{"gene":"AGBL2","run_date":"2026-06-09T22:02:42","timeline":{"discoveries":[{"year":2011,"finding":"AGBL2 (CCP2) functions as a tubulin tyrosine carboxypeptidase: knockdown of AGBL2 results in failure of cells to detyrosinate the C-terminal EEY region of α-tubulin, identifying it as a candidate for the long-sought tubulin tyrosine carboxypeptidase important in microtubule dynamics regulation.","method":"siRNA knockdown of AGBL2 in cancer cells with measurement of detyrosinated α-tubulin levels; co-immunoprecipitation showing AGBL2 interacts with RARRES1","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with defined cellular/molecular phenotype, Co-IP interaction, single lab with two orthogonal methods","pmids":["21303978"],"is_preprint":false},{"year":2011,"finding":"RARRES1 (retinoic acid receptor responder 1) acts as a transmembrane carboxypeptidase inhibitor that physically interacts with AGBL2; knockdown of RARRES1 increases levels of detyrosinated α-tubulin, consistent with RARRES1 being the cognate inhibitor of AGBL2.","method":"Co-immunoprecipitation of RARRES1 and AGBL2; siRNA knockdown of RARRES1 with measurement of detyrosinated α-tubulin","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal functional knockdown with defined molecular readout plus Co-IP, single lab","pmids":["21303978"],"is_preprint":false},{"year":2014,"finding":"CCP2 (AGBL2) is a deglutamylase: it catalyzes posttranslational removal of glutamic acid residues from carboxy-terminal tails of tubulin and other substrates; CCP2 is highly regulated and confined to ciliated tissues.","method":"Enzymatic characterization using in vitro carboxypeptidase activity assays on tubulin and other substrates; tissue expression analysis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro enzymatic assay completing functional characterization of the CCP family, replicating and extending prior deglutamylase findings","pmids":["25103237"],"is_preprint":false},{"year":2014,"finding":"AGBL2 interacts with latexin (a carboxypeptidase inhibitor), forming immune complexes, indicating latexin is a binding partner/inhibitor of AGBL2 that modulates the tubulin tyrosination cycle in breast cancer stem cells.","method":"Co-immunoprecipitation (immunoprecipitation of AGBL2 and latexin from breast cancer cell lysates)","journal":"World journal of surgical oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP experiment, single lab, no functional mutagenesis or reconstitution","pmids":["24884516"],"is_preprint":false},{"year":2015,"finding":"AGBL2 interacts with latexin in gastric cancer cells, forming immune complexes, and both proteins are related to cell proliferation and chemotherapy resistance.","method":"Co-immunoprecipitation of AGBL2 and latexin; immunohistochemistry on gastric cancer specimens","journal":"Hepato-gastroenterology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP, single lab, limited mechanistic follow-up","pmids":["25916089"],"is_preprint":false},{"year":2017,"finding":"AGBL2 overexpression in hepatocellular carcinoma cells inhibits apoptosis by enhancing IRGM-regulated autophagy and upregulates TPX2 and Aurora A kinase activity to promote cell proliferation.","method":"Ectopic overexpression and knockdown of AGBL2 in HCC cell lines; measurement of Aurora A activity, TPX2 expression, and autophagy markers; in vivo tumor growth assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function experiments with multiple defined molecular readouts, single lab","pmids":["29126912"],"is_preprint":false},{"year":2024,"finding":"AGBL2 promotes renal cell carcinoma cell proliferation and migration via α-tubulin detyrosination; AGBL2 is predominantly located in the nucleus in RCC cells and enhances AKT phosphorylation; inhibition of tubulin carboxypeptidase activity with parthenolide partially blocks AGBL2-driven proliferation and migration.","method":"AGBL2 knockdown and overexpression in RCC cell lines; TCP inhibitor (parthenolide) treatment; measurement of α-tubulin detyrosination, cell proliferation and migration assays; RNA sequencing of AGBL2 knockdown cells; AKT phosphorylation assay; subcellular localization by imaging","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (KD/OE, pharmacological