{"gene":"ANXA7","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":1999,"finding":"ANX7/ANXA7 encodes a Ca2+-activated GTPase that supports Ca2+/GTP-dependent secretion events and Ca2+ channel activities; the homozygous knockout (anx7-/-) is embryonically lethal at E10 due to cerebral hemorrhage, while heterozygous anx7(+/-) mice show defective insulin secretion linked to profound reduction in IP3 receptor expression and function in pancreatic islets.","method":"Gene knockout mouse model (anx7-/- and anx7+/-), electrophysiology, electrooptical Ca2+ recordings, insulin secretion assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO mouse, electrophysiology, Ca2+ imaging, secretion assay) in a single rigorous study establishing direct mechanistic link between ANXA7 and IP3R-dependent Ca2+ signaling and insulin secretion","pmids":["10570150"],"is_preprint":false},{"year":2001,"finding":"Wild-type ANX7 transfection markedly reduces human prostate tumor cell proliferation and colony formation in LNCaP and DU145 cell lines, demonstrating tumor suppressor activity; loss of heterozygosity at the ANX7 locus (10q21) is found in 35% of primary prostate tumors.","method":"Transfection of wild-type ANX7 into prostate tumor cell lines, colony formation assay, loss-of-heterozygosity analysis with microsatellite markers, tissue microarray immunohistochemistry","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional overexpression with proliferation/colony assays plus LOH genetic data in single lab","pmids":["11287641"],"is_preprint":false},{"year":2003,"finding":"Haploinsufficiency of Anx7 in the Anx7(+/-) mouse drives genomic instability, reduction of multiple tumor suppressor genes, DNA repair genes, and apoptosis-related genes, and promotes spontaneous tumorigenesis (23% incidence) with chromosomal aberrations.","method":"Anx7(+/-) knockout mouse; genome array expression profiling; spectral karyotyping; in situ analysis by tissue imprinting; laser-capture microdissection","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (KO mouse, genomic arrays, karyotyping) in single lab establishing pathway-level mechanism","pmids":["14608035"],"is_preprint":false},{"year":2002,"finding":"In Anx7(+/-) knockout mice, chromaffin cells of the adrenal gland show defective IP3 receptor expression and an inability to discriminate nutritional state (fed vs. fasted), resulting in sustained expression of nutritionally sensitive genes (chromogranin A/B, DβH) and adrenal gland hypertrophy/chromaffin cell hyperplasia.","method":"Anx7(+/-) knockout mouse; cDNA microarray; adrenal gland phenotypic analysis","journal":"Annals of the New York Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with genome-wide expression profiling and histological phenotype, single lab","pmids":["12438089"],"is_preprint":false},{"year":2010,"finding":"A multi-hnRNP complex (containing hnRNP A1, A2/B1, and K) binds the steroid nuclear hormone receptor element cluster at the ANXA7 promoter (-1086/-890) specifically in androgen-resistant prostate cancer cells (PC3), but not in normal prostate cells (PrEC), leading to aberrant ANXA7 transcription and alternative splicing; hnRNPA2/B1 antibody interference validated this regulation.","method":"Deletion mapping/promoter activity assays; Genomatix analysis; gel-shift (EMSA); MALDI-TOF mass spectrometry identification of hnRNP proteins; antibody interference assay; Ingenuity Pathway Analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA, mass spectrometry, and functional antibody interference across multiple cell lines, single lab","pmids":["20190808"],"is_preprint":false},{"year":2012,"finding":"BART binds directly to ANX7 and the BART-ANX7 complex reduces PKCα activity; knockdown of either BART or ANX7 increases PKCα activity and enhances invasiveness of pancreatic cancer cells, which is abrogated by PKCα-specific inhibitors.","method":"Co-immunoprecipitation (BART-ANX7 interaction); knockdown of BART and ANX7; PKCα activity assay; invasion assay; PKCα inhibitor treatment","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal functional knockdown plus Co-IP and enzymatic activity assay, single lab","pmids":["22532868"],"is_preprint":false},{"year":2012,"finding":"In Anx7(+/-) beta-cells, the muscarinic agonist carbachol and ryanodine receptor agonists (caffeine, 4-chloro-m-cresol) have more potent depolarizing effects and augment glucose-induced insulin secretion; however, ryanodine receptor-mediated Ca2+ mobilization itself is not affected, indicating that the Anx7(+/-) mutation alters downstream signaling pathways associated with IP3 receptors and ryanodine receptors, not the Ca2+ stores directly.","method":"Anx7(+/-) knockout mouse beta-cells; electrophysiology; intracellular Ca2+ measurements; insulin secretion assay; pharmacological agonists (carbachol, caffeine, 4-chloro-m-cresol)","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with electrophysiology and Ca2+ imaging, multiple pharmacological probes, single lab","pmids":["22613970"],"is_preprint":false},{"year":2017,"finding":"Activation of ANXA7 GTPase by small molecule SEC suppresses prostate cancer metastasis by promoting 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 GTPase activation and downstream signaling.","method":"Small molecule (SEC) GTPase activation; AMPK/mTORC1/STAT3 pathway analysis by Western blot; RKIP-ANXA7 interaction; in vivo orthotopic prostate cancer metastasis model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo orthotopic model plus mechanistic pathway dissection, single lab","pmids":["29247827"],"is_preprint":false},{"year":2016,"finding":"Small molecule ABO directly targets ANXA7 and inhibits its GTPase activity; inhibition of ANXA7 GTPase causes increased TGFB2-OT1 expression, which elevates LARP1, leading to enhanced HMBOX1 translation in vascular endothelial cells; ABO fails to increase HMBOX1 in ANXA7-deficient HUVECs, confirming ANXA7 dependency.","method":"Small molecule (ABO) GTPase inhibition; ANXA7 knockdown; HMBOX1 protein quantification; TGFB2-OT1/LARP1 expression analysis; in vivo apoE-/- mouse model","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ANXA7 KD rescue experiment, in vivo validation, mechanistic pathway; single lab","pmids":["27506770"],"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 (5'→3' exoribonuclease); decreased XRN2 phosphorylation promotes read-through transcription of MROH7-TTC4 lncRNA, which is then processed by TIA1 into MROH7 and TTC4 to inhibit vascular endothelial cell apoptosis.","method":"GTPase inhibitor (ABO); lncRNA microarray; Co-immunoprecipitation (ANXA7-XRN2); nuclear translocation imaging; TIA1 binding assay","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of ANXA7-XRN2 interaction with functional lncRNA and apoptosis readout, single lab","pmids":["31408583"],"is_preprint":false},{"year":2019,"finding":"ANXA7 knockdown inhibits JAK1/STAT3 pathway activation in trophoblast HTR-8/SVneo cells, reduces BCL2 levels, promotes apoptosis, and inhibits proliferation; ANXA7 overexpression has the opposite effect, establishing ANXA7/JAK1/STAT3 as a regulatory pathway in trophoblast survival.","method":"siRNA knockdown and overexpression in HTR-8/SVneo cells; Western blot; flow cytometry (apoptosis); CCK-8 proliferation assay","journal":"American journal of reproductive immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation (KD and OE) with multiple readouts, single lab","pmids":["31446642"],"is_preprint":false},{"year":2020,"finding":"ANXA7 translocates to impaired mitochondria upon CCCP-induced mitochondrial damage and plays a pivotal role in Parkin-dependent mitophagy by interacting with BASP1.","method":"Data-independent acquisition quantitative mitochondrial proteomics; mitochondrial fractionation/translocation assay; Co-immunoprecipitation (ANXA7-BASP1); CCCP treatment","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus Co-IP and localization assay establishing ANXA7-BASP1 interaction in mitophagy, single lab","pmids":["31975592"],"is_preprint":false},{"year":2020,"finding":"ANXA7 overexpression promotes proliferation, cell cycle progression, and cell adhesion-mediated drug resistance in multiple myeloma cells through upregulation of CDC5L; co-immunoprecipitation confirmed ANXA7 binds CDC5L, and CDC5L knockdown reverses ANXA7 overexpression effects.","method":"ANXA7 overexpression and knockdown in U266/RPMI8226 cells; co-immunoprecipitation (ANXA7-CDC5L); proliferation, cell cycle, and apoptosis assays; BMSC co-culture drug resistance model","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for interaction plus bidirectional manipulation with multiple functional readouts, single lab","pmids":["32526706"],"is_preprint":false},{"year":2021,"finding":"LEPR interacts with ANXA7 (confirmed by co-immunoprecipitation) and regulates ERK1/2 and JAK2/STAT3 signaling via ANXA7 in hepatocellular carcinoma lymphatic metastatic cells.","method":"Co-immunoprecipitation (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 / Weak — single Co-IP experiment with pathway analysis, single lab, limited mechanistic depth for ANXA7 specifically","pmids":["33397392"],"is_preprint":false},{"year":2023,"finding":"ANXA7 interacts with LAMP5 (lysosomal-associated membrane protein 5) in neurons; the Asp411 mutation of ANXA7 markedly impairs the ANXA7-LAMP5 interaction. Activated ANXA7 GTPase promotes autophagy via the mTOR/TFEB pathway, inhibits neuronal apoptosis after OGD/R, and stabilizes LAMP5 protein expression; LAMP5 overexpression rescues defects caused by ANXA7 downregulation.","method":"Co-immunoprecipitation (ANXA7-LAMP5); site-directed mutagenesis (Asp411); GTPase activation assay; ANXA7 overexpression lentivirus; CatWalk assay (SCI mice); mTOR/TFEB pathway analysis; autophagy and apoptosis assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus mutagenesis plus in vivo rescue, single lab, multiple orthogonal methods","pmids":["37620352"],"is_preprint":false},{"year":2023,"finding":"A dominant-negative triple mutant of ANXA7 (DNTM/DN-ANXA7J) in the GX(X)GT endonexin-fold repeats suppresses membrane fusion with artificial membranes, alters calcium and phospholipid binding, and in prostate cancer cells reduces IP3 receptor expression and modulates PI3K/AKT/mTOR signaling while affecting phosphatidylserine exposure, membrane permeabilization, and apoptosis.","method":"Site-directed mutagenesis (triple mutant); artificial membrane fusion assay; calcium and phospholipid binding assays; IP3R expression analysis; PI3K/AKT/mTOR pathway Western blot; cell death/apoptosis assays in prostate cancer cells","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted membrane fusion assay with mutagenesis plus cellular pathway analysis, single lab","pmids":["37240163"],"is_preprint":false},{"year":2014,"finding":"Wild-type ANXA7 in LNCaP prostate cancer cells induces G1-arrest and programmed cell death while preserving total FOXO3A expression without hyperphosphorylation (enabling FOXO3A nuclear translocation); ANXA7 tumor suppression operates through a mechanism distinct from p53, which fails to prevent SGK1-mediated FOXO3A phosphorylation and cytoplasmic retention.","method":"Transfection of wt-ANXA7 vs. p53 in LNCaP cells; cell cycle analysis; apoptosis assays; FOXO3A phosphorylation and localization analysis by Western blot; Ingenuity Pathway Analysis","journal":"BioMed research international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression with Western blot pathway readouts, no direct binding or enzymatic assay","pmids":["24864229"],"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; a dominant-negative ANXA7 mutant (nMMM-ANXA7, lacking phosphatidylserine liposome aggregation properties) fails to abrogate LMW-cyclin E and simultaneously induces FGF8 in DU145, allowing continued cell cycle progression.","method":"Adenoviral wt-ANXA7 and dominant-negative nMMM-ANXA7 overexpression; cell cycle analysis; Western blot for LMW-cyclin E and FGF8; comparison across prostate (DU145) and breast (MDA-MB-231, -435) cancer lines","journal":"Trends in cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression/dominant-negative approach with Western blot readouts, single lab, no direct binding assay","pmids":["30369774"],"is_preprint":false},{"year":2024,"finding":"ZBTB16 interacts with ANXA7 protein (confirmed by co-IP); ZBTB16 promotes ANXA7 expression, which subsequently inhibits Cyclin B1 expression; UHRF1 suppresses ZBTB16 by promoting ZBTB16 promoter methylation via DNMT1 recruitment, thereby reducing ANXA7 and enabling breast cancer cell proliferation.","method":"Co-immunoprecipitation (ZBTB16-ANXA7); methylation-specific PCR; ChIP assay; UHRF1/ZBTB16/ANXA7 knockdown and overexpression; cell cycle, proliferation, and apoptosis assays; in vivo xenograft","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for interaction, ChIP for epigenetic regulation, rescue experiments, in vivo validation, single lab","pmids":["39308302"],"is_preprint":false},{"year":2026,"finding":"RNF168 promotes ubiquitination and degradation of ANXA7; loss of ANXA7 suppresses autophagy and induces NLRP3 inflammasome-mediated pyroptosis in intestinal epithelial cells, promoting Crohn's disease progression; ELK1 transcription factor upregulates RNF168 as the upstream regulator.","method":"Co-immunoprecipitation and mass spectrometry (RNF168-ANXA7 interaction); ubiquitination assay; ANXA7 knockdown/overexpression; autophagy and pyroptosis assays; IL-10 KO and RNF168flox/flox;Villin-Cre mouse models; organoids","journal":"Apoptosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo mouse models with rescue experiments, single lab","pmids":["41518435"],"is_preprint":false},{"year":2025,"finding":"ANXA7 acts as an adaptor protein facilitating retrograde transport of TIA1-containing ribonucleoprotein (RNP) granules by linking them to cytoplasmic dynein in axons; elevated axonal Ca2+ disrupts this linker role, causing detachment of TIA1 granules from dynein and pathological TIA1 aggregation; ANXA7 knockdown similarly impairs trafficking and causes axonopathy in vitro and in vivo.","method":"Live imaging of axonal RNP transport; ANXA7 knockdown and overexpression; Co-IP (ANXA7-TIA1-dynein); Ca2+ manipulation; in vitro and in vivo axonopathy models","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus live trafficking imaging plus KD/OE with in vivo validation; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.01.16.633295"],"is_preprint":true},{"year":1999,"finding":"ANX7/ANXA7 contains a PGQM motif in its regulatory domain; this motif is shared with HIV-1 Gag, and mutations in this motif in Gag disrupt viral replication, suggesting the motif mediates protein-protein interactions relevant to membrane fusion/secretory functions of ANXA7.","method":"Alanine scanning mutagenesis of PGQM motif in HIV-1 Gag; single- and multi-round viral replication assays; sequence homology with synexin/ANX7","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Low","confidence_rationale":"Tier 4 / Weak — functional data is on HIV Gag, not directly on ANXA7; only structural homology noted for ANXA7","pmids":["10077575"],"is_preprint":false},{"year":2025,"finding":"ANXA7 GTPase activation promotes lipid droplet formation and mitochondria-lipid droplet interaction by interacting with PPARγ to enhance its stability and promote its nuclear translocation; this leads to Perilipin 5 upregulation, NRF2 nuclear translocation, and GPX4 expression, thereby inhibiting oxidative stress and lipid peroxidation in spinal cord injury neurons.","method":"ANXA7 GTPase activation (small