{"gene":"ANXA7","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1999,"finding":"ANX7 encodes a Ca2+-activated GTPase that supports Ca2+/GTP-dependent secretion events and Ca2+ channel activities; knockout of anx7 in mice results in profound reduction of IP3 receptor expression and function in pancreatic islets, directly linking ANX7 to IP3-dependent Ca2+ signaling and insulin secretion.","method":"Anx7 knockout mouse model (anx7+/- and -/-), electrophysiology, electrooptical recordings of intracellular calcium, insulin secretion assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (KO mouse, electrophysiology, Ca2+ imaging, secretion assay) with clear mechanistic phenotype, replicated in follow-up studies","pmids":["10570150"],"is_preprint":false},{"year":2001,"finding":"Wild-type ANXA7 acts as a tumor suppressor gene in prostate cancer; transfection of wt-ANX7 into LNCaP and DU145 prostate tumor cell lines markedly reduces cell proliferation and colony formation.","method":"Transfection of wt-ANX7 into tumor cell lines, proliferation assays, colony formation assays, loss-of-heterozygosity analysis with microsatellite markers","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — clean gain-of-function with defined cellular phenotype, replicated across two cell lines and validated in human tissue microarrays","pmids":["11287641"],"is_preprint":false},{"year":2003,"finding":"Haploinsufficiency of Anx7 in mice leads to genomic instability, reduced expression of tumor suppressor genes, DNA repair genes, and apoptosis-related genes, and cancer-prone phenotype with chromosomal instability, placing ANXA7 upstream of a discrete tumor suppressor signaling pathway.","method":"Anx7+/- knockout mouse, genome array analysis, spectral karyotyping, tissue imprinting, laser-capture microdissection","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO model with multiple orthogonal methods including genomic and cytogenetic analysis","pmids":["14608035"],"is_preprint":false},{"year":2002,"finding":"In Anx7+/- knockout mice, adrenal chromaffin cells are unable to discriminate between fed and fasted states, with sustained expression of nutritionally sensitive genes (chromogranin A/B, DbetaH), implicating the ANX7/IP3R signaling axis in nutrient-regulated secretory gene expression in chromaffin cells.","method":"Anx7+/- knockout mouse, cDNA microarray, feeding/fasting challenge","journal":"Annals of the New York Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO with genome-wide expression profiling, single lab","pmids":["12438089"],"is_preprint":false},{"year":2010,"finding":"A multi-hnRNP complex (hnRNP A1, A2/B1, K) binds to the steroid nuclear hormone receptor element cluster in the ANXA7 promoter in androgen-resistant prostate cancer cells (PC3), causing aberrant ANXA7 transcription and splicing; hnRNP A2/B1 antibody interference validates this regulatory role.","method":"Deletion mapping/promoter reporter assays, gelshift/EMSA, MALDI-TOF mass spectrometry, hnRNP A2/B1 antibody interference, RT-PCR, western blot","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (EMSA, MS, antibody interference) in single lab","pmids":["20190808"],"is_preprint":false},{"year":2012,"finding":"BART (binder of Arl two) binds directly to ANX7, and the BART-ANX7 complex translocates to cell protrusions in migrating cells where it reduces PKCα activity; knockdown of BART or ANX7 increases PKCα activity and enhances invasiveness of pancreatic cancer cells, which is abrogated by PKCα inhibitors.","method":"Co-IP, pulldown, PKCα activity assay, BART/ANX7 siRNA knockdown, invasion assays, confocal imaging of complex localization","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP interaction with functional validation by KD and pharmacological inhibition in single lab","pmids":["22532868"],"is_preprint":false},{"year":2012,"finding":"In Anx7+/- mouse beta-cells, muscarinic agonist (carbachol) and ryanodine receptor agonists (caffeine, 4-chloro-m-cresol) elicit more potent depolarizing effects and augmented insulin secretion compared to controls, demonstrating that the Anx7+/- mutation alters IP3 receptor and ryanodine receptor signaling pathways regulating beta-cell membrane potential.","method":"Anx7+/- knockout mouse, electrophysiology, intracellular Ca2+ measurements, insulin secretion assays, pharmacological agonists","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — multiple electrophysiological and secretory methods in KO model, single lab","pmids":["22613970"],"is_preprint":false},{"year":2014,"finding":"Wild-type ANXA7 in LNCaP prostate cancer cells preserves total FOXO3A expression without hyperphosphorylation, enabling FOXO3A nuclear translocation and proapoptotic transcription, while inducing G1-arrest and programmed cell death; this is mechanistically distinct from p53 effects and linked to SGK1/FOXO3A/Akt pathway regulation.","method":"ANXA7 and p53 transfection into LNCaP cells, western blot for phospho/total FOXO3A, cell cycle analysis, apoptosis assays, Ingenuity Pathway Analysis","journal":"BioMed research international","confidence":"Medium","confidence_rationale":"Tier 2-3 — defined cellular phenotype with molecular pathway analysis, single lab","pmids":["24864229"],"is_preprint":false},{"year":2016,"finding":"Inhibition of ANXA7 GTPase activity by small molecule ABO elevates HMBOX1 protein through translational upregulation; ANXA7 translocates to the nucleus upon GTPase inhibition and interacts with XRN2, reducing XRN2 phosphorylation and promoting TGFB2-OT1 lncRNA expression, which increases LARP1 and subsequently HMBOX1 translation.","method":"Small molecule ABO treatment, ANXA7-deficient HUVECs, western blot, ANXA7 nuclear fractionation, Co-IP of ANXA7-XRN2, lncRNA microarray, in vivo apoE-/- mouse model","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal approaches (KD, small molecule, Co-IP, in vivo) in single lab","pmids":["27506770"],"is_preprint":false},{"year":2017,"finding":"Activation of ANXA7 GTPase by small molecule SEC promotes AMPK phosphorylation, leading to decreased mTORC1 activity, suppressed STAT3 nuclear translocation, and downregulation of pro-metastatic genes (CCL2, APLN, IL6ST); RKIP interacts with ANXA7 and impairs SEC-induced ANXA7 GTPase activation and downstream signaling.","method":"SEC small molecule treatment, RKIP-ANXA7 Co-IP, AMPK/mTORC1/STAT3 pathway analysis, in vivo orthotopic prostate cancer metastasis assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP interaction plus pathway analysis and in vivo functional validation, single lab","pmids":["29247827"],"is_preprint":false},{"year":2018,"finding":"Wild-type ANXA7 abolishes expression of oncogenic low-molecular weight (LMW) cyclin E in hormone-resistant prostate (DU145) and breast cancer cells; dominant-negative nMMM-ANXA7 (lacking phosphatidylserine liposome aggregation properties) fails to abrogate LMW-cyclin E and simultaneously induces FGF8 in DU145, consistent with continuing cell cycle progression.","method":"wt-ANXA7 and dominant-negative ANXA7 transfection, western blot for LMW-cyclin E and FGF8, cell cycle analysis, apoptosis assays in multiple cancer cell lines","journal":"Trends in cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 — comparison of wt vs dominant-negative ANXA7 with defined molecular readouts, single