundance is set by competing post-translational modification: ubiquitination by TRIM65, NEDD4L, and FBXW10 (the latter K63-linked, driving membrane translocation) [PMID:30075204, PMID:35977942, PMID:37277019], opposed by USP4-mediated deubiquitination, acetylation, and the S100A11 stabilizing interaction [PMID:31430050, PMID:40185997]; deacetylation by HDAC9 and chaperone binding (HSPA, HSPB1) further tune stability and aggregation [PMID:37690046, PMID:38481805]. ANXA2 transcription is itself a regulatory node, repressed by ERG and SRF [PMID:25344575, PMID:35900381] and activated by p-STAT3, MOF/JUN-driven H4K16 acetylation, and XAB2 [PMID:36324154, PMID:38317006, PMID:40069750]. Beyond cancer, ANXA2 acts upstream of NF-κB in inflammation and insulin resistance [PMID:30462534, PMID:35900381], serves as a hijacked host factor for assembly/replication of HIV-1, EV71, influenza, and HBV [PMID:19325895, PMID:34196914, PMID:28893180, PMID:34645932], and in neurons is scaffolded by Ahnak into a p11/ANXA2 complex coupled to L-type voltage-gated calcium channels, linking it to calcium signaling and depression-like behavior [PMID:30760886, PMID:37690046].","teleology":[{"year":2000,"claim":"Established the molecular architecture of the ANXA2/p11 heterotetramer, defining how ANXA2 assembles its cell-surface complex.","evidence":"Computational docking validated against cryo-EM projected density maps","pmids":["11108962"],"confidence":"Medium","gaps":["No mutagenesis confirmation of the electrostatic interface in this work","Does not address functional consequences of complex assembly"]},{"year":2012,"claim":"Linked ANXA2 abundance to a proliferative/invasive program, showing it raises c-myc and cyclin D1 via ERK1/2.","evidence":"Overexpression with pathway readout and xenograft validation in breast cancer cells","pmids":["22452352"],"confidence":"Medium","gaps":["Mechanism connecting ANXA2 to ERK activation not resolved","Direct binding partners not identified"]},{"year":2015,"claim":"Identified the ANXA2-STAT3 axis as a direct transcriptional mechanism driving EMT and G1/S progression, moving ANXA2 from membrane protein to nuclear transcriptional co-regulator.","evidence":"Reciprocal Co-IP, siRNA loss-of-function, cell-cycle analysis, and in vivo metastasis models","pmids":["26307676","26253946"],"confidence":"High","gaps":["Did not establish phosphorylation requirement for STAT3 binding","Structural basis of ANXA2-STAT3 interaction unknown"]},{"year":2014,"claim":"Defined ANXA2 as a transcriptionally repressed target of ERG that maintains epithelial polarity, establishing its cytoskeletal/junctional role and an upstream transcriptional control point.","evidence":"ERG ChIP, promoter binding, immunofluorescence for apical localization and actin, CDC42/RHOA/cofilin analysis","pmids":["25344575"],"confidence":"Medium","gaps":["Direct ANXA2 effect on Rho GTPases not biochemically dissected","Single lab"]},{"year":2017,"claim":"Identified Src/YES1-mediated Tyr23/Tyr24 phosphorylation as the switch controlling ANXA2 nuclear translocation and partner engagement, mechanistically connecting kinase input to MYC stabilization and STAT3 sensitization.","evidence":"Phosphomutant constructs, Co-IP, ubiquitination assays, ChIP, reporter assays, xenografts across esophageal and breast cancer","pmids":["30081903","28470457"],"confidence":"High","gaps":["Tyr23 vs Tyr24 functional distinction not fully separated","How phosphorylation alters nuclear import machinery unknown"]},{"year":2019,"claim":"Resolved how Src is delivered to ANXA2, identifying RACK1 as the scaffold mediating Src-dependent Tyr23 phosphorylation required for invasion.","evidence":"Reciprocal Co-IP of the RACK1/Src/ANXA2 ternary complex, siRNA, inhibitors, rescue, in vivo metastasis","pmids":["31113450"],"confidence":"High","gaps":["Whether RACK1 acts in all ANXA2-phosphorylating contexts unknown","Stoichiometry of the complex not defined"]},{"year":2019,"claim":"Established Ahnak as the neuronal scaffold organizing the p11/ANXA2 complex onto the L-type VGCC, linking ANXA2 to calcium currents and depression-like behavior.","evidence":"Co-IP, conditional knockout mice, electrophysiology, behavioral assays","pmids":["30760886"],"confidence":"High","gaps":["Direct contribution of ANXA2 itself (vs p11/Ahnak) to channel regulation not isolated","Calcium-binding requirement not tested"]},{"year":2021,"claim":"Extended the kinase-input map by showing EphA2-activated YES1 phosphorylates ANXA2 at Tyr24 to drive nuclear localization and invasion, and confirmed AIIt as an oncogene-regulated plasminogen receptor.","evidence":"Phosphomutant (Tyr24F) rescue, knockdown/overexpression, in vivo models; biochemical review of AIIt plasminogen activity","pmids":["33941853","34944416"],"confidence":"High","gaps":["Crosstalk between Tyr23 and Tyr24 phosphorylation pathways unresolved","AIIt review does not add new primary data"]},{"year":2022,"claim":"Demonstrated that ANXA2 stability is governed by competing ubiquitination and that ncRNAs and adaptors tune this, with LINC00941 acting as a NEDD4L decoy and RalA amplifying Src phosphorylation.","evidence":"RNA pulldown/MS, domain-mapped Co-IP, GST-pulldown, ChIP-seq, in vivo CTC models","pmids":["35977942","36229838"],"confidence":"High","gaps":["Hierarchy among competing E3 ligases unknown","Ubiquitination site mapping incomplete in some cases"]},{"year":2022,"claim":"Positioned ANXA2 transcription as a tunable node, repressed by SRF and activated by p-STAT3, coupling it to NF-κB-driven inflammation, pyroptosis, and fibrosis.","evidence":"ChIP/ChIP-seq, reporter assays, Co-IP, knockdown, disease mouse models (pancreatitis, NASH)","pmids":["35900381","36324154","30462534"],"confidence":"Medium","gaps":["Direct biochemical link between ANXA2 and p50 nuclear translocation not defined","Tissue specificity of regulation unclear"]},{"year":2024,"claim":"Defined an additional ubiquitin/acetylation/chaperone layer—USP4, HDAC9, HSPB1, HSPA, MOF/USP10—that controls ANXA2 stability, aggregation, and downstream STAT3/BMX, autophagy, and redox outputs.","evidence":"Linkage-specific ubiquitination assays, IP-MS, acetylation/phospho mutants, multiple KO mouse models, ChIP-seq","pmids":["40185997","37690046","38481805","38290972","38317006"],"confidence":"High","gaps":["Integration of multiple PTMs into a unified regulatory logic not established","Many axes characterized in single labs/single disease contexts"]},{"year":2024,"claim":"Broadened ANXA2's functional reach to receptor-coupled signaling (TIM-4/PI3K-AKT, NINJ1/TLR4, exosomal ANXA2/TLR2) and host-pathogen biology across multiple viruses.","evidence":"Co-IP/MS, competitive binding, conditional KO mice, inhibitor co-culture, viral titer and replication assays","pmids":["36806050","38922800","39709496","34196914","28893180","34645932","19325895"],"confidence":"Medium","gaps":["Whether membrane vs nuclear vs surface ANXA2 pools mediate these distinct functions not delineated","Several interactions rest on single-lab Co-IP"]},{"year":null,"claim":"How the