inhibition, sequencing), single lab","pmids":["39315218"],"is_preprint":false}],"current_model":"AGBL2 (CCP2) is a cytosolic carboxypeptidase that functions as a deglutamylase and tubulin tyrosine carboxypeptidase, catalyzing posttranslational removal of glutamic acid (and aspartic acid) residues from carboxy-terminal tails of α-tubulin and other substrates; it is inhibited by the transmembrane protein RARRES1 and by latexin, and its detyrosination activity promotes cancer cell proliferation and migration, with additional oncogenic roles via enhancement of IRGM-regulated autophagy, Aurora A kinase activity, and AKT phosphorylation."},"narrative":{"mechanistic_narrative":"AGBL2 (CCP2) is a cytosolic carboxypeptidase that catalyzes posttranslational modification of the carboxy-terminal tails of α-tubulin, acting both as a tubulin tyrosine carboxypeptidase that removes the C-terminal EEY tyrosine to generate detyrosinated tubulin [PMID:21303978] and as a deglutamylase that excises glutamic acid residues from tubulin and other substrate tails [PMID:25103237]. Its enzymatic activity is restrained by binding partners: the transmembrane carboxypeptidase inhibitor RARRES1, whose depletion raises detyrosinated α-tubulin levels [PMID:21303978], and the carboxypeptidase inhibitor latexin [PMID:24884516]. Through its detyrosination activity AGBL2 promotes cancer cell proliferation and migration and is associated with AKT phosphorylation, an effect partially blocked by the tubulin carboxypeptidase inhibitor parthenolide [PMID:39315218]. In hepatocellular carcinoma it additionally suppresses apoptosis by enhancing IRGM-regulated autophagy and elevates TPX2 expression and Aurora A kinase activity to drive proliferation [PMID:29126912]. Beyond these tubulin-centered and oncogenic roles, the broader substrate repertoire and the structural basis of substrate selection have not been characterized in the available corpus.","teleology":[{"year":2011,"claim":"Established AGBL2 as the candidate enzyme responsible for the long-sought tubulin tyrosine carboxypeptidase activity and identified its inhibitor, resolving how detyrosination of α-tubulin is controlled.","evidence":"siRNA knockdown of AGBL2 in cancer cells measuring detyrosinated α-tubulin, plus reciprocal RARRES1 knockdown, with Co-IP showing AGBL2–RARRES1 interaction","pmids":["21303978"],"confidence":"Medium","gaps":["Activity inferred from cellular knockdown rather than reconstituted enzymology","Direct catalytic residues and mechanism of detyrosination not defined","RARRES1 inhibition shown functionally but not biochemically reconstituted"]},{"year":2014,"claim":"Defined AGBL2/CCP2 biochemically as a deglutamylase acting on tubulin C-terminal tails, extending its function beyond tyrosine removal and placing it within the CCP enzyme family.","evidence":"In vitro carboxypeptidase activity assays on tubulin and other substrates plus tissue expression analysis","pmids":["25103237"],"confidence":"High","gaps":["Full non-tubulin substrate range not enumerated","Confinement to ciliated tissues not connected to a defined ciliary phenotype"]},{"year":2014,"claim":"Identified latexin as an additional binding partner/inhibitor of AGBL2, implicating regulation of the tubulin tyrosination cycle in breast cancer stem cells.","evidence":"Co-immunoprecipitation of AGBL2 and latexin from breast cancer cell lysates","pmids":["24884516"],"confidence":"Low","gaps":["Single Co-IP without reciprocal validation or mutagenesis","Inhibition of catalytic activity not directly demonstrated"]},{"year":2015,"claim":"Extended the AGBL2–latexin interaction to gastric cancer and linked both proteins to proliferation and chemoresistance.","evidence":"Co-immunoprecipitation of AGBL2 and latexin plus immunohistochemistry on gastric cancer specimens","pmids":["25916089"],"confidence":"Low","gaps":["Single Co-IP, limited mechanistic follow-up","Causal link between interaction and chemoresistance not established"]},{"year":2017,"claim":"Showed AGBL2 has oncogenic outputs beyond tubulin modification, suppressing apoptosis and promoting proliferation through autophagy and mitotic kinase pathways.","evidence":"Gain- and loss-of-function