{"gene":"GGA2","run_date":"2026-04-28T18:06:52","timeline":{"discoveries":[{"year":2001,"finding":"The VHS domain of GGA2 binds directly to the acidic cluster-dileucine sorting motif in the cytoplasmic tail of the cation-independent mannose 6-phosphate receptor (CI-MPR), and the hinge domain of GGA2 binds clathrin, positioning GGA2 as a link between cargo molecules and clathrin-coated vesicle assembly for lysosomal enzyme targeting.","method":"Pulldown assays, mutagenesis of CI-MPR sorting motif, clathrin-binding assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding assay with mutagenesis, replicated across multiple labs","pmids":["11387476"],"is_preprint":false},{"year":2001,"finding":"The VHS domain of GGA2 binds the cytoplasmic tail of sortilin, identifying sortilin as the first mammalian receptor targeted by the GGA family of cytosolic sorting proteins for Golgi-endosome transport.","method":"Binding assays with sortilin chimeric receptors, functional sorting assays in MPR knockout cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — direct binding demonstrated with functional validation of sorting, replicated across labs","pmids":["11331584"],"is_preprint":false},{"year":2000,"finding":"GGA2 (Vear) localizes to the Golgi complex, as shown by colocalization with gamma-adaptin Golgi marker and sensitivity to brefeldin A treatment; its VHS domain shows diffuse membrane/vesicle distribution while the ear domain is sufficient for Golgi association.","method":"Immunofluorescence microscopy, brefeldin A treatment, cell fractionation, domain truncation transfection experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization with functional domain dissection, single lab","pmids":["10702286"],"is_preprint":false},{"year":2002,"finding":"The VHS domains of GGA1 and GGA2 bind the cytosolic domain of memapsin 2 (beta-secretase), with Asp496, Leu499, and Leu500 being essential residues for binding, suggesting GGA2 mediates endocytosis and intracellular transport of memapsin 2.","method":"Pulldown with gel-immobilized VHS domains, site-directed mutagenesis, binding from mammalian cell lysates","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 1-2 — in vitro pulldown with mutagenesis, single lab","pmids":["12135764"],"is_preprint":false},{"year":2007,"finding":"Specific depletion of GGA2 (to ~5% of normal levels) by RNAi in HeLa cells causes increased secretion of the lysosomal enzyme cathepsin D, establishing GGA2 as required for efficient sorting of lysosomal enzymes at the TGN independently of GGA1 and GGA3.","method":"Stable RNAi knockdown cell lines, cathepsin D secretion assay, immunofluorescence","journal":"Archives of histology and cytology","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with specific enzymatic phenotype, single lab","pmids":["18431031"],"is_preprint":false},{"year":2009,"finding":"In yeast, Gga2 mediates sequential ubiquitin-independent sorting of ARN1 from TGN to endosome and ubiquitin-dependent sorting into multivesicular bodies; a ubiquitin-binding mutant of Gga2 causes accumulation of ubiquitinated Arn1p on the vacuolar membrane.","method":"Genetic mutant analysis, subcellular fractionation, ubiquitin-binding mutant characterization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with defined mechanistic steps, single lab","pmids":["19574226"],"is_preprint":false},{"year":2018,"finding":"GGA2 interacts with the cytoplasmic juxtamembrane region of EGFR through its VHS-GAT domains (dependent on N108 in VHS domain); GGA2 depletion causes enhanced lysosomal degradation of EGFR and reduced steady-state EGFR expression, while additional depletion of GGA1 or GGA3 reverses this, indicating GGA1/GGA3 promote EGFR degradation that GGA2 opposes.","method":"RNAi knockdown, pulldown assays, proximity ligation assay, VHS-GAT domain mutagenesis (N108), xenograft experiments","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding with mutagenesis, proximity ligation in situ, functional rescue, replicated in subsequent study","pmids":["29358589"],"is_preprint":false},{"year":2019,"finding":"GGA2 associates with active (but not inactive) β1-integrin and promotes recycling of active β1-integrin to the plasma membrane; proximity BioID identified RAB13 and RAB10 as novel GGA2 interactors, and RAB13 silencing phenocopies GGA2 depletion in reducing active β1-integrin in focal adhesions and impairing cell migration.","method":"RNAi screen, co-immunoprecipitation, BioID proximity labeling, focal adhesion