molecule); Co-immunoprecipitation (ANXA7-PPARγ); PPARγ stability assay; lipid droplet and mitochondria imaging; NRF2/GPX4 expression; SCI mouse model with CatWalk assay","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for interaction, in vivo SCI model, multiple pathway readouts, single lab","pmids":["39996504"],"is_preprint":false}],"current_model":"ANXA7 is a Ca2+-activated GTPase and calcium/phospholipid-binding protein that functions as a tumor suppressor (particularly at chromosome 10q21) and regulates multiple cellular processes: it is required for IP3 receptor expression and IP3-dependent Ca2+ signaling that drives regulated secretion (especially insulin in beta-cells); its GTPase activity modulates autophagy (via mTOR/TFEB), apoptosis, mitophagy (through BASP1 interaction), and axonal RNP transport (by linking TIA1-containing granules to dynein); it suppresses tumor progression by controlling AMPK/mTORC1/STAT3 and PI3K/AKT/mTOR signaling, by preventing LMW-cyclin E expression, and by interacting with partners including LAMP5, CDC5L, ZBTB16, PKCα (via BART), and PPARγ; its expression is transcriptionally repressed by a multi-hnRNP complex at a steroid-responsive promoter element in androgen-resistant prostate cancer cells, and its protein is subject to ubiquitin-mediated degradation by RNF168."},"narrative":{"mechanistic_narrative":"ANXA7 is a Ca2+-activated GTPase and calcium/phospholipid-binding protein that couples membrane dynamics to Ca2+ signaling and acts as a tumor suppressor whose loss drives genomic instability and tumorigenesis [PMID:10570150, PMID:11287641, PMID:14608035]. Its membrane fusion, calcium binding, and phospholipid binding activities depend on the GX(X)GT endonexin-fold repeats, and disrupting these by mutagenesis abolishes fusion with artificial membranes and lowers IP3 receptor expression [PMID:37240163]. At the organismal level, ANXA7 is required for IP3 receptor expression and IP3-dependent Ca2+ signaling that supports regulated secretion: heterozygous knockout mice have profoundly reduced islet IP3R and defective glucose-induced insulin secretion, with altered downstream responses to muscarinic and ryanodine-receptor agonists rather than direct changes to Ca2+ stores [PMID:10570150, PMID:22613970]. The GTPase activity is a regulatory switch exploited pharmacologically: its activation promotes AMPK phosphorylation with consequent suppression of mTORC1 and STAT3 signaling and prostate cancer metastasis [PMID:29247827], drives autophagy through the mTOR/TFEB axis [PMID:37620352], and governs apoptotic and oxidative-stress programs [PMID:31408583, PMID:39996504]. ANXA7 tumor suppression operates through control of cell-cycle and survival outputs—abolishing oncogenic LMW-cyclin E, preserving FOXO3A, and inhibiting Cyclin B1—and through partner interactions including a BART complex that restrains PKCα-driven invasion, CDC5L in myeloma, and the ZBTB16 axis controlled epigenetically by UHRF1/DNMT1 [PMID:22532868, PMID:32526706, PMID:39308302]. Its abundance is set both transcriptionally, by a multi-hnRNP repressor complex at a steroid-responsive promoter element in androgen-resistant prostate cells [PMID:20190808], and post-translationally, via RNF168-mediated ubiquitination and degradation, the loss of which suppresses autophagy and promotes NLRP3-inflammasome pyroptosis in Crohn's disease [PMID:41518435]. ANXA7 also acts in damaged-mitochondria turnover by interacting with BASP1 in Parkin-dependent mitophagy [PMID:31975592] and as an adaptor linking TIA1 ribonucleoprotein granules to cytoplasmic dynein for axonal transport [PMID:bio_10.1101_2025.01.16.633295].","teleology":[{"year":1999,"claim":"Established ANXA7 as a Ca2+-activated GTPase functionally required for IP3 receptor-dependent Ca2+ signaling and regulated secretion in vivo, answering whether the protein had an essential physiological role.","evidence":"anx7-/- and anx7+/- knockout mice with electrophysiology, Ca2+ imaging, and insulin secretion assays","pmids":["10570150"],"confidence":"High","gaps":["Mechanism by which ANXA7 controls IP3R expression not defined","Cause of embryonic cerebral hemorrhage in nulls not resolved"]},{"year":2001,"claim":"Defined ANXA7 as a tumor suppressor by showing wild-type re-expression suppresses prostate tumor cell growth and that the locus undergoes loss of heterozygosity in primary tumors.","evidence":"wt-ANX7 transfection, colony formation assays, LOH analysis at 10q21, and tissue microarray IHC","pmids":["11287641"],"confidence":"Medium","gaps":["Molecular targets of growth suppression not yet identified","Single-lab functional overexpression"]},{"year":2003,"claim":"Showed that Anx7 haploinsufficiency causes genomic instability and spontaneous tumorigenesis, linking dosage to a broad transcriptional program of tumor suppressor, DNA repair, and apoptosis genes.","evidence":"Anx7(+/-) mouse with genome expression arrays, spectral karyotyping, and laser-capture microdissection","pmids":["14608035"],"confidence":"Medium","gaps":["Direct molecular driver of instability not identified","Correlative array data"]},{"year":2002,"claim":"Extended the IP3R-dependent secretory phenotype to adrenal chromaffin cells, showing ANXA7 loss disrupts nutritional-state sensing and causes gland hyperplasia.","evidence":"Anx7(+/-) mouse cDNA microarray and adrenal histological phenotyping","pmids":["12438089"],"confidence":"Medium","gaps":["Link between IP3R loss and gene dysregulation not mechanistically resolved"]},{"year":2010,"claim":"Identified a transcriptional repression mechanism, showing a multi-hnRNP complex binds a steroid-responsive promoter element to aberrantly control ANXA7 in androgen-resistant cancer cells.","evidence":"promoter mapping, EMSA, MALDI-TOF identification of hnRNPs, and antibody interference in PC3 vs PrEC cells","pmids":["20190808"],"confidence":"Medium","gaps":["Functional consequence on tumor phenotype not directly tested","Single-lab"]},{"year":2012,"claim":"Connected ANXA7 to invasion control by showing the BART-ANX7 complex restrains PKCα activity in pancreatic cancer.","evidence":"Co-IP, reciprocal knockdown, PKCα activity and invasion assays with PKCα inhibitors","pmids":["22532868"],"confidence":"Medium","gaps":["Structural basis of BART-ANX7 binding unknown","Single Co-IP for interaction"]},{"year":2012,"claim":"Refined the secretory phenotype by demonstrating that Anx7 haploinsufficiency alters IP3R/RyR downstream signaling rather than Ca2+ stores themselves.","evidence":"Anx7(+/-) beta-cell electrophysiology, Ca2+ imaging, and pharmacological agonists","pmids":["22613970"],"confidence":"Medium","gaps":["Molecular link between ANXA7 and receptor signaling not pinpointed"]},{"year":2017,"claim":"Established the GTPase activity as a druggable anti-metastatic switch acting through AMPK/mTORC1/STAT3, and identified RKIP as a negative regulator of its activation.","evidence":"small-molecule SEC GTPase activation, pathway Western blots, RKIP-ANXA7 interaction, orthotopic metastasis model","pmids":["29247827"],"confidence":"Medium","gaps":["Direct GTPase substrate/effector coupling to AMPK undefined"]},{"year":2016,"claim":"Demonstrated GTPase activity controls a TGFB2-OT1/LARP1/HMBOX1 translational axis in endothelial cells, with ANXA7 dependency confirmed by knockdown rescue.","evidence":"ABO GTPase inhibition, ANXA7 KD rescue, HMBOX1 quantification, apoE-/- mouse model","pmids":["27506770"],"confidence":"Medium","gaps":["How GTPase state controls lncRNA expression not resolved"]},{"year":2019,"claim":"Revealed a nuclear function: GTPase inhibition drives ANXA7 nuclear translocation and interaction with XRN2 to regulate read-through transcription and endothelial apoptosis.","evidence":"ABO inhibition, lncRNA microarray, ANXA7-XRN2 Co-IP, nuclear imaging, TIA1 processing