lab","pmids":["30369774"],"is_preprint":false},{"year":2019,"finding":"Inhibition of ANXA7 GTPase activity by ABO causes ANXA7 to translocate into the nucleus where it interacts with XRN2; reduced XRN2 phosphorylation promotes read-through transcription of MROH7-TTC4 lncRNA, which is processed by TIA1 into MROH7 and TTC4 that inhibit VEC apoptosis.","method":"ABO GTPase inhibitor, nuclear fractionation/localization of ANXA7, Co-IP of ANXA7-XRN2, lncRNA microarray, TIA1 pulldown, apoptosis assays in HUVECs","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP, localization, and functional pathway validated by multiple assays in single lab","pmids":["31408583"],"is_preprint":false},{"year":2019,"finding":"ANXA7 knockdown inhibits JAK1/STAT3 pathway activation in trophoblast cells, reduces BCL2 protein levels, induces apoptosis, and inhibits proliferation; ANXA7 overexpression has the opposite effects, placing ANXA7 upstream of the JAK1/STAT3 anti-apoptotic pathway in trophoblasts.","method":"ANXA7 siRNA knockdown and overexpression in HTR-8/SVneo cells, western blot for BCL2/JAK1/STAT3, flow cytometry for apoptosis, CCK-8 proliferation assay","journal":"American journal of reproductive immunology","confidence":"Medium","confidence_rationale":"Tier 2 — bidirectional (KD and OE) with defined pathway readout, single lab","pmids":["31446642"],"is_preprint":false},{"year":2020,"finding":"ANXA7 translocates to impaired mitochondria upon CCCP treatment and interacts with BASP1 to play a pivotal role in Parkin-dependent mitophagy.","method":"Quantitative mitochondrial proteomics (DIA), CCCP-induced mitophagy assay, ANXA7 KD, Co-IP of ANXA7-BASP1, mitochondrial fractionation","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 2-3 — proteomics discovery with Co-IP and KD functional validation, single lab","pmids":["31975592"],"is_preprint":false},{"year":2020,"finding":"ANXA7 promotes proliferation, cell cycle progression, and cell adhesion-mediated drug resistance in multiple myeloma cells by directly binding to and upregulating CDC5L.","method":"Co-IP of ANXA7-CDC5L, ANXA7 overexpression and knockdown in MM cell lines, CDC5L siRNA rescue experiments, proliferation/apoptosis/cell cycle assays","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP interaction with rescue experiments, single lab","pmids":["32526706"],"is_preprint":false},{"year":2023,"finding":"A dominant-negative triple mutant of ANXA7 (DNTM/DN-ANXA7J, mutating GX(X)GT motifs in endonexin-fold repeats) suppresses membrane fusion with artificial membranes, alters calcium and phospholipid binding, reduces IP3 receptor expression, and modulates PI3K/AKT/mTOR signaling in prostate cancer cells, demonstrating that calcium/phospholipid binding by ANXA7 is required for its tumor suppressor function.","method":"Active-site mutagenesis of ANXA7 endonexin folds, in vitro membrane fusion assay, calcium/phospholipid binding assay, IP3 receptor western blot, PI3K/AKT/mTOR pathway analysis, apoptosis assays in prostate cancer cells","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro reconstitution with mutagenesis and multiple cellular assays, single lab","pmids":["37240163"],"is_preprint":false},{"year":2023,"finding":"ANXA7 GTPase activation protects neurons after OGD/R by enhancing autophagy via the mTOR/TFEB pathway and inhibiting apoptosis; ANXA7 directly interacts with lysosomal membrane protein LAMP5 (with Asp411 mutation impairing this interaction), and ANXA7 stabilizes LAMP5 protein expression to maintain lysosomal acidic environment.","method":"OGD/R neuronal model, ANXA7 GTPase activation/inhibition, Co-IP of ANXA7-LAMP5, Asp411 mutagenesis, LAMP5 overexpression rescue, mTOR/TFEB pathway analysis, in vivo SCI mouse model with lentiviral ANXA7 overexpression, CatWalk assay","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with mutagenesis, in vitro and in vivo functional validation, single lab","pmids":["37620352"],"is_preprint":false},{"year":2024,"finding":"ZBTB16 directly interacts with ANXA7 protein (validated by Co-IP), and ZBTB16 promotes ANXA7 expression which subsequently inhibits Cyclin B1 expression; this ZBTB16/ANXA7/Cyclin B1 axis mediates cell cycle arrest and apoptosis in breast cancer cells downstream of UHRF1 knockdown.","method":"Co-IP of ZBTB16-ANXA7, ANXA7 KD rescue experiments, Cyclin B1 western blot, cell cycle and apoptosis assays, methylation-specific PCR, ChIP for UHRF1/DNMT1 at ZBTB16 promoter","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP interaction with rescue experiments and pathway analysis, single lab","pmids":["39308302"],"is_preprint":false},{"year":2025,"finding":"ANXA7 acts as a critical adaptor for retrograde axonal transport by physically linking TIA1-containing RNPs to cytoplasmic dynein; persistent axonal Ca2+ elevation or ANXA7 knockdown decouples TIA1 granules from dynein, impairing retrograde transport and causing pathological TIA1 aggregation and axonopathy; ANXA7 overexpression enhances RNP trafficking and counteracts TIA1 aggregation.","method":"Live imaging of axonal transport, ANXA7 KD and OE in neurons, Co-IP of ANXA7-TIA1-dynein complex, Ca2+ elevation experiments, in vitro and in vivo axonopathy models","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and live transport imaging with KD/OE functional validation, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.01.16.633295"],"is_preprint":true},{"year":2025,"finding":"ANXA7 GTPase activation promotes lipid droplet formation by interacting with PPARγ to enhance its stability and nuclear translocation, driving Perilipin 5 expression and mitochondria-lipid droplet interaction; this inhibits lipid peroxidation through NRF2/GPX4 and reduces oxidative stress and neuron damage after spinal cord injury.","method":"Co-IP of ANXA7-PPARγ, ANXA7 GTPase activation, PPARγ stability assay, lipid droplet imaging, NRF2/GPX4 western blot, in vivo SCI mouse model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP interaction with in vitro and in vivo functional validation, single lab","pmids":["39996504"],"is_preprint":false},{"year":2026,"finding":"RNF168 E3 ubiquitin ligase promotes ubiquitination and degradation of ANXA7; reduced ANXA7 levels suppress autophagy and enhance NLRP3 inflammasome-mediated pyroptosis in intestinal epithelial cells, driving Crohn's disease progression.","method":"Co-IP and ubiquitination assays (RNF168-ANXA7), ANXA7 KD and OE in NCM460 cells, autophagy and NLRP3 pyroptosis assays, IL-10 KO and RNF168flox/flox;Villin-Cre mice with TNBS colitis, organoid experiments","journal":"Apoptosis","confidence":"Medium","confidence_rationale":"Tier 2 — ubiquitination assay with Co-IP, in vitro and in vivo functional rescue, single lab","pmids":["41518435"],"is_preprint":false},{"year":2014,"finding":"LEPR (Leptin Receptor) physically interacts with ANXA7 (validated by Co-IP), and mechanistically regulates ERK1/2 and JAK2/STAT3 signaling through ANXA7 in hepatocellular carcinoma lymphatic metastatic cells.","method":"Co-immunoprecipitation of LEPR-ANXA7, western blot for ERK1/2 and JAK2/STAT3, LEPR knockdown/overexpression functional assays","journal":"Cancer cell international","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP with limited mechanistic follow-up, single lab","pmids":["33397392"],"is_preprint":false}],"current_model":"ANXA7 is a Ca2+-activated GTPase and calcium/phospholipid-binding protein whose GTPase and membrane fusion activities (dependent on endonexin-fold calcium-binding motifs) underlie its roles as a tumor suppressor—suppressing cell proliferation, LMW-cyclin E, and activating FOXO3A/apoptotic pathways—and as a regulator of IP3 receptor expression, Ca2+-dependent insulin secretion, Parkin-dependent mitophagy (via BASP1 interaction), neuronal RNP retrograde transport (linking TIA1 granules to dynein), and multiple signaling axes (AMPK/mTORC1/STAT3, JAK1/STAT3, PPARγ/NRF2/GPX4, BART-PKCα); its activity is regulated by RKIP binding (impairing GTPase activation), hnRNP complex-mediated aberrant splicing at the promoter, and RNF168-mediated ubiquitination and degradation."