imaging, migration/invasion assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction confirmed by BioID + functional epistasis with RAB13, multiple orthogonal methods","pmids":["31076515"],"is_preprint":false},{"year":2016,"finding":"GGA2 is required for anterograde cell surface transport of α2B-adrenergic receptor (α2B-AR); the GGA2 GAE domain (not hinge as for GGA1) directly interacts with multiple subdomains of the third intracellular loop of α2B-AR, and GGA2 depletion arrests the receptor in the perinuclear region and attenuates receptor-mediated ERK1/2 and cAMP signaling.","method":"shRNA/siRNA knockdown, co-immunoprecipitation, domain-mapping pulldown assays, ERK1/2 and cAMP signaling assays, primary cortical neuron imaging","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — direct interaction domain mapping with functional signaling readout, single lab","pmids":["27901063"],"is_preprint":false},{"year":2021,"finding":"GGA2 and AP-1 function in Rab11-positive recycling endosomes to retrieve endocytosed EGFR back to the plasma membrane; depletion of GGA2 suppresses EGFR recycling (biochemical recycling assay) and reduces steady-state levels of EGFR, MET, and ErbB4.","method":"Triple immunofluorescence, proximity ligation assay, biochemical recycling assay, RNAi knockdown, xenograft model","journal":"Oncogenesis","confidence":"High","confidence_rationale":"Tier 2 — direct recycling assay with colocalization evidence, multiple orthogonal methods","pmids":["34799560"],"is_preprint":false},{"year":2012,"finding":"GGA2 mediates a non-redundant essential function in vivo; Gga2 knockout mice display embryonic or neonatal lethality depending on genetic background, while loss of GGA1 or GGA3 alone is tolerated, establishing that GGA2 cannot be fully compensated by the other GGA family members.","method":"Insertional mutagenesis gene knockout in mice, genetic background analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined lethal phenotype, replicated with two alleles and confirmed in follow-up study","pmids":["22291915"],"is_preprint":false},{"year":2018,"finding":"GGA2 interacts with EGFR (confirmed by co-immunoprecipitation), increases EGFR protein levels, and modifies EGFR degradation after ligand stimulation in lung adenocarcinoma cells; GGA2 overexpression enhances EGFR-mediated transformation.","method":"Co-immunoprecipitation, Western blot, RNAi knockdown, overexpression, colony and tumor forming assays","journal":"Journal of thoracic oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with functional overexpression/KD phenotype, single lab","pmids":["30578931"],"is_preprint":false},{"year":2020,"finding":"In yeast, Gga2 is required for vacuolar delivery of amino acid permeases (including Mup1 and Can1) during glucose starvation, acting at the TGN as a clathrin adaptor; ectopic de-ubiquitination at the TGN redirects permeases to recycling, confirming active Gga2-dependent ubiquitin-recognition sorting.","method":"Genetic deletion analysis, fluorescence microscopy trafficking assays, engineered de-ubiquitination at TGN","journal":"Biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with mechanistic de-ubiquitination rescue experiment, single lab","pmids":["32761633"],"is_preprint":false},{"year":2025,"finding":"Enterovirus (CVB5) protease 2A rapidly depletes GGA2 in beta cells due to GGA2's short half-life; GGA2 depletion impairs insulin secretory granule biogenesis at the TGN, disrupts vacuolar ATPase and cathepsin sorting, causes TGN acidification, and leads to premature lysosomal hydrolase activation and altered MHC class I immunopeptidome.","method":"Immunostaining of patient pancreas sections, viral infection experiments, siRNA depletion, proteomics of immunopeptidome","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — preprint, multiple phenotypic readouts but mechanistic pathway placement partially indirect","pmids":["bio_10.1101_2025.03.28.645506"],"is_preprint":true}],"current_model":"GGA2 is a multidomain Golgi/endosome-localized clathrin adaptor whose VHS domain recognizes acidic cluster-dileucine sorting motifs on cargo proteins (CI-MPR, sortilin, EGFR, β-secretase, α2B-AR), whose hinge domain binds clathrin and whose GAE domain mediates additional cargo interactions, collectively enabling GGA2 to direct cargo from the TGN to endosomes/lysosomes, mediate recycling of active β1-integrin and EGFR from recycling endosomes back to the plasma membrane via RAB13, and sort lysosomal enzymes (cathepsin D) to prevent their mis-secretion."