in HCC cell lines measuring IRGM-autophagy markers, TPX2, Aurora A activity, and in vivo tumor growth","pmids":["29126912"],"confidence":"Medium","gaps":["Whether these effects depend on carboxypeptidase catalytic activity not tested","Mechanistic connection between tubulin modification and Aurora A/IRGM axes unresolved"]},{"year":2024,"claim":"Connected AGBL2 detyrosination activity to RCC proliferation and migration and to AKT phosphorylation, with pharmacological inhibition confirming dependence on tubulin carboxypeptidase activity.","evidence":"Knockdown/overexpression in RCC cells, parthenolide inhibition, RNA-seq, AKT phosphorylation assay, and subcellular imaging showing nuclear localization","pmids":["39315218"],"confidence":"Medium","gaps":["Nuclear localization reconciliation with cytosolic carboxypeptidase role unexplained","Direct mechanism linking detyrosination to AKT phosphorylation not defined","Parthenolide effect partial, implying additional activity-independent contributions"]},{"year":null,"claim":"The structural basis of substrate selection, the full non-tubulin substrate repertoire, and the physiological (e.g. ciliary) function of AGBL2 outside cancer contexts remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of AGBL2 or its substrate complexes","Catalytic mechanism inferred from family membership, not directly mapped","Non-oncogenic physiological roles uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,6]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]}],"pathway":[],"complexes":[],"partners":["RARRES1","LXN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5U5Z8","full_name":"Cytosolic carboxypeptidase 2","aliases":["ATP/GTP-binding protein-like 2","Protein deglutamylase CCP2"],"length_aa":902,"mass_kda":104.2,"function":"Metallocarboxypeptidase that mediates deglutamylation of tubulin and non-tubulin target proteins. Catalyzes the removal of polyglutamate side chains present on the gamma-carboxyl group of glutamate residues within the C-terminal tail of tubulin protein. Specifically cleaves tubulin long-side-chains, while it is not able to remove the branching point glutamate. Also catalyzes the removal of polyglutamate residues from the carboxy-terminus of non-tubulin proteins such as MYLK","subcellular_location":"Cytoplasm, cytosol; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Cytoplasm, cytoskeleton, cilium basal body","url":"https://www.uniprot.org/uniprotkb/Q5U5Z8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AGBL2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/AGBL2","total_profiled":1310},"omim":[{"mim_id":"620485","title":"TUBULIN TYROSINE LIGASE-LIKE 13; TTLL13","url":"https://www.omim.org/entry/620485"},{"mim_id":"618845","title":"VERTEBRAL, CARDIAC, RENAL, AND LIMB DEFECTS SYNDROME 3; VCRL3","url":"https://www.omim.org/entry/618845"},{"mim_id":"618738","title":"TUBULIN TYROSINE LIGASE-LIKE 4; TTLL4","url":"https://www.omim.org/entry/618738"},{"mim_id":"617346","title":"ATP/GTP-BINDING PROTEIN-LIKE 3; AGBL3","url":"https://www.omim.org/entry/617346"},{"mim_id":"617345","title":"ATP/GTP-BINDING PROTEIN-LIKE 2; AGBL2","url":"https://www.omim.org/entry/617345"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli","reliability":"Supported"},{"location":"Basal body","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Flagellar centriole","reliability":"Supported"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"},{"location":"End piece","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"fallopian tube","ntpm":5.1},{"tissue":"testis","ntpm":11.4}],"url":"https://www.proteinatlas.org/search/AGBL2"},"hgnc":{"alias_symbol":["FLJ23598","CCP2"],"prev_symbol":[]},"alphafold":{"accession":"Q5U5Z8","domains":[{"cath_id":"2.60.40.3120","chopping":"181-394","consensus_level":"medium","plddt":91.9024,"start":181,"end":394},{"cath_id":"3.40.630.10","chopping":"399-666","consensus_level":"high","plddt":95.4406,"start":399,"end":666}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5U5Z8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5U5Z8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5U5Z8-F1-predicted_aligned_error_v6.png","plddt_mean":71.