},"narrative":{"teleology":[{"year":1999,"claim":"Establishing ANXA7 as a Ca²⁺-activated GTPase essential for IP3 receptor expression and insulin secretion resolved how this annexin family member couples calcium signaling to secretory function in vivo.","evidence":"Anx7 knockout mouse with electrophysiology, Ca²⁺ imaging, and insulin secretion assays","pmids":["10570150"],"confidence":"High","gaps":["GTPase catalytic mechanism not structurally resolved","whether GTPase activity is required for IP3R regulation was not tested by point mutation"]},{"year":2001,"claim":"Demonstrating that wild-type ANXA7 reintroduction suppresses prostate cancer cell proliferation and colony formation established ANXA7 as a bona fide tumor suppressor, connecting its biochemical activity to growth control.","evidence":"wt-ANXA7 transfection into LNCaP and DU145 cells with proliferation and colony formation assays, LOH analysis in human tissue","pmids":["11287641"],"confidence":"High","gaps":["molecular target through which ANXA7 arrests proliferation was unidentified","in vivo tumor suppression not directly tested"]},{"year":2003,"claim":"Showing that Anx7 haploinsufficiency causes genomic instability, reduced expression of tumor suppressors and DNA repair genes, and a cancer-prone phenotype in mice placed ANXA7 upstream of a broad genomic maintenance network.","evidence":"Anx7+/- knockout mouse with genome array analysis and spectral karyotyping","pmids":["14608035"],"confidence":"High","gaps":["direct mechanism linking ANXA7 to DNA repair gene regulation unknown","whether GTPase activity mediates genomic stability not tested"]},{"year":2010,"claim":"Identifying a multi-hnRNP complex that binds the ANXA7 promoter and causes aberrant splicing in androgen-resistant prostate cancer revealed a transcriptional mechanism for ANXA7 silencing in cancer.","evidence":"Promoter deletion mapping, EMSA, MALDI-TOF MS, and hnRNP A2/B1 antibody interference in PC3 cells","pmids":["20190808"],"confidence":"Medium","gaps":["whether hnRNP-mediated silencing occurs in primary tumors not shown","splice variants not functionally characterized"]},{"year":2012,"claim":"Discovery that BART–ANXA7 complex translocates to cell protrusions and inhibits PKCα activity linked ANXA7 to regulation of cell migration and invasiveness beyond its canonical tumor suppressor role.","evidence":"Co-IP, PKCα activity assay, BART/ANXA7 siRNA knockdown, and invasion assays in pancreatic cancer cells","pmids":["22532868"],"confidence":"Medium","gaps":["structural basis of BART–ANXA7 interaction unknown","single Co-IP without reciprocal pulldown from endogenous lysates"]},{"year":2014,"claim":"Showing that ANXA7 preserves FOXO3A from hyperphosphorylation and enables its nuclear translocation for proapoptotic transcription defined a mechanistic pathway distinct from p53 by which ANXA7 triggers apoptosis.","evidence":"ANXA7 transfection into LNCaP cells, phospho-FOXO3A western blot, cell cycle and apoptosis assays","pmids":["24864229"],"confidence":"Medium","gaps":["whether ANXA7 directly binds FOXO3A or acts through SGK1/Akt not resolved","single cell line"]},{"year":2017,"claim":"Demonstrating that ANXA7 GTPase activation feeds into AMPK/mTORC1/STAT3 signaling and that RKIP binding impairs this activation established a GTPase-centric signal transduction model for ANXA7's anti-metastatic activity.","evidence":"SEC small molecule activator, RKIP–ANXA7 Co-IP, pathway analysis, orthotopic prostate cancer metastasis model","pmids":["29247827"],"confidence":"Medium","gaps":["direct GTPase kinetic parameters with RKIP not measured","SEC specificity for ANXA7 versus other annexins not addressed"]},{"year":2018,"claim":"Showing that wild-type but not dominant-negative ANXA7 (lacking phosphatidylserine binding) abolishes oncogenic LMW-cyclin E linked ANXA7's membrane fusion properties to cell cycle regulation.","evidence":"wt vs. nMMM-ANXA7 transfection, western blot for LMW-cyclin E and FGF8, cell cycle analysis in DU145 and breast cancer cells","pmids":["30369774"],"confidence":"Medium","gaps":["mechanism connecting phospholipid binding to cyclin E regulation not identified","limited to overexpression system"]},{"year":2020,"claim":"Identifying ANXA7 translocation to impaired mitochondria and its interaction with BASP1 during Parkin-dependent mitophagy expanded ANXA7 function beyond secretion and cancer to organelle quality control.","evidence":"Quantitative mitochondrial DIA proteomics, CCCP-induced mitophagy, ANXA7 KD, Co-IP of ANXA7–BASP1","pmids":["31975592"],"confidence":"Medium","gaps":["whether ANXA7 GTPase activity is required for mitophagy not tested","BASP1–ANXA7 interaction not validated by reciprocal approach"]},{"year":2023,"claim":"Mutagenesis of endonexin-fold GX(X)GT motifs proved that calcium/phospholipid binding is required for ANXA7's membrane fusion, IP3R regulation, and tumor suppressor functions, unifying its biochemical and cellular activities.","evidence":"Active-site mutagenesis of ANXA7 endonexin folds, in vitro membrane fusion assay, Ca²⁺/phospholipid binding, IP3R and PI3K/AKT/mTOR pathway analysis","pmids":["37240163"],"confidence":"Medium","gaps":["no crystal structure of mutant ANXA7 to verify fold integrity","in vivo tumor suppression by mutant not tested"]},{"year":2023,"claim":"Demonstrating that ANXA7 interacts with LAMP5 via Asp411 to maintain lysosomal acidity and promote mTOR/TFEB-dependent autophagy after neuronal injury provided a neuroprotective mechanism for ANXA7 GTPase activity.","evidence":"OGD/R neuronal model, Co-IP of ANXA7–LAMP5, Asp411 mutagenesis, in vivo SCI mouse model with lentiviral ANXA7 OE","pmids":["37620352"],"confidence":"Medium","gaps":["whether LAMP5 interaction is Ca²⁺-dependent not tested","single mutagenesis site without comprehensive domain mapping"]},{"year":2025,"claim":"Showing that ANXA7 GTPase activation stabilizes PPARγ, drives lipid droplet biogenesis, and engages NRF2/GPX4 anti-ferroptotic signaling linked ANXA7 to lipid metabolism and oxidative stress defense in neurons.","evidence":"Co-IP of ANXA7–PPARγ, PPARγ stability assay, lipid droplet imaging, NRF2/GPX4 pathway analysis, in vivo SCI model","pmids":["39996504"],"confidence":"Medium","gaps":["direct vs. indirect stabilization of PPARγ not distinguished","whether this pathway operates outside neuronal injury context unknown"]},{"year":2025,"claim":"Identifying ANXA7 as an adaptor linking TIA1-containing RNP granules to cytoplasmic dynein for retrograde axonal transport revealed an entirely new cell-biological role for this annexin in neuronal homeostasis.","evidence":"(preprint) Live axonal transport imaging, ANXA7 