calcium/phospholipid-binding biochemistry of ANXA2 is mechanistically coupled to its phosphorylation-dependent nuclear and surface functions, and how competing PTMs are prioritized in a given cell, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model linking membrane binding to nuclear translocation","No reconstitution of the full PTM-stability network","Relative contributions of monomeric ANXA2 vs AIIt heterotetramer in each phenotype undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[6,10,12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3,30,36]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[35,42]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[10,12,13]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[12,27,41]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[10,16,29,11]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,4,41]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[13,16]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[17,45]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,16,30,31]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,2,20]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[18,42,47]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7,8,16,22]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[25,32]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,12,13,33]}],"complexes":["ANXA2/S100A10 (p11) heterotetramer (AIIt)","Ahnak/p11/ANXA2 neuronal complex","RACK1/Src/ANXA2 complex","RalA/ANXA2/Src complex"],"partners":["STAT3","MYC","S100A10","SRC","RACK1","RALA","KRAS","AHNAK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P07355","full_name":"Annexin A2","aliases":["Annexin II","Annexin-2","Calpactin I heavy chain","Calpactin-1 heavy chain","Chromobindin-8","Lipocortin II","Placental anticoagulant protein IV","PAP-IV","Protein I","p36"],"length_aa":339,"mass_kda":38.6,"function":"Calcium-regulated membrane-binding protein whose affinity for calcium is greatly enhanced by anionic phospholipids. It binds two calcium ions with high affinity. May be involved in heat-stress response. Inhibits PCSK9-enhanced LDLR degradation, probably reduces PCSK9 protein levels via a translational mechanism but also competes with LDLR for binding with PCSK9 (PubMed:18799458, PubMed:22848640, PubMed:24808179). Binds to endosomes damaged by phagocytosis of particulate wear debris and participates in endosomal membrane stabilization, thereby limiting NLRP3 inflammasome activation (By similarity). Required for endothelial cell surface plasmin generation and may support fibrinolytic surveillance and neoangiogenesis (By similarity) (Microbial infection) Binds M.pneumoniae CARDS toxin, probably serves as one receptor for this pathogen. When ANXA2 is down-regulated by siRNA, less toxin binds to human cells and less vacuolization (a symptom of M.pneumoniae infection) is seen","subcellular_location":"Secreted, extracellular space, extracellular matrix, basement membrane; Melanosome","url":"https://www.uniprot.org/uniprotkb/P07355/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ANXA2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ANXA2","total_profiled":1310},"omim":[{"mim_id":"620665","title":"PLECKSTRIN HOMOLOGY DOMAIN- AND RhoGEF DOMAIN-CONTAINING PROTEIN G4B; PLEKHG4B","url":"https://www.omim.org/entry/620665"},{"mim_id":"611296","title":"ANNEXIN A2 RECEPTOR; ANXA2R","url":"https://www.omim.org/entry/611296"},{"mim_id":"605019","title":"HYPOBETALIPOPROTEINEMIA, FAMILIAL, 2; FHBL2","url":"https://www.omim.org/entry/605019"},{"mim_id":"603257","title":"SWI/SNF-RELATED, MATRIX-ASSOCIATED, ACTIN-DEPENDENT REGULATOR OF CHROMATIN, SUBFAMILY A, MEMBER 3; SMARCA3","url":"https://www.omim.org/entry/603257"},{"mim_id":"603009","title":"DYSFERLIN; DYSF","url":"https://www.omim.org/entry/603009"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"esophagus","ntpm":1962.5}],"url":"https://www.proteinatlas.org/search/ANXA2"},"hgnc":{"alias_symbol":["LIP2"],"prev_symbol":["ANX2","ANX2L4","CAL1H","LPC2D"]},"alphafold":{"accession":"P07355","domains":[{"cath_id":"1.10.220.10","chopping":"105-175","consensus_level":"medium","plddt":97.6331,"start":105,"end":175},{"cath_id":"1.10.220.10","chopping":"187-249","consensus_level":"high","plddt":98.0154,"start":187,"end":249},{"cath_id":"1.10.220.10","chopping":"265-323","consensus_level":"high","plddt":97.4861,"start":265,"end":323}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P07355","model_url":"https://alphafold.ebi.ac.uk/files/AF-P07355-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P07355-F1-predicted_aligned_error_v6.png","plddt_mean":94.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANXA2","jax_strain_url":"https://www.jax.org/strain/search?query=ANXA2"},"sequence":{"accession":"P07355","fasta_url":"https://rest.uniprot.org/uniprotkb/P07355.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P07355/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P07355"}},"corpus_meta":[{"pmid":"28947421","id":"PMC_28947421","title":"Mesenchymal Stem Cells Promote Hepatocarcinogenesis via lncRNA-MUF Interaction with ANXA2 and miR-34a.","date":"2017","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/28947421","citation_count":208,"is_preprint":false},{"pmid":"29253515","id":"PMC_29253515","title":"Cancer-associated fibroblasts promote epithelial-mesenchymal transition and EGFR-TKI resistance of non-small cell lung cancers via HGF/IGF-1/ANXA2 signaling.","date":"2017","source":"Biochimica et biophysica acta. 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nuclear phospho-ANXA2(Tyr23) interacts with MYC, inhibiting MYC's ubiquitin-dependent proteasomal degradation, thereby stabilizing MYC which then activates HIF1A transcription and downstream VEGF expression to promote esophageal cancer metastasis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, ChIP, reporter assay, confocal immunofluorescence, siRNA knockdown, in vivo xenograft\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ubiquitination assay, ChIP, reporter, confocal), single lab with rigorous mechanistic dissection\",\n      \"pmids\": [\"30081903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Tyr23 phosphorylation of ANXA2 is required for its interaction with STAT3 and for enhancing STAT3 sensitivity to IL-6 activation, leading to increased cyclin D1 and MMP2/9 expression and promoting breast cancer cell proliferation and invasion.