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AGBL2","jax_strain_url":"https://www.jax.org/strain/search?query=AGBL2"},"sequence":{"accession":"Q5U5Z8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5U5Z8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5U5Z8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5U5Z8"}},"corpus_meta":[{"pmid":"25103237","id":"PMC_25103237","title":"The cytosolic carboxypeptidases CCP2 and CCP3 catalyze posttranslational removal of acidic amino acids.","date":"2014","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/25103237","citation_count":66,"is_preprint":false},{"pmid":"30700425","id":"PMC_30700425","title":"Porphyromonas gingivalis experimentally induces periodontis and an anti-CCP2-associated arthritis in the rat.","date":"2019","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/30700425","citation_count":64,"is_preprint":false},{"pmid":"21303978","id":"PMC_21303978","title":"Tumor suppressor RARRES1 interacts with cytoplasmic carboxypeptidase AGBL2 to regulate the α-tubulin tyrosination cycle.","date":"2011","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/21303978","citation_count":57,"is_preprint":false},{"pmid":"17286215","id":"PMC_17286215","title":"Autoantibodies to cyclic citrullinated peptide 2 (CCP2) are superior to other potential diagnostic biomarkers for predicting rheumatoid arthritis in early undifferentiated arthritis.","date":"2007","source":"Clinical rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/17286215","citation_count":37,"is_preprint":false},{"pmid":"29126912","id":"PMC_29126912","title":"AGBL2 promotes cancer cell growth through IRGM-regulated autophagy and enhanced Aurora A activity in hepatocellular carcinoma.","date":"2017","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/29126912","citation_count":34,"is_preprint":false},{"pmid":"22580581","id":"PMC_22580581","title":"Autoantibodies to citrullinated fibrinogen compared with anti-MCV and anti-CCP2 antibodies in diagnosing rheumatoid arthritis at an early stage: data from the French ESPOIR cohort.","date":"2012","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/22580581","citation_count":33,"is_preprint":false},{"pmid":"23592053","id":"PMC_23592053","title":"Superior performance of the CCP3.1 test compared to CCP2 and MCV in the rheumatoid factor-negative RA population.","date":"2013","source":"Immunologic research","url":"https://pubmed.ncbi.nlm.nih.gov/23592053","citation_count":29,"is_preprint":false},{"pmid":"11090879","id":"PMC_11090879","title":"Positively charged amino acids at the interface between alpha-chain CCP1 and CCP2 of C4BP are required for regulation of the classical C3-convertase.","date":"2000","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11090879","citation_count":26,"is_preprint":false},{"pmid":"29895567","id":"PMC_29895567","title":"Number of individual ACPA reactivities in synovial fluid immune complexes, but not serum anti-CCP2 levels, associate with inflammation and joint destruction in rheumatoid arthritis.","date":"2018","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/29895567","citation_count":20,"is_preprint":false},{"pmid":"15370715","id":"PMC_15370715","title":"Second generation anti-cyclic citrullinated peptide (anti-CCP2) antibodies can replace other anti-filaggrin antibodies and improve rheumatoid arthritis diagnosis.","date":"2004","source":"Scandinavian journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/15370715","citation_count":20,"is_preprint":false},{"pmid":"30656490","id":"PMC_30656490","title":"Occurrence of anti-CCP2 and RF isotypes and their relation to age and disease severity among Sudanese patients with rheumatoid arthritis.","date":"2019","source":"Clinical rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/30656490","citation_count":11,"is_preprint":false},{"pmid":"18415774","id":"PMC_18415774","title":"Measurement characteristics of a new rapid anti-CCP2 test compared to the anti-CCP2 ELISA.","date":"2008","source":"Scandinavian journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/18415774","citation_count":11,"is_preprint":false},{"pmid":"24884516","id":"PMC_24884516","title":"Clinical implications of AGBL2 expression and its inhibitor latexin in