KD/OE in neurons, Co-IP of ANXA7–TIA1–dynein complex, Ca²⁺ elevation experiments","pmids":["bio_10.1101_2025.01.16.633295"],"confidence":"Medium","gaps":["preprint not yet peer-reviewed","whether Ca²⁺-dependent uncoupling involves GTPase activity not tested","structural basis of ANXA7–dynein interaction unknown"]},{"year":2026,"claim":"Demonstrating that RNF168 ubiquitinates and degrades ANXA7, suppressing autophagy and promoting NLRP3 inflammasome-driven pyroptosis, established a post-translational regulatory mechanism for ANXA7 levels with disease relevance in Crohn's disease.","evidence":"Co-IP and ubiquitination assays, ANXA7 KD/OE in NCM460 cells, RNF168flox/flox;Villin-Cre mice with TNBS colitis, organoid experiments","pmids":["41518435"],"confidence":"Medium","gaps":["ubiquitination sites on ANXA7 not mapped","whether RNF168-ANXA7 axis operates in non-intestinal contexts unknown"]},{"year":null,"claim":"The structural basis of ANXA7 GTPase activity, the identity of a physiological GEF or GAP, and how GTPase cycling is coordinated with calcium-dependent membrane binding remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["no crystal or cryo-EM structure of ANXA7","no GEF/GAP identified","GTPase kinetic parameters under physiological conditions not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,9,15,16,19]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[10,15]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[18]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,9,12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,11]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[13]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,9]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,15]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[16]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[19]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,6,9,12,16,19]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,7,10,17,20]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[7,10,14,17]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[13,16,20]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,14,20]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,6]}],"complexes":[],"partners":["RKIP","BASP1","BART","XRN2","LAMP5","ZBTB16","TIA1","PPARG"],"other_free_text":[]},"mechanistic_narrative":"ANXA7 is a calcium- and phospholipid-binding protein with intrinsic GTPase activity that functions as a tumor suppressor, a regulator of intracellular calcium signaling, and an adaptor linking ribonucleoprotein cargo to the dynein motor for retrograde axonal transport. Its GTPase activity, dependent on endonexin-fold calcium-binding motifs, drives membrane fusion, IP3 receptor expression, and downstream signaling through AMPK/mTORC1/STAT3 and PI3K/AKT/mTOR pathways; loss of ANXA7 in mice causes profound reduction of IP3 receptor function, impaired insulin secretion, genomic instability, and cancer susceptibility [PMID:10570150, PMID:14608035, PMID:37240163]. ANXA7 suppresses oncogenic low-molecular-weight cyclin E and Cyclin B1 expression, activates FOXO3A-dependent apoptosis, and its tumor suppressor activity is abrogated by dominant-negative mutations that impair calcium/phospholipid binding [PMID:11287641, PMID:24864229, PMID:30369774, PMID:39308302]. Beyond cancer, ANXA7 translocates to damaged mitochondria to promote Parkin-dependent mitophagy via BASP1 interaction, stabilizes PPARγ to drive lipid droplet formation and NRF2/GPX4-mediated anti-ferroptotic protection in neurons, interacts with LAMP5 to maintain lysosomal function and autophagy, and is itself targeted for ubiquitin-dependent degradation by RNF168, linking its loss to NLRP3 inflammasome activation and Crohn's disease pathology [PMID:31975592, PMID:37620352, PMID:39996504, PMID:41518435]."},"prefetch_data":{"uniprot":{"accession":"P20073","full_name":"Annexin A7","aliases":["Annexin VII","Annexin-7","Synexin"],"length_aa":488,"mass_kda":52.7,"function":"Calcium/phospholipid-binding protein which promotes membrane fusion and is involved in exocytosis","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P20073/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ANXA7","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ANXA7","total_profiled":1310},"omim":[{"mim_id":"602396","title":"ANNEXIN A8; ANXA8","url":"https://www.omim.org/entry/602396"},{"mim_id":"186360","title":"ANNEXIN A7; ANXA7","url":"https://www.omim.org/entry/186360"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ANXA7"},"hgnc":{"alias_symbol":[],"prev_symbol":["ANX7"]},"alphafold":{"accession":"P20073","domains":[{"cath_id":"1.10.220.10","chopping":"188-244","consensus_level":"high","plddt":96.8589,"start":188,"end":244},{"cath_id":"1.10.220.10","chopping":"419-487","consensus_level":"high","plddt":97.287,"start":419,"end":487}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P20073","model_url":"https://alphafold.ebi.ac.uk/files/AF-P20073-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P20073-F1-predicted_aligned_error_v6.png","plddt_mean":76.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANXA7","jax_strain_url":"https://www.jax.org/strain/search?query=ANXA7"},"sequence":{"accession":"P20073","fasta_url":"https://rest.uniprot.org/uniprotkb/P20073.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P20073/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P20073"}},"corpus_meta":[{"pmid":"11287641","id":"PMC_11287641","title":"ANX7, a candidate tumor suppressor gene for prostate cancer.","date":"2001","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11287641","citation_count":108,"is_preprint":false},{"pmid":"10570150","id":"PMC_10570150","title":"Defects in inositol 1,4,5-trisphosphate receptor expression, Ca(2+) signaling, and insulin secretion in the anx7(+/-) knockout mouse.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10570150","citation_count":108,"is_preprint":false},{"pmid":"14608035","id":"PMC_14608035","title":"Haploinsufficiency of Anx7 tumor suppressor gene and consequent genomic instability promotes tumorigenesis in the Anx7(+/-) mouse.","date":"2003","source":"Proceedings of the National Academy of Sciences of the United States of 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lung adenocarcinoma progression via miR-331/LAD1 axis.","date":"2021","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/33536022","citation_count":18,"is_preprint":false},{"pmid":"33397392","id":"PMC_33397392","title":"Leptin Receptor (LEPR) promotes proliferation, migration, and invasion and inhibits apoptosis in hepatocellular carcinoma by regulating ANXA7.","date":"2021","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/33397392","citation_count":18,"is_preprint":false},{"pmid":"23582794","id":"PMC_23582794","title":"Down-regulation of ANXA7 decreases metastatic potential of human hepatocellular carcinoma cells in vitro.","date":"2013","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/23582794","citation_count":17,"is_preprint":false},{"pmid":"32526706","id":"PMC_32526706","title":"ANXA7 promotes the cell cycle, proliferation and cell adhesion-mediated drug resistance of multiple myeloma cells by up-regulating CDC5L.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32526706","citation_count":16,"is_preprint":false},{"pmid":"37620352","id":"PMC_37620352","title":"Targeting ANXA7/LAMP5-mTOR axis attenuates spinal cord injury by inhibiting neuronal apoptosis via enhancing autophagy in mice.