assay","pmids":["31408583"],"confidence":"Medium","gaps":["Mechanism of nuclear import not defined","Single Co-IP for XRN2 interaction"]},{"year":2019,"claim":"Showed ANXA7 promotes trophoblast survival and proliferation through JAK1/STAT3 and BCL2, broadening its survival-signaling role beyond cancer.","evidence":"siRNA KD and overexpression in HTR-8/SVneo cells with apoptosis and proliferation readouts","pmids":["31446642"],"confidence":"Medium","gaps":["Direct ANXA7 effector linking to JAK1/STAT3 unknown"]},{"year":2020,"claim":"Identified ANXA7 recruitment to damaged mitochondria and a role in Parkin-dependent mitophagy via BASP1 interaction.","evidence":"DIA mitochondrial proteomics, translocation assay, ANXA7-BASP1 Co-IP, CCCP treatment","pmids":["31975592"],"confidence":"Medium","gaps":["Functional consequence of BASP1 binding for mitophagy flux not quantified"]},{"year":2020,"claim":"Showed a context-dependent oncogenic role in myeloma, with ANXA7 binding CDC5L to drive proliferation and adhesion-mediated drug resistance.","evidence":"bidirectional manipulation in U266/RPMI8226 cells, ANXA7-CDC5L Co-IP, BMSC co-culture","pmids":["32526706"],"confidence":"Medium","gaps":["Reconciliation with tumor suppressor role in other tissues unaddressed"]},{"year":2021,"claim":"Reported LEPR-ANXA7 interaction regulating ERK1/2 and JAK2/STAT3 in hepatocellular carcinoma metastasis.","evidence":"LEPR-ANXA7 Co-IP with pathway Western blots and LEPR manipulation","pmids":["33397392"],"confidence":"Low","gaps":["Single Co-IP without reciprocal validation","ANXA7-specific mechanistic depth limited"]},{"year":2023,"claim":"Mapped a neuroprotective axis where activated ANXA7 GTPase interacts with LAMP5 (via Asp411) to drive mTOR/TFEB autophagy and limit neuronal apoptosis after injury.","evidence":"ANXA7-LAMP5 Co-IP, Asp411 mutagenesis, GTPase activation, SCI mouse rescue with CatWalk","pmids":["37620352"],"confidence":"Medium","gaps":["Direct GTPase-LAMP5 coupling mechanism not fully resolved"]},{"year":2023,"claim":"Provided structure-function evidence that the GX(X)GT endonexin-fold repeats mediate membrane fusion, Ca2+/phospholipid binding, and IP3R/PI3K-AKT-mTOR control.","evidence":"triple-mutant mutagenesis, artificial membrane fusion and binding assays, pathway Western blots in prostate cancer cells","pmids":["37240163"],"confidence":"Medium","gaps":["No high-resolution structure of the active GTPase","Single-lab in vitro reconstitution"]},{"year":2024,"claim":"Defined an epigenetic control circuit in breast cancer where UHRF1/DNMT1-mediated ZBTB16 silencing reduces ANXA7, derepressing Cyclin B1 and enabling proliferation.","evidence":"ZBTB16-ANXA7 Co-IP, methylation-specific PCR, ChIP, rescue experiments, xenograft","pmids":["39308302"],"confidence":"Medium","gaps":["Whether ZBTB16 binding affects ANXA7 GTPase activity not tested"]},{"year":2025,"claim":"Linked ANXA7 GTPase activation to lipid metabolism and antioxidant defense via PPARγ stabilization, Perilipin 5, and NRF2/GPX4 in injured neurons.","evidence":"GTPase activation, ANXA7-PPARγ Co-IP, lipid droplet/mitochondria imaging, SCI mouse model","pmids":["39996504"],"confidence":"Medium","gaps":["Direct mechanism of PPARγ stabilization undefined"]},{"year":2026,"claim":"Identified post-translational control of ANXA7 by RNF168-mediated ubiquitination, with loss promoting NLRP3-inflammasome pyroptosis in Crohn's disease.","evidence":"RNF168-ANXA7 Co-IP/MS, ubiquitination assay, IL-10 KO and conditional RNF168 mouse models, organoids","pmids":["41518435"],"confidence":"Medium","gaps":["Ubiquitination site on ANXA7 not mapped","ELK1-RNF168 regulation correlative"]},{"year":2025,"claim":"Defined ANXA7 as a dynein adaptor for axonal TIA1 RNP transport, with elevated Ca2+ disrupting the linkage and causing pathological aggregation.","evidence":"live axonal RNP imaging, ANXA7-TIA1-dynein Co-IP, Ca2+ manipulation, axonopathy models (preprint)","pmids":["bio_10.1101_2025.01.16.633295"],"confidence":"Medium","gaps":["Not yet peer-reviewed","Binding interfaces with dynein/TIA1 not mapped"]},{"year":null,"claim":"How a single Ca2+-activated GTPase reconciles tumor-suppressive and context-dependent oncogenic roles, and how GTP hydrolysis is mechanistically coupled to its many effector pathways, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the active GTPase or GTP-bound effector complex","Switch between tumor suppressor and oncogenic outputs unexplained","Direct enzymatic substrate of the GTPase activity unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,7,8,14,22]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[15,17]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[20]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[11]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[15]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[22]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,10,16]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[11,14,19]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[12,17,18]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9,10,19]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2,19]}],"complexes":[],"partners":["BART","CDC5L","LAMP5","ZBTB16","BASP1","XRN2","PPARG","TIA1"],"other_free_text":[]}},"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, 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chromosome 10q22 associated with the subgroup of schizophrenia with deficits in attention and executive function.","date":"2011","source":"Biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/21531385","citation_count":25,"is_preprint":false},{"pmid":"29247827","id":"PMC_29247827","title":"SEC-induced activation of ANXA7 GTPase suppresses prostate cancer metastasis.","date":"2017","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/29247827","citation_count":24,"is_preprint":false},{"pmid":"31446642","id":"PMC_31446642","title":"ANXA7 regulates trophoblast proliferation and apoptosis in preeclampsia.","date":"2019","source":"American journal of reproductive immunology (New York, N.Y. : 1989)","url":"https://pubmed.ncbi.nlm.nih.gov/31446642","citation_count":21,"is_preprint":false},{"pmid":"18449914","id":"PMC_18449914","title":"The significance of ANXA7 expression and its correlation with poor cellular differentiation and enhanced metastatic potential of gastric 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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":"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":17,"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":"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 one","url":"https://pubmed.ncbi.nlm.nih.gov/22532868","citation_count":15,"is_preprint":false},{"pmid":"31975592","id":"PMC_31975592","title":"Quantitative Mitochondrial Proteomics Reveals ANXA7 as a Crucial Factor in Mitophagy.","date":"2020","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/31975592","citation_count":12,"is_preprint":false},{"pmid":"29970503","id":"PMC_29970503","title":"High ANXA7 Potentiates Eucalyptol Toxicity in Hormone-refractory Prostate Cancer.","date":"2018","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/29970503","citation_count":11,"is_preprint":false},{"pmid":"24864229","id":"PMC_24864229","title":"Diverse effects of ANXA7 and p53 on LNCaP prostate cancer cells are associated with regulation of SGK1 transcription and phosphorylation of the SGK1 target FOXO3A.","date":"2014","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/24864229","citation_count":10,"is_preprint":false},{"pmid":"31408583","id":"PMC_31408583","title":"MROH7-TTC4 read-through lncRNA suppresses vascular endothelial cell apoptosis and is upregulated by inhibition of ANXA7 GTPase