breast cancer.","date":"2014","source":"World journal of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/24884516","citation_count":10,"is_preprint":false},{"pmid":"12492479","id":"PMC_12492479","title":"Role of CCP2 of the C4b-binding protein beta-chain in protein S binding evaluated by mutagenesis and monoclonal antibodies.","date":"2003","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12492479","citation_count":9,"is_preprint":false},{"pmid":"32307444","id":"PMC_32307444","title":"Expression of RARRES1 and AGBL2 and progression of conventional renal cell carcinoma.","date":"2020","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32307444","citation_count":8,"is_preprint":false},{"pmid":"31319568","id":"PMC_31319568","title":"Initiated Babesia ovata Sexual Stages under In Vitro Conditions Were Recognized by Anti-CCp2 Antibodies, Showing Changes in the DNA Content by Imaging Flow Cytometry.","date":"2019","source":"Pathogens (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/31319568","citation_count":7,"is_preprint":false},{"pmid":"25916089","id":"PMC_25916089","title":"Effects of AGBL2 on cell proliferation and chemotherapy resistance of gastric cancer.","date":"2015","source":"Hepato-gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/25916089","citation_count":3,"is_preprint":false},{"pmid":"39315218","id":"PMC_39315218","title":"AGBL2 promotes renal cell carcinoma cells proliferation and migration via α-tubulin detyrosination.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/39315218","citation_count":2,"is_preprint":false},{"pmid":"38599655","id":"PMC_38599655","title":"Utility of testing for third-generation anticyclic citrullinated peptide (anti-CCP3) antibodies in individuals who present with new musculoskeletal symptoms but have a negative second-generation anticyclic citrullinated peptide (anti-CCP2) antibody test.","date":"2024","source":"RMD open","url":"https://pubmed.ncbi.nlm.nih.gov/38599655","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12041,"output_tokens":1702,"usd":0.030826,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8565,"output_tokens":2359,"usd":0.0509,"stage2_stop_reason":"end_turn"},"total_usd":0.081726,"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\": 2011,\n      \"finding\": \"AGBL2 (CCP2) functions as a tubulin tyrosine carboxypeptidase: knockdown of AGBL2 results in failure of cells to detyrosinate the C-terminal EEY region of α-tubulin, identifying it as a candidate for the long-sought tubulin tyrosine carboxypeptidase important in microtubule dynamics regulation.\",\n      \"method\": \"siRNA knockdown of AGBL2 in cancer cells with measurement of detyrosinated α-tubulin levels; co-immunoprecipitation showing AGBL2 interacts with RARRES1\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with defined cellular/molecular phenotype, Co-IP interaction, single lab with two orthogonal methods\",\n      \"pmids\": [\"21303978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RARRES1 (retinoic acid receptor responder 1) acts as a transmembrane carboxypeptidase inhibitor that physically interacts with AGBL2; knockdown of RARRES1 increases levels of detyrosinated α-tubulin, consistent with RARRES1 being the cognate inhibitor of AGBL2.\",\n      \"method\": \"Co-immunoprecipitation of RARRES1 and AGBL2; siRNA knockdown of RARRES1 with measurement of detyrosinated α-tubulin\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional knockdown with defined molecular readout plus Co-IP, single lab\",\n      \"pmids\": [\"21303978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CCP2 (AGBL2) is a deglutamylase: it catalyzes posttranslational removal of glutamic acid residues from carboxy-terminal tails of tubulin and other substrates; CCP2 is highly regulated and confined to ciliated tissues.\",\n      \"method\": \"Enzymatic characterization using in vitro carboxypeptidase activity assays on tubulin and other substrates; tissue expression analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro enzymatic assay completing functional characterization of the CCP family, replicating and extending prior deglutamylase findings\",\n      \"pmids\": [\"25103237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AGBL2 interacts with latexin (a carboxypeptidase inhibitor), forming immune complexes, indicating latexin is a binding partner/inhibitor of AGBL2 that modulates the tubulin tyrosination cycle in breast cancer stem cells.