\",\n      \"method\": \"Co-immunoprecipitation, phosphomutant constructs (Tyr23), Western blot, in vitro and in vivo functional assays\",\n      \"journal\": \"Breast cancer research and treatment\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus phosphomutant rescue experiments, consistent with prior STAT3 binding data from same group, two orthogonal methods\",\n      \"pmids\": [\"28470457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RACK1 acts as a scaffold protein that mediates the interaction between SRC kinase and ANXA2, facilitating Src-dependent phosphorylation of ANXA2 at Tyr23, which is required for invasion and metastasis in multidrug-resistant breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, small molecule inhibitors, rescue experiments, in vivo metastasis model\",\n      \"journal\": \"Breast cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP of RACK1/Src/ANXA2 ternary complex, siRNA knockdown with specific phenotypic readout, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"31113450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EphA2 activates YES1 kinase, which phosphorylates ANXA2 at Tyr24, leading to ANXA2 activation and increased nuclear localization; reexpression of wild-type but not Tyr24F mutant ANXA2 in ANXA2-KD cells restores YES1-induced invasion and migration in gastric cancer.\",\n      \"method\": \"Knockdown, overexpression, phosphomutant rescue (Tyr24F), in vitro invasion/migration assays, in vivo tumor growth models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphomutant rescue establishes mechanistic specificity, in vitro and in vivo validation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"33941853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"P-glycoprotein (P-gp) interacts with ANXA2 and promotes invasion of multidrug-resistant breast cancer cells by modulating Src-dependent tyrosine phosphorylation of ANXA2; P-gp also interacts with Src kinase upstream of ANXA2.\",\n      \"method\": \"Co-immunoprecipitation, co-localization, P-gp inhibitors and MDR1 knockdown, Western blot\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP interaction confirmed, multiple inhibitor approaches, but mechanism linking P-gp activity to ANXA2 phosphorylation is indirect; replicated across two publications from same group\",\n      \"pmids\": [\"27754360\", \"24239898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The ANXA2/S100A10 (p11) heterotetramer complex structure was modeled by docking algorithms against cryo-electron microscopy projected density maps, revealing that the interaction between the ANXA2 core and p11 is primarily electrostatic in character, stabilized through charged residues.\",\n      \"method\": \"Computational docking with validation against cryo-EM projected density maps\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structural modeling with cryo-EM density validation, but computational/modeling approach without mutagenesis confirmation in this paper\",\n      \"pmids\": [\"11108962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM65 E3 ubiquitin ligase ubiquitinates ANXA2, promoting its degradation and thereby modulating cytoskeleton rearrangement and EMT in bladder cancer cells.\",\n      \"method\": \"Ubiquitination assay, Co-IP, siRNA knockdown, in vitro and in vivo functional assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ubiquitination assay plus Co-IP confirm the TRIM65-ANXA2 ubiquitination relationship, single lab\",\n      \"pmids\": [\"30075204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LINC00941 (lncRNA) directly binds the Annexin 1 domain of ANXA2 and acts as a decoy to prevent NEDD4L (E3 ligase) from binding the same domain, thereby suppressing NEDD4L-mediated ubiquitin-proteasomal degradation of ANXA2, leading to ANXA2 stabilization and FAK/AKT signaling activation in pancreatic cancer.\",\n      \"method\": \"RNA pulldown, mass spectrometry, RIP, Co-IP/MS, knockdown and rescue experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pulldown, mass spectrometry, Co-IP/MS collectively identify binding partners and mechanism; domain mapping and functional rescue experiments provide mechanistic specificity, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35977942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Ahnak scaffolds a trimeric complex of Ahnak/p11(S100A10)/ANXA2 in hippocampal neurons; through its N-terminal region Ahnak binds the L-type VGCC pore-forming α1 subunit, and through its C-terminal region it bridges the β subunit and the p11/ANXA2 complex. Ahnak knockout reduces L-type calcium current and channel surface expression, and phenocopies p11 knockout depression-like behavior.\",\n      \"method\": \"Co-IP, knockout mouse models (constitutive and cell-type-specific), electrophysiology, behavioral assays, fractionation\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP defining ternary complex, multiple conditional KO models with specific cellular and behavioral phenotypes, electrophysiology validation; multiple orthogonal methods\",\n      \"pmids\": [\"30760886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ANXA2 interacts with HIV-1 Gag at phosphatidylinositol (4,5) bisphosphate-containing lipid raft membrane domains where Gag mediates viral assembly; ANXA2 expression in 293T cells increases Gag processing and HIV-1 production.\",\n      \"method\": \"Bimolecular fluorescence complementation, overexpression, HIV-1 titer measurement\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — BiFC interaction at specific membrane microdomains, overexpression with viral output phenotype, single lab\",\n      \"pmids\": [\"19325895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MIEN1 physically interacts with ANXA2 (confirmed by FRET); ITAM-phosphorylated MIEN1 enhances Tyr23 phosphorylation of ANXA2 and stimulates ANXA2 cell-surface translocation, increasing ANXA2 proteolytic activity and tumor cell motility.\",\n      \"method\": \"FRET, Co-immunoprecipitation, Western blot, wound healing assay, phosphomutant constructs\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET confirms physical interaction, phosphomutant analysis links Tyr23 phosphorylation to cell surface translocation; single lab with orthogonal methods\",\n      \"pmids\": [\"26272794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ANXA2 interacts with EV71 3D polymerase (RNA-dependent RNA polymerase) via its annexin domain, localizes to viral replication organelles (ROs), and interacts with PI4KB; ANXA2 overexpression stimulates PI4P formation and promotes the PI4KB-3D interaction, facilitating EV71 RNA replication complex assembly and viral replication.\",\n      \"method\": \"Co-immunoprecipitation, knockout cell lines, confocal localization, PI4P quantification, overexpression\",\n      \"journal\": \"Virologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP defines interaction network, domain mapping, ANXA2-KO cells confirm functional requirement for PI4P production, single lab\",\n      \"pmids\": [\"34196914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ANXA2 interacts with influenza NS1 protein in the cell cytoplasm; ANXA2 overexpression significantly increases H5N1 HPAIV titer while siRNA-mediated knockdown inhibits viral protein expression and reduces progeny virus titer.\",\n      \"method\": \"Co-immunoprecipitation, confocal co-localization, siRNA knockdown, overexpression, viral titer assay\",\n      \"journal\": \"BMC microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and co-localization plus gain/loss-of-function with quantitative viral output, single lab\",\n      \"pmids\": [\"28893180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ANXA2 depletion inhibits EGF-induced STAT3 phosphorylation and downstream cyclin D1 expression, decelerating G1-to-S phase transition and reducing breast cancer cell proliferation; the effect is mediated through STAT3 as a key transcriptional regulator of cyclin D1.