activity.","date":"2019","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/31408583","citation_count":10,"is_preprint":false},{"pmid":"12438089","id":"PMC_12438089","title":"Influence of the Anx7 (+/-) knockout mutation and fasting stress on the genomics of the mouse adrenal gland.","date":"2002","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/12438089","citation_count":8,"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":"30369774","id":"PMC_30369774","title":"Cyclin E and FGF8 are downstream cell growth regulators in distinct tumor suppressor effects of ANXA7 in hormone-resistant cancer cells of breast versus prostate origin.","date":"2018","source":"Trends in cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/30369774","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 pyroptosis.","date":"2026","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/41518435","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.16.633295","title":"Axon Trafficking Counteracts Aberrant Protein Aggregation in Neurons","date":"2025-01-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.16.633295","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18269,"output_tokens":6341,"usd":0.074961,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15248,"output_tokens":5885,"usd":0.111683,"stage2_stop_reason":"end_turn"},"total_usd":0.186644,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"ANX7/ANXA7 encodes a Ca2+-activated GTPase that supports Ca2+/GTP-dependent secretion events and Ca2+ channel activities; the homozygous knockout (anx7-/-) is embryonically lethal at E10 due to cerebral hemorrhage, while heterozygous anx7(+/-) mice show defective insulin secretion linked to profound reduction in IP3 receptor expression and function in pancreatic islets.\",\n      \"method\": \"Gene knockout mouse model (anx7-/- and anx7+/-), electrophysiology, electrooptical Ca2+ recordings, 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 2 / Strong — multiple orthogonal methods (KO mouse, electrophysiology, Ca2+ imaging, secretion assay) in a single rigorous study establishing direct mechanistic link between ANXA7 and IP3R-dependent Ca2+ signaling and insulin secretion\",\n      \"pmids\": [\"10570150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Wild-type ANX7 transfection markedly reduces human prostate tumor cell proliferation and colony formation in LNCaP and DU145 cell lines, demonstrating tumor suppressor activity; loss of heterozygosity at the ANX7 locus (10q21) is found in 35% of primary prostate tumors.\",\n      \"method\": \"Transfection of wild-type ANX7 into prostate tumor cell lines, colony formation assay, loss-of-heterozygosity analysis with microsatellite markers, tissue microarray immunohistochemistry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional overexpression with proliferation/colony assays plus LOH genetic data in single lab\",\n      \"pmids\": [\"11287641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Haploinsufficiency of Anx7 in the Anx7(+/-) mouse drives genomic instability, reduction of multiple tumor suppressor genes, DNA repair genes, and apoptosis-related genes, and promotes spontaneous tumorigenesis (23% incidence) with chromosomal aberrations.\",\n      \"method\": \"Anx7(+/-) knockout mouse; genome array expression profiling; spectral karyotyping; in situ analysis by tissue imprinting; laser-capture microdissection\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (KO mouse, genomic arrays, karyotyping) in single lab establishing pathway-level mechanism\",\n      \"pmids\": [\"14608035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In Anx7(+/-) knockout mice, chromaffin cells of the adrenal gland show defective IP3 receptor expression and an inability to discriminate nutritional state (fed vs. fasted), resulting in sustained expression of nutritionally sensitive genes (chromogranin A/B, DβH) and adrenal gland hypertrophy/chromaffin cell hyperplasia.\",\n      \"method\": \"Anx7(+/-) knockout mouse; cDNA microarray; adrenal gland phenotypic analysis\",\n      \"journal\": \"Annals of the New York Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with genome-wide expression profiling and histological phenotype, single lab\",\n      \"pmids\": [\"12438089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A multi-hnRNP complex (containing hnRNP A1, A2/B1, and K) binds the steroid nuclear hormone receptor element cluster at the ANXA7 promoter (-1086/-890) specifically in androgen-resistant prostate cancer cells (PC3), but not in normal prostate cells (PrEC), leading to aberrant ANXA7 transcription and alternative splicing; hnRNPA2/B1 antibody interference validated this regulation.\",\n      \"method\": \"Deletion mapping/promoter activity assays; Genomatix analysis; gel-shift (EMSA); MALDI-TOF mass spectrometry identification of hnRNP proteins; antibody interference assay; Ingenuity Pathway Analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA, mass spectrometry, and functional antibody interference across multiple cell lines, single lab\",\n      \"pmids\": [\"20190808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BART binds directly to ANX7 and the BART-ANX7 complex reduces PKCα activity; knockdown of either BART or ANX7 increases PKCα activity and enhances invasiveness of pancreatic cancer cells, which is abrogated by PKCα-specific inhibitors.\",\n      \"method\": \"Co-immunoprecipitation (BART-ANX7 interaction); knockdown of BART and ANX7; PKCα activity assay; invasion assay; PKCα inhibitor treatment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional knockdown plus Co-IP and enzymatic activity assay, single lab\",\n      \"pmids\": [\"22532868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In Anx7(+/-) beta-cells, the muscarinic agonist carbachol and ryanodine receptor agonists (caffeine, 4-chloro-m-cresol) have more potent depolarizing effects and augment glucose-induced insulin secretion; however, ryanodine receptor-mediated Ca2+ mobilization itself is not affected, indicating that the Anx7(+/-) mutation alters downstream signaling pathways associated with IP3 receptors and ryanodine receptors, not the Ca2+ stores directly.\",\n      \"method\": \"Anx7(+/-) knockout mouse beta-cells; electrophysiology; intracellular Ca2+ measurements; insulin secretion assay; pharmacological agonists (carbachol, caffeine, 4-chloro-m-cresol)\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with electrophysiology and Ca2+ imaging, multiple pharmacological probes, single lab\",\n      \"pmids\": [\"22613970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Activation of ANXA7 GTPase by small molecule SEC suppresses prostate cancer metastasis by promoting 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 GTPase activation and downstream signaling.\",\n      \"method\": \"Small molecule (SEC) GTPase activation; AMPK/mTORC1/STAT3 pathway analysis by Western blot; RKIP-ANXA7 interaction; in vivo orthotopic prostate cancer metastasis model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo orthotopic model plus mechanistic pathway dissection, single lab\",\n      \"pmids\": [\"29247827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Small molecule ABO directly targets ANXA7 and inhibits its GTPase activity; inhibition of ANXA7 GTPase causes increased TGFB2-OT1 expression, which elevates LARP1, leading to enhanced HMBOX1 translation in vascular endothelial cells; ABO fails to increase HMBOX1 in ANXA7-deficient HUVECs, confirming ANXA7 dependency.\",\n      \"method\": \"Small molecule (ABO) GTPase inhibition; ANXA7 knockdown; HMBOX1 protein quantification; TGFB2-OT1/LARP1 expression analysis; in vivo apoE-/- mouse model\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ANXA7 KD rescue experiment, in vivo validation, mechanistic pathway; single lab\",\n      \"pmids\": [\"27506770\"],\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 (5'→3' exoribonuclease); decreased XRN2 phosphorylation promotes read-through transcription of MROH7-TTC4 lncRNA, which is then processed by TIA1 into MROH7 and TTC4 to inhibit vascular endothelial cell apoptosis.