\",\n      \"method\": \"Co-immunoprecipitation (immunoprecipitation of AGBL2 and latexin from breast cancer cell lysates)\",\n      \"journal\": \"World journal of surgical oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP experiment, single lab, no functional mutagenesis or reconstitution\",\n      \"pmids\": [\"24884516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AGBL2 interacts with latexin in gastric cancer cells, forming immune complexes, and both proteins are related to cell proliferation and chemotherapy resistance.\",\n      \"method\": \"Co-immunoprecipitation of AGBL2 and latexin; immunohistochemistry on gastric cancer specimens\",\n      \"journal\": \"Hepato-gastroenterology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"25916089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AGBL2 overexpression in hepatocellular carcinoma cells inhibits apoptosis by enhancing IRGM-regulated autophagy and upregulates TPX2 and Aurora A kinase activity to promote cell proliferation.\",\n      \"method\": \"Ectopic overexpression and knockdown of AGBL2 in HCC cell lines; measurement of Aurora A activity, TPX2 expression, and autophagy markers; in vivo tumor growth assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function experiments with multiple defined molecular readouts, single lab\",\n      \"pmids\": [\"29126912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AGBL2 promotes renal cell carcinoma cell proliferation and migration via α-tubulin detyrosination; AGBL2 is predominantly located in the nucleus in RCC cells and enhances AKT phosphorylation; inhibition of tubulin carboxypeptidase activity with parthenolide partially blocks AGBL2-driven proliferation and migration.\",\n      \"method\": \"AGBL2 knockdown and overexpression in RCC cell lines; TCP inhibitor (parthenolide) treatment; measurement of α-tubulin detyrosination, cell proliferation and migration assays; RNA sequencing of AGBL2 knockdown cells; AKT phosphorylation assay; subcellular localization by imaging\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (KD/OE, pharmacological inhibition, sequencing), single lab\",\n      \"pmids\": [\"39315218\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AGBL2 (CCP2) is a cytosolic carboxypeptidase that functions as a deglutamylase and tubulin tyrosine carboxypeptidase, catalyzing posttranslational removal of glutamic acid (and aspartic acid) residues from carboxy-terminal tails of α-tubulin and other substrates; it is inhibited by the transmembrane protein RARRES1 and by latexin, and its detyrosination activity promotes cancer cell proliferation and migration, with additional oncogenic roles via enhancement of IRGM-regulated autophagy, Aurora A kinase activity, and AKT phosphorylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AGBL2 (CCP2) is a cytosolic carboxypeptidase that catalyzes posttranslational modification of the carboxy-terminal tails of α-tubulin, acting both as a tubulin tyrosine carboxypeptidase that removes the C-terminal EEY tyrosine to generate detyrosinated tubulin [#0] and as a deglutamylase that excises glutamic acid residues from tubulin and other substrate tails [#2]. Its enzymatic activity is restrained by binding partners: the transmembrane carboxypeptidase inhibitor RARRES1, whose depletion raises detyrosinated α-tubulin levels [#1], and the carboxypeptidase inhibitor latexin [#3]. Through its detyrosination activity AGBL2 promotes cancer cell proliferation and migration and is associated with AKT phosphorylation, an effect partially blocked by the tubulin carboxypeptidase inhibitor parthenolide [#6]. In hepatocellular carcinoma it additionally suppresses apoptosis by enhancing IRGM-regulated autophagy and elevates TPX2 expression and Aurora A kinase activity to drive proliferation [#5]. Beyond these tubulin-centered and oncogenic roles, the broader substrate repertoire and the structural basis of substrate selection have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established AGBL2 as the candidate enzyme responsible for the long-sought tubulin tyrosine carboxypeptidase activity and identified its inhibitor, resolving how detyrosination of α-tubulin is controlled.