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/37620352","citation_count":16,"is_preprint":false},{"pmid":"27807828","id":"PMC_27807828","title":"ANXA7-GTPase as Tumor Suppressor: Mechanisms and Therapeutic Opportunities.","date":"2017","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/27807828","citation_count":15,"is_preprint":false},{"pmid":"22532868","id":"PMC_22532868","title":"BART inhibits pancreatic cancer cell invasion by PKCα inactivation through binding to ANX7.","date":"2012","source":"PloS 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origin.","date":"2018","source":"Trends in cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/30369774","citation_count":7,"is_preprint":false},{"pmid":"39996504","id":"PMC_39996504","title":"Lipid Droplets Metabolism Mediated by ANXA7-PPARγ Signaling Axis Regulates Spinal Cord Injury Repair in Mice.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39996504","citation_count":7,"is_preprint":false},{"pmid":"37240163","id":"PMC_37240163","title":"A Dominant-Negative Mutant of ANXA7 Impairs Calcium Signaling and Enhances the Proliferation of Prostate Cancer Cells by Downregulating the IP3 Receptor and the PI3K/mTOR Pathway.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37240163","citation_count":6,"is_preprint":false},{"pmid":"10077575","id":"PMC_10077575","title":"HIV-1 Gag shares a signature motif with annexin (Anx7), which is required for virus replication.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10077575","citation_count":4,"is_preprint":false},{"pmid":"39308302","id":"PMC_39308302","title":"UHRF1 knockdown induces cell cycle arrest and apoptosis in breast cancer cells through the ZBTB16/ANXA7/Cyclin B1 axis.","date":"2024","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/39308302","citation_count":3,"is_preprint":false},{"pmid":"39684934","id":"PMC_39684934","title":"Role of Annexin 7 (ANXA7) as a Tumor Suppressor and a Regulator of Drug Resistance in Thyroid Cancer.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39684934","citation_count":1,"is_preprint":false},{"pmid":"41518435","id":"PMC_41518435","title":"RNF168 promotes chronic colitis through ANXA7-mediated autophagy and NLRP3-driven 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and Ca2+ channel activities; knockout of anx7 in mice results in profound reduction of IP3 receptor expression and function in pancreatic islets, directly linking ANX7 to IP3-dependent Ca2+ signaling and insulin secretion.\",\n      \"method\": \"Anx7 knockout mouse model (anx7+/- and -/-), electrophysiology, electrooptical recordings of intracellular calcium, insulin secretion assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (KO mouse, electrophysiology, Ca2+ imaging, secretion assay) with clear mechanistic phenotype, replicated in follow-up studies\",\n      \"pmids\": [\"10570150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Wild-type ANXA7 acts as a tumor suppressor gene in prostate cancer; transfection of wt-ANX7 into LNCaP and DU145 prostate tumor cell lines markedly reduces cell proliferation and colony formation.\",\n      \"method\": \"Transfection of wt-ANX7 into tumor cell lines, proliferation assays, colony formation assays, loss-of-heterozygosity analysis with microsatellite markers\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean gain-of-function with defined cellular phenotype, replicated across two cell lines and validated in human tissue microarrays\",\n      \"pmids\": [\"11287641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Haploinsufficiency of Anx7 in mice leads to genomic instability, reduced expression of tumor suppressor genes, DNA repair genes, and apoptosis-related genes, and cancer-prone phenotype with chromosomal instability, placing ANXA7 upstream of a discrete tumor suppressor signaling pathway.\",\n      \"method\": \"Anx7+/- knockout mouse, genome array analysis, spectral karyotyping, tissue imprinting, laser-capture microdissection\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO model with multiple orthogonal methods including genomic and cytogenetic analysis\",\n      \"pmids\": [\"14608035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In Anx7+/- knockout mice, adrenal chromaffin cells are unable to discriminate between fed and fasted states, with sustained expression of nutritionally sensitive genes (chromogranin A/B, DbetaH), implicating the ANX7/IP3R signaling axis in nutrient-regulated secretory gene expression in chromaffin cells.\",\n      \"method\": \"Anx7+/- knockout mouse, cDNA microarray, feeding/fasting challenge\",\n      \"journal\": \"Annals of the New York Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with genome-wide expression profiling, single lab\",\n      \"pmids\": [\"12438089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A multi-hnRNP complex (hnRNP A1, A2/B1, K) binds to the steroid nuclear hormone receptor element cluster in the ANXA7 promoter in androgen-resistant prostate cancer cells (PC3), causing aberrant ANXA7 transcription and splicing; hnRNP A2/B1 antibody interference validates this regulatory role.\",\n      \"method\": \"Deletion mapping/promoter reporter assays, gelshift/EMSA, MALDI-TOF mass spectrometry, hnRNP A2/B1 antibody interference, RT-PCR, western blot\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (EMSA, MS, antibody interference) in single lab\",\n      \"pmids\": [\"20190808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BART (binder of Arl two) binds directly to ANX7, and the BART-ANX7 complex translocates to cell protrusions in migrating cells where it reduces PKCα activity; knockdown of BART or ANX7 increases PKCα activity and enhances invasiveness of pancreatic cancer cells, which is abrogated by PKCα inhibitors.\",\n      \"method\": \"Co-IP, pulldown, PKCα activity assay, BART/ANX7 siRNA knockdown, invasion assays, confocal imaging of complex localization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP interaction with functional validation by KD and pharmacological inhibition in single lab\",\n      \"pmids\": [\"22532868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In Anx7+/- mouse beta-cells, muscarinic agonist (carbachol) and ryanodine receptor agonists (caffeine, 4-chloro-m-cresol) elicit more potent depolarizing effects and augmented insulin secretion compared to controls, demonstrating that the Anx7+/- mutation alters IP3 receptor and ryanodine receptor signaling pathways regulating beta-cell membrane potential.\",\n      \"method\": \"Anx7+/- knockout mouse, electrophysiology, intracellular Ca2+ measurements, insulin secretion assays, pharmacological agonists\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple electrophysiological and secretory methods in KO model, single lab\",\n      \"pmids\": [\"22613970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Wild-type ANXA7 in LNCaP prostate cancer cells preserves total FOXO3A expression without hyperphosphorylation, enabling FOXO3A nuclear translocation and proapoptotic transcription, while inducing G1-arrest and programmed cell death; this is mechanistically distinct from p53 effects and linked to SGK1/FOXO3A/Akt pathway regulation.