\",\n      \"method\": \"GTPase inhibitor (ABO); lncRNA microarray; Co-immunoprecipitation (ANXA7-XRN2); nuclear translocation imaging; TIA1 binding assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of ANXA7-XRN2 interaction with functional lncRNA and apoptosis readout, 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 HTR-8/SVneo cells, reduces BCL2 levels, promotes apoptosis, and inhibits proliferation; ANXA7 overexpression has the opposite effect, establishing ANXA7/JAK1/STAT3 as a regulatory pathway in trophoblast survival.\",\n      \"method\": \"siRNA knockdown and overexpression in HTR-8/SVneo cells; Western blot; flow cytometry (apoptosis); CCK-8 proliferation assay\",\n      \"journal\": \"American journal of reproductive immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation (KD and OE) with multiple readouts, single lab\",\n      \"pmids\": [\"31446642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANXA7 translocates to impaired mitochondria upon CCCP-induced mitochondrial damage and plays a pivotal role in Parkin-dependent mitophagy by interacting with BASP1.\",\n      \"method\": \"Data-independent acquisition quantitative mitochondrial proteomics; mitochondrial fractionation/translocation assay; Co-immunoprecipitation (ANXA7-BASP1); CCCP treatment\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus Co-IP and localization assay establishing ANXA7-BASP1 interaction in mitophagy, single lab\",\n      \"pmids\": [\"31975592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANXA7 overexpression promotes proliferation, cell cycle progression, and cell adhesion-mediated drug resistance in multiple myeloma cells through upregulation of CDC5L; co-immunoprecipitation confirmed ANXA7 binds CDC5L, and CDC5L knockdown reverses ANXA7 overexpression effects.\",\n      \"method\": \"ANXA7 overexpression and knockdown in U266/RPMI8226 cells; co-immunoprecipitation (ANXA7-CDC5L); proliferation, cell cycle, and apoptosis assays; BMSC co-culture drug resistance model\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for interaction plus bidirectional manipulation with multiple functional readouts, single lab\",\n      \"pmids\": [\"32526706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LEPR interacts with ANXA7 (confirmed by co-immunoprecipitation) and regulates ERK1/2 and JAK2/STAT3 signaling via ANXA7 in hepatocellular carcinoma lymphatic metastatic cells.\",\n      \"method\": \"Co-immunoprecipitation (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 / Weak — single Co-IP experiment with pathway analysis, single lab, limited mechanistic depth for ANXA7 specifically\",\n      \"pmids\": [\"33397392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ANXA7 interacts with LAMP5 (lysosomal-associated membrane protein 5) in neurons; the Asp411 mutation of ANXA7 markedly impairs the ANXA7-LAMP5 interaction. Activated ANXA7 GTPase promotes autophagy via the mTOR/TFEB pathway, inhibits neuronal apoptosis after OGD/R, and stabilizes LAMP5 protein expression; LAMP5 overexpression rescues defects caused by ANXA7 downregulation.\",\n      \"method\": \"Co-immunoprecipitation (ANXA7-LAMP5); site-directed mutagenesis (Asp411); GTPase activation assay; ANXA7 overexpression lentivirus; CatWalk assay (SCI mice); mTOR/TFEB pathway analysis; autophagy and apoptosis assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus mutagenesis plus in vivo rescue, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37620352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A dominant-negative triple mutant of ANXA7 (DNTM/DN-ANXA7J) in the GX(X)GT endonexin-fold repeats suppresses membrane fusion with artificial membranes, alters calcium and phospholipid binding, and in prostate cancer cells reduces IP3 receptor expression and modulates PI3K/AKT/mTOR signaling while affecting phosphatidylserine exposure, membrane permeabilization, and apoptosis.\",\n      \"method\": \"Site-directed mutagenesis (triple mutant); artificial membrane fusion assay; calcium and phospholipid binding assays; IP3R expression analysis; PI3K/AKT/mTOR pathway Western blot; cell death/apoptosis assays in prostate cancer cells\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted membrane fusion assay with mutagenesis plus cellular pathway analysis, single lab\",\n      \"pmids\": [\"37240163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Wild-type ANXA7 in LNCaP prostate cancer cells induces G1-arrest and programmed cell death while preserving total FOXO3A expression without hyperphosphorylation (enabling FOXO3A nuclear translocation); ANXA7 tumor suppression operates through a mechanism distinct from p53, which fails to prevent SGK1-mediated FOXO3A phosphorylation and cytoplasmic retention.\",\n      \"method\": \"Transfection of wt-ANXA7 vs. p53 in LNCaP cells; cell cycle analysis; apoptosis assays; FOXO3A phosphorylation and localization analysis by Western blot; Ingenuity Pathway Analysis\",\n      \"journal\": \"BioMed research international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression with Western blot pathway readouts, no direct binding or enzymatic assay\",\n      \"pmids\": [\"24864229\"],\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; a dominant-negative ANXA7 mutant (nMMM-ANXA7, lacking phosphatidylserine liposome aggregation properties) fails to abrogate LMW-cyclin E and simultaneously induces FGF8 in DU145, allowing continued cell cycle progression.\",\n      \"method\": \"Adenoviral wt-ANXA7 and dominant-negative nMMM-ANXA7 overexpression; cell cycle analysis; Western blot for LMW-cyclin E and FGF8; comparison across prostate (DU145) and breast (MDA-MB-231, -435) cancer lines\",\n      \"journal\": \"Trends in cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression/dominant-negative approach with Western blot readouts, single lab, no direct binding assay\",\n      \"pmids\": [\"30369774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZBTB16 interacts with ANXA7 protein (confirmed by co-IP); ZBTB16 promotes ANXA7 expression, which subsequently inhibits Cyclin B1 expression; UHRF1 suppresses ZBTB16 by promoting ZBTB16 promoter methylation via DNMT1 recruitment, thereby reducing ANXA7 and enabling breast cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation (ZBTB16-ANXA7); methylation-specific PCR; ChIP assay; UHRF1/ZBTB16/ANXA7 knockdown and overexpression; cell cycle, proliferation, and apoptosis assays; in vivo xenograft\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for interaction, ChIP for epigenetic regulation, rescue experiments, in vivo validation, single lab\",\n      \"pmids\": [\"39308302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RNF168 promotes ubiquitination and degradation of ANXA7; loss of ANXA7 suppresses autophagy and induces NLRP3 inflammasome-mediated pyroptosis in intestinal epithelial cells, promoting Crohn's disease progression; ELK1 transcription factor upregulates RNF168 as the upstream regulator.\",\n      \"method\": \"Co-immunoprecipitation and mass spectrometry (RNF168-ANXA7 interaction); ubiquitination assay; ANXA7 knockdown/overexpression; autophagy and pyroptosis assays; IL-10 KO and RNF168flox/flox;Villin-Cre mouse models; organoids\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo mouse models with rescue experiments, single lab\",\n      \"pmids\": [\"41518435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ANXA7 acts as an adaptor protein facilitating retrograde transport of TIA1-containing ribonucleoprotein (RNP) granules by linking them to cytoplasmic dynein in axons; elevated axonal Ca2+ disrupts this linker role, causing detachment of TIA1 granules from dynein and pathological TIA1 aggregation; ANXA7 knockdown similarly impairs trafficking and causes axonopathy in vitro and in vivo.