\",\n      \"method\": \"siRNA knockdown, cell cycle analysis (flow cytometry), Western blot, qRT-PCR\",\n      \"journal\": \"Breast cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function with cell cycle phenotype and pathway analysis, single lab, consistent with multiple papers on ANXA2-STAT3 axis\",\n      \"pmids\": [\"26253946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ANXA2 upregulation promotes breast cancer cell proliferation, migration, and invasion by increasing c-myc and cyclin D1 expression via activation of Erk1/2 signaling pathways.\",\n      \"method\": \"Overexpression, Western blot, in vitro migration/invasion assays, in vivo xenograft\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gain-of-function with defined pathway readout and in vivo validation, single lab\",\n      \"pmids\": [\"22452352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXW10 promotes K63-linked polyubiquitination of ANXA2 in a process requiring S6K1-mediated phosphorylation; K63-ubiquitinated ANXA2 translocates from cytoplasm to cell membrane, binds KRAS, and activates the MEK/ERK pathway to drive hepatocellular carcinoma proliferation and metastasis.\",\n      \"method\": \"Ubiquitination assays (K63-linkage specific), Co-IP, subcellular fractionation, knockdown, in vitro and in vivo functional assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — K63-specific ubiquitination assay plus membrane translocation and KRAS binding by Co-IP, in vivo validation; single lab\",\n      \"pmids\": [\"37277019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ERG oncoprotein directly binds the ANXA2 promoter and transcriptionally represses ANXA2 expression; ERG-mediated ANXA2 repression disrupts apical ANXA2 localization, actin bundling at cell-cell junctions, and epithelial cell polarity, promoting EMT through inhibition of CDC42/RHOA and cofilin activation.\",\n      \"method\": \"ERG siRNA, ChIP defining promoter binding, immunofluorescence for apical ANXA2 localization, gain- and loss-of-function, immunohistochemistry\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms ERG promoter binding for transcriptional repression, localization studies with functional consequences; single lab, multiple methods\",\n      \"pmids\": [\"25344575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ANXA2 knockdown in obesity-induced insulin-resistant cells inhibits NF-κB p50 nuclear translocation, reduces pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) and SOCS3, and restores insulin signaling (IRS1 phosphorylation, glucose uptake), placing ANXA2 upstream of NF-κB in obesity-induced insulin resistance.\",\n      \"method\": \"siRNA knockdown in palmitic acid-induced IR cell model, high-fat diet mouse model, glucose tolerance test, Western blot, flow cytometry\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function with specific metabolic and signaling phenotypes in both cell and mouse models, single lab\",\n      \"pmids\": [\"30462534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"S100A11 interacts with ANXA2 and decreases ubiquitination and proteasomal degradation of ANXA2; this stabilizes ANXA2 which activates NF-κB signaling; NF-κB in turn transcriptionally activates S100A11, forming a positive feedback loop that promotes GBM progression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, in vivo orthotopic xenograft\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirms S100A11-ANXA2 interaction, ubiquitination assay supports mechanistic model, in vivo validation; single lab\",\n      \"pmids\": [\"31430050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"p-STAT3 (phospho-STAT3) binds to the Anxa2 promoter and drives its transcription; elevated ANXA2 then promotes caspase-1-mediated hepatocyte pyroptosis and fibrosis in non-alcoholic steatohepatitis; inhibition of p-STAT3 suppresses pyroptosis which is rescued by ANXA2 overexpression.\",\n      \"method\": \"ChIP-seq, ChIP-qPCR, promoter reporter assay, siRNA knockdown, overexpression, NASH mouse model, in vitro NASH model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms transcription factor binding to promoter, rescue experiments establish pathway order; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36324154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DBT (dihydrolipoamide branched chain transacylase E2) interacts with ANXA2 via its lipoyl-binding domain; the DBT-ANXA2 interaction activates Hippo signaling, decreasing nuclear YAP localization and repressing transcription of lipogenic genes in clear cell renal cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, mutational studies, luciferase reporter assay, subcellular fractionation, in vitro and in vivo functional assays\",\n      \"journal\": \"Cancer communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain-mapping mutagenesis, reporter assay and YAP localization readout; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36860124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP4 deubiquitinase interacts with ANXA2, cleaving Lys48- and Lys63-linked polyubiquitin chains; Lys63-linked ubiquitination of ANXA2 at K28 specifically mediates Y24 phosphorylation; K10 acetylation of ANXA2 enhances its interaction with USP4. USP4-stabilized ANXA2 promotes GSC maintenance and radioresistance through BMX-mediated STAT3 activation.\",\n      \"method\": \"Co-IP, ubiquitination assays (linkage-specific), acetylation mutant constructs, phosphomutant (Y24), knockdown, in vivo models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple PTM-specific assays (ubiquitination, acetylation, phosphorylation) with defined mechanistic connections, single lab\",\n      \"pmids\": [\"40185997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HDAC9 interacts with ANXA2 (identified by IP-MS) and deacetylates it; this interaction inhibits ubiquitinated ANXA2 degradation, stabilizing ANXA2 and mediating depression-like behavior; HDAC9 knockdown/knockout in hippocampal neurons alleviates depression phenotypes.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry, Co-IP, HDAC9 knockdown/knockout mouse model, behavioral assays\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS identifies interaction and deacetylation, in vivo behavioral phenotype with KO confirmation; single lab\",\n      \"pmids\": [\"37690046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LUCAT1 lncRNA inhibits phosphorylation of ANXA2, which reduces degradation of the ANXA2-S100A10 heterotetramer (AIIt), resulting in accelerated conversion of plasminogen to plasmin and activation of metalloprotease proteins in hepatocellular carcinoma.