\",\n      \"method\": \"ANXA7 and p53 transfection into LNCaP cells, western blot for phospho/total FOXO3A, cell cycle analysis, apoptosis assays, Ingenuity Pathway Analysis\",\n      \"journal\": \"BioMed research international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — defined cellular phenotype with molecular pathway analysis, single lab\",\n      \"pmids\": [\"24864229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Inhibition of ANXA7 GTPase activity by small molecule ABO elevates HMBOX1 protein through translational upregulation; ANXA7 translocates to the nucleus upon GTPase inhibition and interacts with XRN2, reducing XRN2 phosphorylation and promoting TGFB2-OT1 lncRNA expression, which increases LARP1 and subsequently HMBOX1 translation.\",\n      \"method\": \"Small molecule ABO treatment, ANXA7-deficient HUVECs, western blot, ANXA7 nuclear fractionation, Co-IP of ANXA7-XRN2, lncRNA microarray, in vivo apoE-/- mouse model\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches (KD, small molecule, Co-IP, in vivo) in single lab\",\n      \"pmids\": [\"27506770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Activation of ANXA7 GTPase by small molecule SEC promotes AMPK phosphorylation, leading to decreased mTORC1 activity, suppressed STAT3 nuclear translocation, and downregulation of pro-metastatic genes (CCL2, APLN, IL6ST); RKIP interacts with ANXA7 and impairs SEC-induced ANXA7 GTPase activation and downstream signaling.\",\n      \"method\": \"SEC small molecule treatment, RKIP-ANXA7 Co-IP, AMPK/mTORC1/STAT3 pathway analysis, in vivo orthotopic prostate cancer metastasis assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP interaction plus pathway analysis and in vivo functional validation, single lab\",\n      \"pmids\": [\"29247827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Wild-type ANXA7 abolishes expression of oncogenic low-molecular weight (LMW) cyclin E in hormone-resistant prostate (DU145) and breast cancer cells; dominant-negative nMMM-ANXA7 (lacking phosphatidylserine liposome aggregation properties) fails to abrogate LMW-cyclin E and simultaneously induces FGF8 in DU145, consistent with continuing cell cycle progression.\",\n      \"method\": \"wt-ANXA7 and dominant-negative ANXA7 transfection, western blot for LMW-cyclin E and FGF8, cell cycle analysis, apoptosis assays in multiple cancer cell lines\",\n      \"journal\": \"Trends in cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — comparison of wt vs dominant-negative ANXA7 with defined molecular readouts, single lab\",\n      \"pmids\": [\"30369774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Inhibition of ANXA7 GTPase activity by ABO causes ANXA7 to translocate into the nucleus where it interacts with XRN2; reduced XRN2 phosphorylation promotes read-through transcription of MROH7-TTC4 lncRNA, which is processed by TIA1 into MROH7 and TTC4 that inhibit VEC apoptosis.\",\n      \"method\": \"ABO GTPase inhibitor, nuclear fractionation/localization of ANXA7, Co-IP of ANXA7-XRN2, lncRNA microarray, TIA1 pulldown, apoptosis assays in HUVECs\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP, localization, and functional pathway validated by multiple assays in single lab\",\n      \"pmids\": [\"31408583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ANXA7 knockdown inhibits JAK1/STAT3 pathway activation in trophoblast cells, reduces BCL2 protein levels, induces apoptosis, and inhibits proliferation; ANXA7 overexpression has the opposite effects, placing ANXA7 upstream of the JAK1/STAT3 anti-apoptotic pathway in trophoblasts.\",\n      \"method\": \"ANXA7 siRNA knockdown and overexpression in HTR-8/SVneo cells, western blot for BCL2/JAK1/STAT3, flow cytometry for apoptosis, CCK-8 proliferation assay\",\n      \"journal\": \"American journal of reproductive immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional (KD and OE) with defined pathway readout, single lab\",\n      \"pmids\": [\"31446642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANXA7 translocates to impaired mitochondria upon CCCP treatment and interacts with BASP1 to play a pivotal role in Parkin-dependent mitophagy.\",\n      \"method\": \"Quantitative mitochondrial proteomics (DIA), CCCP-induced mitophagy assay, ANXA7 KD, Co-IP of ANXA7-BASP1, mitochondrial fractionation\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — proteomics discovery with Co-IP and KD functional validation, single lab\",\n      \"pmids\": [\"31975592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANXA7 promotes proliferation, cell cycle progression, and cell adhesion-mediated drug resistance in multiple myeloma cells by directly binding to and upregulating CDC5L.\",\n      \"method\": \"Co-IP of ANXA7-CDC5L, ANXA7 overexpression and knockdown in MM cell lines, CDC5L siRNA rescue experiments, proliferation/apoptosis/cell cycle assays\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP interaction with rescue experiments, single lab\",\n      \"pmids\": [\"32526706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A dominant-negative triple mutant of ANXA7 (DNTM/DN-ANXA7J, mutating GX(X)GT motifs in endonexin-fold repeats) suppresses membrane fusion with artificial membranes, alters calcium and phospholipid binding, reduces IP3 receptor expression, and modulates PI3K/AKT/mTOR signaling in prostate cancer cells, demonstrating that calcium/phospholipid binding by ANXA7 is required for its tumor suppressor function.\",\n      \"method\": \"Active-site mutagenesis of ANXA7 endonexin folds, in vitro membrane fusion assay, calcium/phospholipid binding assay, IP3 receptor western blot, PI3K/AKT/mTOR pathway analysis, apoptosis assays in prostate cancer cells\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with mutagenesis and multiple cellular assays, single lab\",\n      \"pmids\": [\"37240163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ANXA7 GTPase activation protects neurons after OGD/R by enhancing autophagy via the mTOR/TFEB pathway and inhibiting apoptosis; ANXA7 directly interacts with lysosomal membrane protein LAMP5 (with Asp411 mutation impairing this interaction), and ANXA7 stabilizes LAMP5 protein expression to maintain lysosomal acidic environment.\",\n      \"method\": \"OGD/R neuronal model, ANXA7 GTPase activation/inhibition, Co-IP of ANXA7-LAMP5, Asp411 mutagenesis, LAMP5 overexpression rescue, mTOR/TFEB pathway analysis, in vivo SCI mouse model with lentiviral ANXA7 overexpression, CatWalk assay\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with mutagenesis, in vitro and in vivo functional validation, single lab\",\n      \"pmids\": [\"37620352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZBTB16 directly interacts with ANXA7 protein (validated by Co-IP), and ZBTB16 promotes ANXA7 expression which subsequently inhibits Cyclin B1 expression; this ZBTB16/ANXA7/Cyclin B1 axis mediates cell cycle arrest and apoptosis in breast cancer cells downstream of UHRF1 knockdown.\",\n      \"method\": \"Co-IP of ZBTB16-ANXA7, ANXA7 KD rescue experiments, Cyclin B1 western blot, cell cycle and apoptosis assays, methylation-specific PCR, ChIP for UHRF1/DNMT1 at ZBTB16 promoter\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP interaction with rescue experiments and pathway analysis, single lab\",\n      \"pmids\": [\"39308302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ANXA7 acts as a critical adaptor for retrograde axonal transport by physically linking TIA1-containing RNPs to cytoplasmic dynein; persistent axonal Ca2+ elevation or ANXA7 knockdown decouples TIA1 granules from dynein, impairing retrograde transport and causing pathological TIA1 aggregation and axonopathy; ANXA7 overexpression enhances RNP trafficking and counteracts TIA1 aggregation.