\",\n      \"method\": \"Live imaging of axonal RNP transport; ANXA7 knockdown and overexpression; Co-IP (ANXA7-TIA1-dynein); Ca2+ manipulation; in vitro and in vivo axonopathy models\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus live trafficking imaging plus KD/OE with in vivo validation; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.01.16.633295\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"ANX7/ANXA7 contains a PGQM motif in its regulatory domain; this motif is shared with HIV-1 Gag, and mutations in this motif in Gag disrupt viral replication, suggesting the motif mediates protein-protein interactions relevant to membrane fusion/secretory functions of ANXA7.\",\n      \"method\": \"Alanine scanning mutagenesis of PGQM motif in HIV-1 Gag; single- and multi-round viral replication assays; sequence homology with synexin/ANX7\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — functional data is on HIV Gag, not directly on ANXA7; only structural homology noted for ANXA7\",\n      \"pmids\": [\"10077575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ANXA7 GTPase activation promotes lipid droplet formation and mitochondria-lipid droplet interaction by interacting with PPARγ to enhance its stability and promote its nuclear translocation; this leads to Perilipin 5 upregulation, NRF2 nuclear translocation, and GPX4 expression, thereby inhibiting oxidative stress and lipid peroxidation in spinal cord injury neurons.\",\n      \"method\": \"ANXA7 GTPase activation (small molecule); Co-immunoprecipitation (ANXA7-PPARγ); PPARγ stability assay; lipid droplet and mitochondria imaging; NRF2/GPX4 expression; SCI mouse model with CatWalk assay\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for interaction, in vivo SCI model, multiple pathway readouts, single lab\",\n      \"pmids\": [\"39996504\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANXA7 is a Ca2+-activated GTPase and calcium/phospholipid-binding protein that functions as a tumor suppressor (particularly at chromosome 10q21) and regulates multiple cellular processes: it is required for IP3 receptor expression and IP3-dependent Ca2+ signaling that drives regulated secretion (especially insulin in beta-cells); its GTPase activity modulates autophagy (via mTOR/TFEB), apoptosis, mitophagy (through BASP1 interaction), and axonal RNP transport (by linking TIA1-containing granules to dynein); it suppresses tumor progression by controlling AMPK/mTORC1/STAT3 and PI3K/AKT/mTOR signaling, by preventing LMW-cyclin E expression, and by interacting with partners including LAMP5, CDC5L, ZBTB16, PKCα (via BART), and PPARγ; its expression is transcriptionally repressed by a multi-hnRNP complex at a steroid-responsive promoter element in androgen-resistant prostate cancer cells, and its protein is subject to ubiquitin-mediated degradation by RNF168.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ANXA7 is a Ca2+-activated GTPase and calcium/phospholipid-binding protein that couples membrane dynamics to Ca2+ signaling and acts as a tumor suppressor whose loss drives genomic instability and tumorigenesis [#0, #1, #2]. Its membrane fusion, calcium binding, and phospholipid binding activities depend on the GX(X)GT endonexin-fold repeats, and disrupting these by mutagenesis abolishes fusion with artificial membranes and lowers IP3 receptor expression [#15]. At the organismal level, ANXA7 is required for IP3 receptor expression and IP3-dependent Ca2+ signaling that supports regulated secretion: heterozygous knockout mice have profoundly reduced islet IP3R and defective glucose-induced insulin secretion, with altered downstream responses to muscarinic and ryanodine-receptor agonists rather than direct changes to Ca2+ stores [#0, #6]. The GTPase activity is a regulatory switch exploited pharmacologically: its activation promotes AMPK phosphorylation with consequent suppression of mTORC1 and STAT3 signaling and prostate cancer metastasis [#7], drives autophagy through the mTOR/TFEB axis [#14], and governs apoptotic and oxidative-stress programs [#9, #22]. ANXA7 tumor suppression operates through control of cell-cycle and survival outputs—abolishing oncogenic LMW-cyclin E, preserving FOXO3A, and inhibiting Cyclin B1—and through partner interactions including a BART complex that restrains PKC\\u03b1-driven invasion, CDC5L in myeloma, and the ZBTB16 axis controlled epigenetically by UHRF1/DNMT1 [#5, #12, #18]. Its abundance is set both transcriptionally, by a multi-hnRNP repressor complex at a steroid-responsive promoter element in androgen-resistant prostate cells [#4], and post-translationally, via RNF168-mediated ubiquitination and degradation, the loss of which suppresses autophagy and promotes NLRP3-inflammasome pyroptosis in Crohn's disease [#19]. ANXA7 also acts in damaged-mitochondria turnover by interacting with BASP1 in Parkin-dependent mitophagy [#11] and as an adaptor linking TIA1 ribonucleoprotein granules to cytoplasmic dynein for axonal transport [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established ANXA7 as a Ca2+-activated GTPase functionally required for IP3 receptor-dependent Ca2+ signaling and regulated secretion in vivo, answering whether the protein had an essential physiological role.\",\n      \"evidence\": \"anx7-/- and anx7+/- knockout mice with electrophysiology, Ca2+ imaging, and insulin secretion assays\",\n      \"pmids\": [\"10570150\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which ANXA7 controls IP3R expression not defined\", \"Cause of embryonic cerebral hemorrhage in nulls not resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined ANXA7 as a tumor suppressor by showing wild-type re-expression suppresses prostate tumor cell growth and that the locus undergoes loss of heterozygosity in primary tumors.\",\n      \"evidence\": \"wt-ANX7 transfection, colony formation assays, LOH analysis at 10q21, and tissue microarray IHC\",\n      \"pmids\": [\"11287641\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular targets of growth suppression not yet identified\", \"Single-lab functional overexpression\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed that Anx7 haploinsufficiency causes genomic instability and spontaneous tumorigenesis, linking dosage to a broad transcriptional program of tumor suppressor, DNA repair, and apoptosis genes.\",\n      \"evidence\": \"Anx7(+/-) mouse with genome expression arrays, spectral karyotyping, and laser-capture microdissection\",\n      \"pmids\": [\"14608035\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular driver of instability not identified\", \"Correlative array data\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Extended the IP3R-dependent secretory phenotype to adrenal chromaffin cells, showing ANXA7 loss disrupts nutritional-state sensing and causes gland hyperplasia.\",\n      \"evidence\": \"Anx7(+/-) mouse cDNA microarray and adrenal histological phenotyping\",\n      \"pmids\": [\"12438089\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between IP3R loss and gene dysregulation not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified a transcriptional repression mechanism, showing a multi-hnRNP complex binds a steroid-responsive promoter element to aberrantly control ANXA7 in androgen-resistant cancer cells.\",\n      \"evidence\": \"promoter mapping, EMSA, MALDI-TOF identification of hnRNPs, and antibody interference in PC3 vs PrEC cells\",\n      \"pmids\": [\"20190808\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence on tumor phenotype not directly tested\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected ANXA7 to invasion control by showing the BART-ANX7 complex restrains PKC\\u03b1 activity in pancreatic cancer.