\",\n      \"method\": \"RNA pulldown, Western blot, loss/gain-of-function experiments\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RNA pulldown confirms LUCAT1-ANXA2 interaction, Western blot tracks phosphorylation state and downstream plasmin pathway; single lab\",\n      \"pmids\": [\"30588744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANXA2 upregulates phosphorylation of HSF1, leading to transcriptional activation of ATG7; MTORC2 is required for ANXA2-mediated ATG7 transcription by HSF1 and contributes to ANXA2 protein stability; HSPA (Hsp70) interacts with ANXA2 and may protect it from lysosomal proteolysis. ANXA2-driven autophagy contributes to TNBC tumor aggressiveness.\",\n      \"method\": \"Bafilomycin A1 autophagic flux assay, ChIP, Western blot, Co-IP for ANXA2-HSPA interaction, siRNA knockdown, in vivo xenograft\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms transcriptional activation mechanism, autophagic flux assay validates functional output, Co-IP for binding; single lab, multiple methods\",\n      \"pmids\": [\"38290972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Hspb1 directly interacts with Anxa2, decreasing Anxa2 aggregation and phosphorylation; Hspb1 also uses Anxa2 as an intermediary to interact with and maintain the antioxidative activity of Prdx1 by reducing Thr-90 phosphorylation of Prdx1; Hspb1 overexpression did not protect acinar-specific Prdx1-KO mice, establishing the Hspb1/Anxa2/Prdx1 axis for ROS control in acute pancreatitis.\",\n      \"method\": \"Co-IP, Hspb1 KO and Anxa2 KO mice, AAV8-Hspb1 overexpression, acinar-specific Prdx1 KO mice, ROS measurements, phosphorylation analysis\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple KO mouse models establish epistasis, Co-IP identifies direct interactions, genetic rescue (AAV8-Hspb1) and Prdx1-KO epistasis rigorously validate the three-protein axis\",\n      \"pmids\": [\"38481805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SMN depletion reduces axonal transport of ANXA2 mRNA in motor neuron-like cells; a G-rich motif near the 3'UTR of Anxa2 mRNA is required for its axonal localization; mutations in this motif abolish targeting of Anxa2 reporter mRNAs to axon-like structures in SMN-sufficient cells, and localization is restricted to cell body in SMN-depleted cells.\",\n      \"method\": \"SMN depletion, reporter mRNA localization assays, site-directed mutagenesis of 3'UTR G-rich motif, fluorescence imaging in differentiated NSC-34 cells\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of cis-acting element confirms necessity for axonal localization; SMN depletion epistasis links localization to SMN complex; single lab, two orthogonal approaches\",\n      \"pmids\": [\"28258160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ANXA2 knockdown in renal tubular epithelial cells globally alters transcription and alternative splicing of inflammatory response genes, including chemokine CCL5, interferon-regulating genes (ISG15, IFI6, IFI44, IFITM1, IRF7), and alternative splicing of UBA52, RBCK1, and LITAF, indicating ANXA2 regulates inflammatory signaling at the level of gene expression and RNA processing.\",\n      \"method\": \"RNA-sequencing of ANXA2-knockdown HK2 cells, qRT-PCR validation, bioinformatics pathway analysis\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — transcriptomic loss-of-function identifies specific downstream genes and pathways; single lab, two methods (RNA-seq + qRT-PCR validation)\",\n      \"pmids\": [\"35906541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The ANXA2/S100A10 heterotetramer (AIIt) functions as a cell surface plasminogen receptor that both promotes plasmin formation at the cell surface and regulates plasmin destruction; AIIt is activated by oncogenes including SRC, RAS, HIF1α, and PML-RAR and is epigenetically regulated by DNA methylation.\",\n      \"method\": \"Review synthesizing biochemical reconstitution, Co-IP, and genetic studies from multiple labs (cited primary literature)\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — established from multiple primary experiments across labs as summarized; review paper itself does not add new experiments, but underlying evidence is strong\",\n      \"pmids\": [\"34944416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FOXD1 transcriptionally induces RalA expression; RalA forms a complex with ANXA2 and Src, enhancing the ANXA2-Src interaction and increasing Tyr23 phosphorylation of ANXA2, which activates ERK1/2 signaling to promote circulating tumor cell formation and breast cancer metastasis; inhibiting RalA-GTP form attenuates ANXA2-Src interaction.\",\n      \"method\": \"GST-pulldown, Co-IP, ChIP-seq, CUT&Tag-seq, in vivo CTC models, ERK1/2 inhibitor treatment\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GST-pulldown and Co-IP define the RalA-ANXA2-Src complex; ChIP establishes FOXD1-RalA transcriptional link; in vivo CTC validation; single lab with multiple methods\",\n      \"pmids\": [\"36229838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PFN1 (profilin-1) interacts with phospho-ANXA2 by recruiting Src kinase to phosphorylate ANXA2, which promotes STAT3 phosphorylation and transcriptional activity, driving VSMC phenotype switching and neointimal hyperplasia.\",\n      \"method\": \"Co-IP, single-cell RNA sequencing, SMC-specific PFN1 knockout mice, Western blot, wire-injury neointimal hyperplasia model\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP defines PFN1-ANXA2-Src complex, SMC-specific KO with defined phenotype; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39508106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ADAM8 metalloproteinase binds ANXA2 and promotes phosphorylation of ANXA2 at Ser26; ADAM8 knockout impedes ANXA2 Ser26 phosphorylation, which in turn inhibits mTOR Ser2448 phosphorylation and activates autophagy in macrophages, promoting cardiac repair after myocardial infarction.\",\n      \"method\": \"COIP/mass spectrometry, macrophage-specific ADAM8 KO mice, AAV6-overexpression, phosphorylation analysis, autophagy markers\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — COIP/MS identifies direct ADAM8-ANXA2 binding, KO mice establish in vivo epistasis through defined phosphorylation-autophagy axis; single lab\",\n      \"pmids\": [\"39097092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The S100A10/ANXA2 complex facilitates exocytosis of HBV virions across trophoblast cells; HBV virions co-localize with S100A10/ANXA2 and the autophagosome marker LC3; knockdown of either AnxA2 or S100A10 reduces the amount of exo-virus in Transwell assays.\",\n      \"method\": \"Co-localization (confocal), knockdown, Transwell exocytosis assay, immunohistochemistry of placental tissues\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function for both complex partners with quantitative exocytosis readout; co-localization with functional validation; single lab\",\n      \"pmids\": [\"34645932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANXA2 mediates endocytosis of microplastics into breast cancer cells; once internalized, MPs bound to ANXA2 regulate mitophagy by inhibiting IL-17 exocytosis, causing mitochondrial damage.