\",\n      \"method\": \"Live imaging of axonal transport, ANXA7 KD and OE in neurons, Co-IP of ANXA7-TIA1-dynein complex, Ca2+ elevation experiments, in vitro and in vivo axonopathy models\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and live transport imaging with KD/OE functional validation, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.01.16.633295\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ANXA7 GTPase activation promotes lipid droplet formation by interacting with PPARγ to enhance its stability and nuclear translocation, driving Perilipin 5 expression and mitochondria-lipid droplet interaction; this inhibits lipid peroxidation through NRF2/GPX4 and reduces oxidative stress and neuron damage after spinal cord injury.\",\n      \"method\": \"Co-IP of ANXA7-PPARγ, ANXA7 GTPase activation, PPARγ stability assay, lipid droplet imaging, NRF2/GPX4 western blot, in vivo SCI mouse model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP interaction with in vitro and in vivo functional validation, single lab\",\n      \"pmids\": [\"39996504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RNF168 E3 ubiquitin ligase promotes ubiquitination and degradation of ANXA7; reduced ANXA7 levels suppress autophagy and enhance NLRP3 inflammasome-mediated pyroptosis in intestinal epithelial cells, driving Crohn's disease progression.\",\n      \"method\": \"Co-IP and ubiquitination assays (RNF168-ANXA7), ANXA7 KD and OE in NCM460 cells, autophagy and NLRP3 pyroptosis assays, IL-10 KO and RNF168flox/flox;Villin-Cre mice with TNBS colitis, organoid experiments\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ubiquitination assay with Co-IP, in vitro and in vivo functional rescue, single lab\",\n      \"pmids\": [\"41518435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LEPR (Leptin Receptor) physically interacts with ANXA7 (validated by Co-IP), and mechanistically regulates ERK1/2 and JAK2/STAT3 signaling through ANXA7 in hepatocellular carcinoma lymphatic metastatic cells.\",\n      \"method\": \"Co-immunoprecipitation of LEPR-ANXA7, western blot for ERK1/2 and JAK2/STAT3, LEPR knockdown/overexpression functional assays\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with limited mechanistic follow-up, single lab\",\n      \"pmids\": [\"33397392\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANXA7 is a Ca2+-activated GTPase and calcium/phospholipid-binding protein whose GTPase and membrane fusion activities (dependent on endonexin-fold calcium-binding motifs) underlie its roles as a tumor suppressor—suppressing cell proliferation, LMW-cyclin E, and activating FOXO3A/apoptotic pathways—and as a regulator of IP3 receptor expression, Ca2+-dependent insulin secretion, Parkin-dependent mitophagy (via BASP1 interaction), neuronal RNP retrograde transport (linking TIA1 granules to dynein), and multiple signaling axes (AMPK/mTORC1/STAT3, JAK1/STAT3, PPARγ/NRF2/GPX4, BART-PKCα); its activity is regulated by RKIP binding (impairing GTPase activation), hnRNP complex-mediated aberrant splicing at the promoter, and RNF168-mediated ubiquitination and degradation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ANXA7 is a calcium- and phospholipid-binding protein with intrinsic GTPase activity that functions as a tumor suppressor, a regulator of intracellular calcium signaling, and an adaptor linking ribonucleoprotein cargo to the dynein motor for retrograde axonal transport. Its GTPase activity, dependent on endonexin-fold calcium-binding motifs, drives membrane fusion, IP3 receptor expression, and downstream signaling through AMPK/mTORC1/STAT3 and PI3K/AKT/mTOR pathways; loss of ANXA7 in mice causes profound reduction of IP3 receptor function, impaired insulin secretion, genomic instability, and cancer susceptibility [PMID:10570150, PMID:14608035, PMID:37240163]. ANXA7 suppresses oncogenic low-molecular-weight cyclin E and Cyclin B1 expression, activates FOXO3A-dependent apoptosis, and its tumor suppressor activity is abrogated by dominant-negative mutations that impair calcium/phospholipid binding [PMID:11287641, PMID:24864229, PMID:30369774, PMID:39308302]. Beyond cancer, ANXA7 translocates to damaged mitochondria to promote Parkin-dependent mitophagy via BASP1 interaction, stabilizes PPARγ to drive lipid droplet formation and NRF2/GPX4-mediated anti-ferroptotic protection in neurons, interacts with LAMP5 to maintain lysosomal function and autophagy, and is itself targeted for ubiquitin-dependent degradation by RNF168, linking its loss to NLRP3 inflammasome activation and Crohn's disease pathology [PMID:31975592, PMID:37620352, PMID:39996504, PMID:41518435].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing ANXA7 as a Ca²⁺-activated GTPase essential for IP3 receptor expression and insulin secretion resolved how this annexin family member couples calcium signaling to secretory function in vivo.\",\n      \"evidence\": \"Anx7 knockout mouse with electrophysiology, Ca²⁺ imaging, and insulin secretion assays\",\n      \"pmids\": [\"10570150\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GTPase catalytic mechanism not structurally resolved\", \"whether GTPase activity is required for IP3R regulation was not tested by point mutation\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrating that wild-type ANXA7 reintroduction suppresses prostate cancer cell proliferation and colony formation established ANXA7 as a bona fide tumor suppressor, connecting its biochemical activity to growth control.\",\n      \"evidence\": \"wt-ANXA7 transfection into LNCaP and DU145 cells with proliferation and colony formation assays, LOH analysis in human tissue\",\n      \"pmids\": [\"11287641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"molecular target through which ANXA7 arrests proliferation was unidentified\", \"in vivo tumor suppression not directly tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showing that Anx7 haploinsufficiency causes genomic instability, reduced expression of tumor suppressors and DNA repair genes, and a cancer-prone phenotype in mice placed ANXA7 upstream of a broad genomic maintenance network.\",\n      \"evidence\": \"Anx7+/- knockout mouse with genome array analysis and spectral karyotyping\",\n      \"pmids\": [\"14608035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"direct mechanism linking ANXA7 to DNA repair gene regulation unknown\", \"whether GTPase activity mediates genomic stability not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identifying a multi-hnRNP complex that binds the ANXA7 promoter and causes aberrant splicing in androgen-resistant prostate cancer revealed a transcriptional mechanism for ANXA7 silencing in cancer.\",\n      \"evidence\": \"Promoter deletion mapping, EMSA, MALDI-TOF MS, and hnRNP A2/B1 antibody interference in PC3 cells\",\n      \"pmids\": [\"20190808\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether hnRNP-mediated silencing occurs in primary tumors not shown\", \"splice variants not functionally characterized\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that BART–ANXA7 complex translocates to cell protrusions and inhibits PKCα activity linked ANXA7 to regulation of cell migration and invasiveness beyond its canonical tumor suppressor role.