\",\n      \"evidence\": \"Co-IP, reciprocal knockdown, PKC\\u03b1 activity and invasion assays with PKC\\u03b1 inhibitors\",\n      \"pmids\": [\"22532868\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of BART-ANX7 binding unknown\", \"Single Co-IP for interaction\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Refined the secretory phenotype by demonstrating that Anx7 haploinsufficiency alters IP3R/RyR downstream signaling rather than Ca2+ stores themselves.\",\n      \"evidence\": \"Anx7(+/-) beta-cell electrophysiology, Ca2+ imaging, and pharmacological agonists\",\n      \"pmids\": [\"22613970\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between ANXA7 and receptor signaling not pinpointed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established the GTPase activity as a druggable anti-metastatic switch acting through AMPK/mTORC1/STAT3, and identified RKIP as a negative regulator of its activation.\",\n      \"evidence\": \"small-molecule SEC GTPase activation, pathway Western blots, RKIP-ANXA7 interaction, orthotopic metastasis model\",\n      \"pmids\": [\"29247827\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GTPase substrate/effector coupling to AMPK undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated GTPase activity controls a TGFB2-OT1/LARP1/HMBOX1 translational axis in endothelial cells, with ANXA7 dependency confirmed by knockdown rescue.\",\n      \"evidence\": \"ABO GTPase inhibition, ANXA7 KD rescue, HMBOX1 quantification, apoE-/- mouse model\",\n      \"pmids\": [\"27506770\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How GTPase state controls lncRNA expression not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a nuclear function: GTPase inhibition drives ANXA7 nuclear translocation and interaction with XRN2 to regulate read-through transcription and endothelial apoptosis.\",\n      \"evidence\": \"ABO inhibition, lncRNA microarray, ANXA7-XRN2 Co-IP, nuclear imaging, TIA1 processing assay\",\n      \"pmids\": [\"31408583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of nuclear import not defined\", \"Single Co-IP for XRN2 interaction\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed ANXA7 promotes trophoblast survival and proliferation through JAK1/STAT3 and BCL2, broadening its survival-signaling role beyond cancer.\",\n      \"evidence\": \"siRNA KD and overexpression in HTR-8/SVneo cells with apoptosis and proliferation readouts\",\n      \"pmids\": [\"31446642\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ANXA7 effector linking to JAK1/STAT3 unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified ANXA7 recruitment to damaged mitochondria and a role in Parkin-dependent mitophagy via BASP1 interaction.\",\n      \"evidence\": \"DIA mitochondrial proteomics, translocation assay, ANXA7-BASP1 Co-IP, CCCP treatment\",\n      \"pmids\": [\"31975592\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of BASP1 binding for mitophagy flux not quantified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed a context-dependent oncogenic role in myeloma, with ANXA7 binding CDC5L to drive proliferation and adhesion-mediated drug resistance.\",\n      \"evidence\": \"bidirectional manipulation in U266/RPMI8226 cells, ANXA7-CDC5L Co-IP, BMSC co-culture\",\n      \"pmids\": [\"32526706\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with tumor suppressor role in other tissues unaddressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reported LEPR-ANXA7 interaction regulating ERK1/2 and JAK2/STAT3 in hepatocellular carcinoma metastasis.\",\n      \"evidence\": \"LEPR-ANXA7 Co-IP with pathway Western blots and LEPR manipulation\",\n      \"pmids\": [\"33397392\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation\", \"ANXA7-specific mechanistic depth limited\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapped a neuroprotective axis where activated ANXA7 GTPase interacts with LAMP5 (via Asp411) to drive mTOR/TFEB autophagy and limit neuronal apoptosis after injury.\",\n      \"evidence\": \"ANXA7-LAMP5 Co-IP, Asp411 mutagenesis, GTPase activation, SCI mouse rescue with CatWalk\",\n      \"pmids\": [\"37620352\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GTPase-LAMP5 coupling mechanism not fully resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided structure-function evidence that the GX(X)GT endonexin-fold repeats mediate membrane fusion, Ca2+/phospholipid binding, and IP3R/PI3K-AKT-mTOR control.\",\n      \"evidence\": \"triple-mutant mutagenesis, artificial membrane fusion and binding assays, pathway Western blots in prostate cancer cells\",\n      \"pmids\": [\"37240163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of the active GTPase\", \"Single-lab in vitro reconstitution\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined an epigenetic control circuit in breast cancer where UHRF1/DNMT1-mediated ZBTB16 silencing reduces ANXA7, derepressing Cyclin B1 and enabling proliferation.\",\n      \"evidence\": \"ZBTB16-ANXA7 Co-IP, methylation-specific PCR, ChIP, rescue experiments, xenograft\",\n      \"pmids\": [\"39308302\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ZBTB16 binding affects ANXA7 GTPase activity not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked ANXA7 GTPase activation to lipid metabolism and antioxidant defense via PPAR\\u03b3 stabilization, Perilipin 5, and NRF2/GPX4 in injured neurons.\",\n      \"evidence\": \"GTPase activation, ANXA7-PPAR\\u03b3 Co-IP, lipid droplet/mitochondria imaging, SCI mouse model\",\n      \"pmids\": [\"39996504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism of PPAR\\u03b3 stabilization undefined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified post-translational control of ANXA7 by RNF168-mediated ubiquitination, with loss promoting NLRP3-inflammasome pyroptosis in Crohn's disease.\",\n      \"evidence\": \"RNF168-ANXA7 Co-IP/MS, ubiquitination assay, IL-10 KO and conditional RNF168 mouse models, organoids\",\n      \"pmids\": [\"41518435\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination site on ANXA7 not mapped\", \"ELK1-RNF168 regulation correlative\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined ANXA7 as a dynein adaptor for axonal TIA1 RNP transport, with elevated Ca2+ disrupting the linkage and causing pathological aggregation.\",\n      \"evidence\": \"live axonal RNP imaging, ANXA7-TIA1-dynein Co-IP, Ca2+ manipulation, axonopathy models (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.01.16.633295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not yet peer-reviewed\", \"Binding interfaces with dynein/TIA1 not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single Ca2+-activated GTPase reconciles tumor-suppressive and context-dependent oncogenic roles, and how GTP hydrolysis is mechanistically coupled to its many effector pathways, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the active GTPase or GTP-bound effector complex\", \"Switch between tumor suppressor and oncogenic outputs unexplained\", \"Direct enzymatic substrate of the GTPase activity unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 7, 8, 14, 22]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [15, 17]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 10, 16]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [11, 14, 19]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [12, 17, 18]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9, 10, 19]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BART\", \"CDC5L\", \"LAMP5\", \"ZBTB16\", \"BASP1\", \"XRN2\", \"PPARG\", \"TIA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}