\",\n      \"evidence\": \"siRNA knockdown of AGBL2 in cancer cells measuring detyrosinated α-tubulin, plus reciprocal RARRES1 knockdown, with Co-IP showing AGBL2–RARRES1 interaction\",\n      \"pmids\": [\"21303978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Activity inferred from cellular knockdown rather than reconstituted enzymology\", \"Direct catalytic residues and mechanism of detyrosination not defined\", \"RARRES1 inhibition shown functionally but not biochemically reconstituted\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined AGBL2/CCP2 biochemically as a deglutamylase acting on tubulin C-terminal tails, extending its function beyond tyrosine removal and placing it within the CCP enzyme family.\",\n      \"evidence\": \"In vitro carboxypeptidase activity assays on tubulin and other substrates plus tissue expression analysis\",\n      \"pmids\": [\"25103237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full non-tubulin substrate range not enumerated\", \"Confinement to ciliated tissues not connected to a defined ciliary phenotype\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified latexin as an additional binding partner/inhibitor of AGBL2, implicating regulation of the tubulin tyrosination cycle in breast cancer stem cells.\",\n      \"evidence\": \"Co-immunoprecipitation of AGBL2 and latexin from breast cancer cell lysates\",\n      \"pmids\": [\"24884516\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation or mutagenesis\", \"Inhibition of catalytic activity not directly demonstrated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended the AGBL2–latexin interaction to gastric cancer and linked both proteins to proliferation and chemoresistance.\",\n      \"evidence\": \"Co-immunoprecipitation of AGBL2 and latexin plus immunohistochemistry on gastric cancer specimens\",\n      \"pmids\": [\"25916089\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP, limited mechanistic follow-up\", \"Causal link between interaction and chemoresistance not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed AGBL2 has oncogenic outputs beyond tubulin modification, suppressing apoptosis and promoting proliferation through autophagy and mitotic kinase pathways.\",\n      \"evidence\": \"Gain- and loss-of-function in HCC cell lines measuring IRGM-autophagy markers, TPX2, Aurora A activity, and in vivo tumor growth\",\n      \"pmids\": [\"29126912\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these effects depend on carboxypeptidase catalytic activity not tested\", \"Mechanistic connection between tubulin modification and Aurora A/IRGM axes unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected AGBL2 detyrosination activity to RCC proliferation and migration and to AKT phosphorylation, with pharmacological inhibition confirming dependence on tubulin carboxypeptidase activity.\",\n      \"evidence\": \"Knockdown/overexpression in RCC cells, parthenolide inhibition, RNA-seq, AKT phosphorylation assay, and subcellular imaging showing nuclear localization\",\n      \"pmids\": [\"39315218\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear localization reconciliation with cytosolic carboxypeptidase role unexplained\", \"Direct mechanism linking detyrosination to AKT phosphorylation not defined\", \"Parthenolide effect partial, implying additional activity-independent contributions\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of substrate selection, the full non-tubulin substrate repertoire, and the physiological (e.g. ciliary) function of AGBL2 outside cancer contexts remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of AGBL2 or its substrate complexes\", \"Catalytic mechanism inferred from family membership, not directly mapped\", \"Non-oncogenic physiological roles uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 6]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"RARRES1\", \"LXN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":4,"faith_pct":75.0}}