\",\n      \"evidence\": \"Co-IP, PKCα activity assay, BART/ANXA7 siRNA knockdown, and invasion assays in pancreatic cancer cells\",\n      \"pmids\": [\"22532868\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"structural basis of BART–ANXA7 interaction unknown\", \"single Co-IP without reciprocal pulldown from endogenous lysates\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing that ANXA7 preserves FOXO3A from hyperphosphorylation and enables its nuclear translocation for proapoptotic transcription defined a mechanistic pathway distinct from p53 by which ANXA7 triggers apoptosis.\",\n      \"evidence\": \"ANXA7 transfection into LNCaP cells, phospho-FOXO3A western blot, cell cycle and apoptosis assays\",\n      \"pmids\": [\"24864229\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether ANXA7 directly binds FOXO3A or acts through SGK1/Akt not resolved\", \"single cell line\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that ANXA7 GTPase activation feeds into AMPK/mTORC1/STAT3 signaling and that RKIP binding impairs this activation established a GTPase-centric signal transduction model for ANXA7's anti-metastatic activity.\",\n      \"evidence\": \"SEC small molecule activator, RKIP–ANXA7 Co-IP, pathway analysis, orthotopic prostate cancer metastasis model\",\n      \"pmids\": [\"29247827\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct GTPase kinetic parameters with RKIP not measured\", \"SEC specificity for ANXA7 versus other annexins not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showing that wild-type but not dominant-negative ANXA7 (lacking phosphatidylserine binding) abolishes oncogenic LMW-cyclin E linked ANXA7's membrane fusion properties to cell cycle regulation.\",\n      \"evidence\": \"wt vs. nMMM-ANXA7 transfection, western blot for LMW-cyclin E and FGF8, cell cycle analysis in DU145 and breast cancer cells\",\n      \"pmids\": [\"30369774\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism connecting phospholipid binding to cyclin E regulation not identified\", \"limited to overexpression system\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying ANXA7 translocation to impaired mitochondria and its interaction with BASP1 during Parkin-dependent mitophagy expanded ANXA7 function beyond secretion and cancer to organelle quality control.\",\n      \"evidence\": \"Quantitative mitochondrial DIA proteomics, CCCP-induced mitophagy, ANXA7 KD, Co-IP of ANXA7–BASP1\",\n      \"pmids\": [\"31975592\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether ANXA7 GTPase activity is required for mitophagy not tested\", \"BASP1–ANXA7 interaction not validated by reciprocal approach\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mutagenesis of endonexin-fold GX(X)GT motifs proved that calcium/phospholipid binding is required for ANXA7's membrane fusion, IP3R regulation, and tumor suppressor functions, unifying its biochemical and cellular activities.\",\n      \"evidence\": \"Active-site mutagenesis of ANXA7 endonexin folds, in vitro membrane fusion assay, Ca²⁺/phospholipid binding, IP3R and PI3K/AKT/mTOR pathway analysis\",\n      \"pmids\": [\"37240163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no crystal structure of mutant ANXA7 to verify fold integrity\", \"in vivo tumor suppression by mutant not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that ANXA7 interacts with LAMP5 via Asp411 to maintain lysosomal acidity and promote mTOR/TFEB-dependent autophagy after neuronal injury provided a neuroprotective mechanism for ANXA7 GTPase activity.\",\n      \"evidence\": \"OGD/R neuronal model, Co-IP of ANXA7–LAMP5, Asp411 mutagenesis, in vivo SCI mouse model with lentiviral ANXA7 OE\",\n      \"pmids\": [\"37620352\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether LAMP5 interaction is Ca²⁺-dependent not tested\", \"single mutagenesis site without comprehensive domain mapping\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showing that ANXA7 GTPase activation stabilizes PPARγ, drives lipid droplet biogenesis, and engages NRF2/GPX4 anti-ferroptotic signaling linked ANXA7 to lipid metabolism and oxidative stress defense in neurons.\",\n      \"evidence\": \"Co-IP of ANXA7–PPARγ, PPARγ stability assay, lipid droplet imaging, NRF2/GPX4 pathway analysis, in vivo SCI model\",\n      \"pmids\": [\"39996504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct vs. indirect stabilization of PPARγ not distinguished\", \"whether this pathway operates outside neuronal injury context unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying ANXA7 as an adaptor linking TIA1-containing RNP granules to cytoplasmic dynein for retrograde axonal transport revealed an entirely new cell-biological role for this annexin in neuronal homeostasis.\",\n      \"evidence\": \"(preprint) Live axonal transport imaging, ANXA7 KD/OE in neurons, Co-IP of ANXA7–TIA1–dynein complex, Ca²⁺ elevation experiments\",\n      \"pmids\": [\"bio_10.1101_2025.01.16.633295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"preprint not yet peer-reviewed\", \"whether Ca²⁺-dependent uncoupling involves GTPase activity not tested\", \"structural basis of ANXA7–dynein interaction unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrating that RNF168 ubiquitinates and degrades ANXA7, suppressing autophagy and promoting NLRP3 inflammasome-driven pyroptosis, established a post-translational regulatory mechanism for ANXA7 levels with disease relevance in Crohn's disease.\",\n      \"evidence\": \"Co-IP and ubiquitination assays, ANXA7 KD/OE in NCM460 cells, RNF168flox/flox;Villin-Cre mice with TNBS colitis, organoid experiments\",\n      \"pmids\": [\"41518435\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ubiquitination sites on ANXA7 not mapped\", \"whether RNF168-ANXA7 axis operates in non-intestinal contexts unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of ANXA7 GTPase activity, the identity of a physiological GEF or GAP, and how GTPase cycling is coordinated with calcium-dependent membrane binding remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"no crystal or cryo-EM structure of ANXA7\", \"no GEF/GAP identified\", \"GTPase kinetic parameters under physiological conditions not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 9, 15, 16, 19]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [10, 15]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 9, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 11]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 15]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 6, 9, 12, 16, 19]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 7, 10, 17, 20]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [7, 10, 14, 17]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [13, 16, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 14, 20]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RKIP\",\n      \"BASP1\",\n      \"BART\",\n      \"XRN2\",\n      \"LAMP5\",\n      \"ZBTB16\",\n      \"TIA1\",\n      \"PPARG\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}