\",\n      \"method\": \"MPs pulldown experiments, mass spectrometry, endocytosis/mitophagy assays, Western blot\",\n      \"journal\": \"Environmental pollution\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pulldown/MS identifies ANXA2-MP binding but the downstream mechanism (ANXA2-IL-17-mitophagy) is supported only by correlative data in a single study\",\n      \"pmids\": [\"39557355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ANXA2 promotes LDL receptor availability and thereby regulates LDL-C levels by serving as an endogenous inhibitor of PCSK9; the ANXA2 repeat-1 (R1) domain binds PCSK9 and blocks its ability to promote LDL-R degradation; the coding SNP V98L in ANXA2-R1 is associated with higher LDL-C and CHD risk.\",\n      \"method\": \"SNP genotype-phenotype association, allele-specific protein binding assay, reporter gene assay, eQTL analysis in human cohorts\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — allele-specific binding assay and reporter gene assay establish functional SNP effects on ANXA2 expression; LDL-C association replicated in two independent cohorts; mechanistic claim of ANXA2-R1 binding PCSK9 based on prior mouse-model literature\",\n      \"pmids\": [\"28456096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HE4 interacts with ANXA2 and MMP2 to form a trimeric HE4-ANXA2-MMP2 protein complex; ANXA2 acts as a bridge mediating HE4 regulation of MMP2 expression and promoting cancer cell migration.\",\n      \"method\": \"Co-immunoprecipitation, double-labeling immunofluorescence, siRNA knockdown, migration/invasion assays\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and co-localization identify the complex but the mechanistic link between HE4-ANXA2-MMP2 is not deeply dissected; single lab, single method (Co-IP)\",\n      \"pmids\": [\"31210752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FLNA (filamin A) interacts with ANXA2 (confirmed by Co-IP) and together they activate the Wnt/β-catenin pathway, contributing to gefitinib resistance in NSCLC; SP1 transcriptionally activates FLNA to regulate this resistance pathway.\",\n      \"method\": \"Co-immunoprecipitation, ChIP for SP1-FLNA promoter binding, siRNA knockdown, overexpression, in vivo mouse models\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and ChIP establish the interaction and upstream regulation, in vivo validation; single lab\",\n      \"pmids\": [\"34018148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SRF (serum response factor) transcription factor binds the ANXA2 promoter and represses its expression; ANXA2 activates NF-κB signaling by inducing nuclear translocation of p50; thus SRF-mediated repression of ANXA2 protects against pancreatitis-associated NF-κB activation.\",\n      \"method\": \"Dual luciferase reporter assay, ChIP, Co-IP, siRNA knockdown, in vivo AP mouse model\",\n      \"journal\": \"Inflammation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms SRF promoter binding, Co-IP confirms molecular interactions, in vivo disease model validation; single lab with multiple methods\",\n      \"pmids\": [\"35900381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MOF histone acetyltransferase (KAT8), stabilized by USP10 deubiquitination at K410, promotes H4K16 acetylation at the ANXA2 promoter in a JUN-dependent manner to transcriptionally activate ANXA2, which subsequently activates Wnt/β-catenin signaling to drive ESCC progression; catalytically inactive MOF fails to promote ANXA2 transcription.\",\n      \"method\": \"ChIP-seq, Co-IP, siRNA/overexpression with catalytic mutant (MOF-E350Q), in vitro and in vivo functional assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq establishes H4K16ac enrichment at ANXA2 promoter, catalytic mutant confirms acetyltransferase dependence, Co-IP for USP10-MOF interaction; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38317006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP10 nuclear expression increases upon oxaliplatin treatment, binds XAB2, and deubiquitinates K48-linked polyubiquitination at K593 of XAB2 to stabilize it; XAB2 then binds the ANXA2 promoter (by ChIP) to transcriptionally upregulate ANXA2, promoting DNA damage repair and oxaliplatin resistance in CRC.\",\n      \"method\": \"Co-IP, mass spectrometry for ubiquitination sites, ChIP-seq, ChIP-qPCR, dual-luciferase reporter, ubiquitin assay, functional assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR and reporter assay establish XAB2-ANXA2 transcriptional regulation; ubiquitination site MS identifies K593; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40069750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"m7G-modified tsRNA (mtiRL), catalyzed by METTL1, specifically binds ANXA2 and promotes its Tyr24 phosphorylation by enhancing the interaction between ANXA2 and YES1 kinase, leading to increased nuclear localization of p-ANXA2-Y24 and bladder cancer malignancy.\",\n      \"method\": \"RNA-protein binding assays, small RNA sequencing, m7G modification chip, Co-IP for ANXA2-YES1 interaction, knockdown/overexpression, in vitro and in vivo models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-protein binding and Co-IP establish mechanism, m7G modification confirmed biochemically, in vivo validation; single lab with multiple methods\",\n      \"pmids\": [\"38894581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NINJ1 competitively binds ANXA2, an inhibitory interacting protein of TLR4, thereby blocking the ANXA2-TLR4 interaction and activating TLR4 signaling; macrophage-specific NINJ1 deficiency inhibits AAA formation and reduces macrophage infiltration via the TLR4/NF-κB/CCR2 pathway.\",\n      \"method\": \"Protein-protein interaction analysis, Co-IP, macrophage-specific KO mice (Ninj1flox/flox Lyz2-Cre), RNA-sequencing, in vitro and in vivo functional assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and competitive binding establish NINJ1-ANXA2-TLR4 relationship, conditional KO mice with specific macrophage phenotype; single lab\",\n      \"pmids\": [\"38922800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANXA2 promotes TIM-4-induced mitochondrial fusion by interacting with TIM-4 to promote PI3K/AKT pathway activation, which increases L-OPA1 protein expression and oxidative phosphorylation in lung cancer cells.\",\n      \"method\": \"Co-IP, siRNA knockdown, PI3K inhibitor treatment, Western blot for OPA1/mitochondrial fusion markers, proliferation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP confirms TIM-4-ANXA2 interaction, pharmacological and genetic perturbations define signaling axis; single lab\",\n      \"pmids\": [\"36806050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANXA2 promotes GBM progression by activating BMX-mediated STAT3 activation; USP4-mediated stabilization of ANXA2 (through deubiquitination) and its K10 acetylation enhance this pathway to support GSC maintenance and radioresistance.\",\n      \"method\": \"Co-IP, knockdown, overexpression, GSC functional assays, in vivo models (cited in same paper as USP4 findings)\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and functional assays, but the specific BMX-STAT3 link downstream of ANXA2 lacks deep mechanistic dissection; single lab\",\n      \"pmids\": [\"40185997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ANXA2 knockdown in prostate epithelial cells (via ERG siRNA) enhances apical ANXA2 localization, promotes bundling of actin filaments at cell-cell junctions, and maintains epithelial polarity; conversely, ERG-driven transcriptional repression of ANXA2 disrupts ANXA2-mediated polarity by inhibiting CDC42 and RHOA and activating cofilin, promoting EMT.\",\n      \"method\": \"ERG siRNA, immunofluorescence for apical ANXA2 localization and actin, Western blot for CDC42/RHOA/cofilin, ChIP for ERG promoter binding\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization experiments directly linked to functional polarity consequences, ChIP establishes upstream transcriptional mechanism; single lab\",\n      \"pmids\": [\"25344575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Exosomal ANXA2 secreted by ovarian cancer cells binds TLR2 on human peritoneal mesothelial cells (HPMCs), activating HPMCs and shifting their phenotype toward mesenchymal cells, increasing LCN2 expression, which in turn promotes ovarian cancer cell adhesion, proliferation, motility, and lipid metabolism reprogramming.\",\n      \"method\": \"ANXA2 inhibitor (LCKLSL) and TLR2 inhibitor (C29) co-culture experiments, RNA-seq of HPMCs, Co-IP, in vivo OvCa xenograft models\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — ligand-receptor interaction supported by inhibitor rescue experiments and transcriptomic output; in vivo validation; single lab\",\n      \"pmids\": [\"39709496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ANXA2 knockdown in acute pancreatitis model cells reduces NF-κB activation (p50 nuclear translocation), inflammation, and apoptosis; the ANXA2 promoter is bound and repressed by SRF, and ANXA2 directly interacts with the NF-κB pathway.\",\n      \"method\": \"siRNA knockdown, AP model (cerulein/LPS), dual luciferase reporter, ChIP, Co-IP, flow cytometry\",\n      \"journal\": \"Inflammation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms SRF binding to ANXA2 promoter, Co-IP identifies ANXA2 interactions in NF-κB pathway, functional assays in disease model; single lab\",\n      \"pmids\": [\"35900381\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANXA2 is a calcium-dependent phospholipid-binding protein that functions as a multifunctional signaling scaffold: its Tyr23/Tyr24 phosphorylation by SRC (or YES1/MIEN1) drives nuclear translocation and enhanced interactions with partners including STAT3, MYC, and KRAS to promote proliferation and invasion; at the cell surface it forms the ANXA2/S100A10 (AIIt) heterotetramer that serves as an oncogenic plasminogen receptor, while RACK1 and RalA organize a ternary complex with Src to amplify phosphorylation; its stability is regulated by competing ubiquitination (by NEDD4L, TRIM65, TRIM21; reversed by USP4, USP10, NUSAP1) and deacetylation (HDAC9), and its transcription is activated by p-STAT3/ERG repression axis; in neurons, Ahnak scaffolds the ANXA2/p11 complex to the L-type voltage-gated calcium channel, linking ANXA2 to calcium signaling and depressive behavior.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ANXA2 is a calcium- and phospholipid-binding scaffold protein that integrates membrane biology, tyrosine-kinase signaling, and transcriptional control to drive cell proliferation, migration, invasion, and inflammatory responses [#1, #29]. Its central regulatory event is tyrosine phosphorylation in its N-terminal tail (Tyr23/Tyr24) by Src-family kinases, which is organized by scaffolds and adaptors: RACK1 bridges Src to ANXA2 [#3], FOXD1-induced RalA forms a ternary RalA/ANXA2/Src complex that amplifies Tyr23 phosphorylation and ERK1/2 signaling [#30], and PFN1 recruits Src to phosphorylate ANXA2 [#31]; EphA2-activated YES1 phosphorylates Tyr24 [#4], and MIEN1 further promotes Tyr23 phosphorylation and cell-surface translocation [#11]. Phosphorylation drives nuclear translocation, where ANXA2 binds STAT3 to enhance IL-6/EGF-responsive transcription of cyclin D1 and MMP2/9 [#0, #2, #14], and binds and stabilizes MYC to activate HIF1A/VEGF [#1]; ANXA2 also engages KRAS at the membrane to activate MEK/ERK [#16] and promotes Wnt/β-catenin signaling [#39]. At the cell surface ANXA2 forms the ANXA2/S100A10 (p11) heterotetramer (AIIt), an electrostatically stabilized complex [#6] that acts as a plasminogen receptor regulating plasmin generation [#24, #29]. ANXA2 abundance is set by competing post-translational modification: ubiquitination by TRIM65, NEDD4L, and FBXW10 (the latter K63-linked, driving membrane translocation) [#7, #8, #16], opposed by USP4-mediated deubiquitination, acetylation, and the S100A11 stabilizing interaction [#19, #22]; deacetylation by HDAC9 and chaperone binding (HSPA, HSPB1) further tune stability and aggregation [#23, #26]. ANXA2 transcription is itself a regulatory node, repressed by ERG and SRF [#17, #38] and activated by p-STAT3, MOF/JUN-driven H4K16 acetylation, and XAB2 [#20, #39, #40]. Beyond cancer, ANXA2 acts upstream of NF-κB in inflammation and insulin resistance [#18, #47], serves as a hijacked host factor for assembly/replication of HIV-1, EV71, influenza, and HBV [#10, #12, #13, #33], and in neurons is scaffolded by Ahnak into a p11/ANXA2 complex coupled to L-type voltage-gated calcium channels, linking it to calcium signaling and depression-like behavior [#9, #23].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the molecular architecture of the ANXA2/p11 heterotetramer, defining how ANXA2 assembles its cell-surface complex.\",\n      \"evidence\": \"Computational docking validated against cryo-EM projected density maps\",\n      \"pmids\": [\"11108962\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis confirmation of the electrostatic interface in this work\", \"Does not address functional consequences of complex assembly\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked ANXA2 abundance to a proliferative/invasive program, showing it raises c-myc and cyclin D1 via ERK1/2.\",\n      \"evidence\": \"Overexpression with pathway readout and xenograft validation in breast cancer cells\",\n      \"pmids\": [\"22452352\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting ANXA2 to ERK activation not resolved\", \"Direct binding partners not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified the ANXA2-STAT3 axis as a direct transcriptional mechanism driving EMT and G1/S progression, moving ANXA2 from membrane protein to nuclear transcriptional co-regulator.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA loss-of-function, cell-cycle analysis, and in vivo metastasis models\",\n      \"pmids\": [\"26307676\", \"26253946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish phosphorylation requirement for STAT3 binding\", \"Structural basis of ANXA2-STAT3 interaction unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined ANXA2 as a transcriptionally repressed target of ERG that maintains epithelial polarity, establishing its cytoskeletal/junctional role and an upstream transcriptional control point.\",\n      \"evidence\": \"ERG ChIP, promoter binding, immunofluorescence for apical localization and actin, CDC42/RHOA/cofilin analysis\",\n      \"pmids\": [\"25344575\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ANXA2 effect on Rho GTPases not biochemically dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified Src/YES1-mediated Tyr23/Tyr24 phosphorylation as the switch controlling ANXA2 nuclear translocation and partner engagement, mechanistically connecting kinase input to MYC stabilization and STAT3 sensitization.\",\n      \"evidence\": \"Phosphomutant constructs, Co-IP, ubiquitination assays, ChIP, reporter assays, xenografts across esophageal and breast cancer\",\n      \"pmids\": [\"30081903\", \"28470457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tyr23 vs Tyr24 functional distinction not fully separated\", \"How phosphorylation alters nuclear import machinery unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved how Src is delivered to ANXA2, identifying RACK1 as the scaffold mediating Src-dependent Tyr23 phosphorylation required for invasion.\",\n      \"evidence\": \"Reciprocal Co-IP of the RACK1/Src/ANXA2 ternary complex, siRNA, inhibitors, rescue, in vivo metastasis\",\n      \"pmids\": [\"31113450\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RACK1 acts in all ANXA2-phosphorylating contexts unknown\", \"Stoichiometry of the complex not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established Ahnak as the neuronal scaffold organizing the p11/ANXA2 complex onto the L-type VGCC, linking ANXA2 to calcium currents and depression-like behavior.\",\n      \"evidence\": \"Co-IP, conditional knockout mice, electrophysiology, behavioral assays\",\n      \"pmids\": [\"30760886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct contribution of ANXA2 itself (vs p11/Ahnak) to channel regulation not isolated\", \"Calcium-binding requirement not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended the kinase-input map by showing EphA2-activated YES1 phosphorylates ANXA2 at Tyr24 to drive nuclear localization and invasion, and confirmed AIIt as an oncogene-regulated plasminogen receptor.\",\n      \"evidence\": \"Phosphomutant (Tyr24F) rescue, knockdown/overexpression, in vivo models; biochemical review of AIIt plasminogen activity\",\n      \"pmids\": [\"33941853\", \"34944416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crosstalk between Tyr23 and Tyr24 phosphorylation pathways unresolved\", \"AIIt review does not add new primary data\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that ANXA2 stability is governed by competing ubiquitination and that ncRNAs and adaptors tune this, with LINC00941 acting as a NEDD4L decoy and RalA amplifying Src phosphorylation.\",\n      \"evidence\": \"RNA pulldown/MS, domain-mapped Co-IP, GST-pulldown, ChIP-seq, in vivo CTC models\",\n      \"pmids\": [\"35977942\", \"36229838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy among competing E3 ligases unknown\", \"Ubiquitination site mapping incomplete in some cases\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Positioned ANXA2 transcription as a tunable node, repressed by SRF and activated by p-STAT3, coupling it to NF-κB-driven inflammation, pyroptosis, and fibrosis.\",\n      \"evidence\": \"ChIP/ChIP-seq, reporter assays, Co-IP, knockdown, disease mouse models (pancreatitis, NASH)\",\n      \"pmids\": [\"35900381\", \"36324154\", \"30462534\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between ANXA2 and p50 nuclear translocation not defined\", \"Tissue specificity of regulation unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined an additional ubiquitin/acetylation/chaperone layer—USP4, HDAC9, HSPB1, HSPA, MOF/USP10—that controls ANXA2 stability, aggregation, and downstream STAT3/BMX, autophagy, and redox outputs.\",\n      \"evidence\": \"Linkage-specific ubiquitination assays, IP-MS, acetylation/phospho mutants, multiple KO mouse models, ChIP-seq\",\n      \"pmids\": [\"40185997\", \"37690046\", \"38481805\", \"38290972\", \"38317006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of multiple PTMs into a unified regulatory logic not established\", \"Many axes characterized in single labs/single disease contexts\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Broadened ANXA2's functional reach to receptor-coupled signaling (TIM-4/PI3K-AKT, NINJ1/TLR4, exosomal ANXA2/TLR2) and host-pathogen biology across multiple viruses.\",\n      \"evidence\": \"Co-IP/MS, competitive binding, conditional KO mice, inhibitor co-culture, viral titer and replication assays\",\n      \"pmids\": [\"36806050\", \"38922800\", \"39709496\", \"34196914\", \"28893180\", \"34645932\", \"19325895\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether membrane vs nuclear vs surface ANXA2 pools mediate these distinct functions not delineated\", \"Several interactions rest on single-lab Co-IP\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the calcium/phospholipid-binding biochemistry of ANXA2 is mechanistically coupled to its phosphorylation-dependent nuclear and surface functions, and how competing PTMs are prioritized in a given cell, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model linking membrane binding to nuclear translocation\", \"No reconstitution of the full PTM-stability network\", \"Relative contributions of monomeric ANXA2 vs AIIt heterotetramer in each phenotype undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [6, 10, 12]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3, 30, 36]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [35, 42]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [10, 12, 13]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [12, 27, 41]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [10, 16, 29, 11]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 4, 41]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [13, 16]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [17, 45]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 16, 30, 31]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 2, 20]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [18, 42, 47]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 8, 16, 22]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [25, 32]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 12, 13, 33]}\n    ],\n    \"complexes\": [\n      \"ANXA2/S100A10 (p11) heterotetramer (AIIt)\",\n      \"Ahnak/p11/ANXA2 neuronal complex\",\n      \"RACK1/Src/ANXA2 complex\",\n      \"RalA/ANXA2/Src complex\"\n    ],\n    \"partners\": [\n      \"STAT3\",\n      \"MYC\",\n      \"S100A10\",\n      \"SRC\",\n      \"RACK1\",\n      \"RalA\",\n      \"KRAS\",\n      \"AHNAK\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}