},"narrative":{"teleology":[{"year":2000,"claim":"Establishing where GGA2 operates: GGA2 was localized to the Golgi complex, with domain dissection showing that the ear (GAE) domain was sufficient for Golgi targeting while the VHS domain distributed to membranes/vesicles, providing the first spatial framework for its sorting function.","evidence":"Immunofluorescence with Golgi markers, brefeldin A sensitivity, and truncation constructs in transfected cells","pmids":["10702286"],"confidence":"Medium","gaps":["Single lab; no endosomal or plasma membrane localization assessed at this stage","Mechanism of Golgi recruitment via ear domain not defined"]},{"year":2001,"claim":"Identifying the molecular logic of cargo recognition: the VHS domain of GGA2 was shown to bind directly to acidic cluster-dileucine motifs in CI-MPR and sortilin cytoplasmic tails, and the hinge domain was shown to bind clathrin, establishing GGA2 as a bridging adaptor between sorting signals and coat assembly for TGN-to-endosome transport.","evidence":"Pulldown assays with mutagenesis of CI-MPR sorting motif; sortilin chimeric receptor binding and sorting assays in MPR-knockout cells; clathrin-binding assays","pmids":["11387476","11331584"],"confidence":"High","gaps":["Whether GGA2 is functionally non-redundant with GGA1/GGA3 not yet tested","In vivo physiological relevance not established"]},{"year":2002,"claim":"Expanding the cargo repertoire to disease-relevant substrates: the VHS domain of GGA2 was found to bind β-secretase (memapsin 2) via D496/L499/L500 in its cytoplasmic tail, implicating GGA2 in the intracellular trafficking of the Alzheimer's-associated protease.","evidence":"Pulldown with immobilized VHS domains and site-directed mutagenesis from mammalian cell lysates","pmids":["12135764"],"confidence":"Medium","gaps":["Functional consequence of GGA2-β-secretase interaction on amyloid processing not demonstrated","In vivo relevance not tested"]},{"year":2007,"claim":"Demonstrating a non-redundant requirement for GGA2 in lysosomal enzyme sorting: specific depletion of GGA2 to ~5% caused increased secretion of cathepsin D, establishing that GGA2 independently ensures efficient TGN-to-lysosome targeting of soluble hydrolases.","evidence":"Stable RNAi knockdown in HeLa cells with cathepsin D secretion assay","pmids":["18431031"],"confidence":"Medium","gaps":["Single lab; cargo receptor (MPR) trafficking kinetics not directly measured","Whether phenotype reflects direct or indirect sorting defect not fully resolved"]},{"year":2009,"claim":"Revealing a dual sorting mechanism in yeast: Gga2 was shown to mediate sequential ubiquitin-independent sorting of Arn1 from TGN to endosome and ubiquitin-dependent sorting into multivesicular bodies, demonstrating that GGA2 family members can read both dileucine and ubiquitin signals at distinct trafficking steps.","evidence":"Genetic mutant analysis with ubiquitin-binding mutant Gga2 and subcellular fractionation in S. cerevisiae","pmids":["19574226"],"confidence":"Medium","gaps":["Whether mammalian GGA2 similarly performs dual ubiquitin-dependent/independent sorting not tested","Structural basis for ubiquitin recognition by Gga2 not defined"]},{"year":2012,"claim":"Establishing essential in vivo function: Gga2 knockout mice exhibited embryonic or neonatal lethality depending on genetic background, while GGA1 and GGA3 knockouts were viable, proving that GGA2 performs a unique essential function that cannot be compensated by its paralogs.","evidence":"Insertional mutagenesis gene knockout in mice across multiple genetic backgrounds","pmids":["22291915"],"confidence":"Medium","gaps":["Specific cargo or tissue responsible for lethality not identified","Conditional knockout to resolve tissue-specific requirements not performed"]},{"year":2016,"claim":"Uncovering a role in anterograde receptor transport and signaling: GGA2 was found to be required for cell-surface delivery of α2B-adrenergic receptor via a GAE domain interaction (distinct from the VHS-mediated cargo interactions), with GGA2 depletion trapping the receptor perinuclearly and attenuating ERK1/2 and cAMP signaling.","evidence":"shRNA/siRNA knockdown, co-immunoprecipitation with domain mapping, signaling assays, and primary cortical neuron imaging","pmids":["27901063"],"confidence":"Medium","gaps":["Whether GAE-mediated cargo interactions represent a general anterograde sorting mechanism not addressed","Single lab observation"]},{"year":2018,"claim":"Defining an antagonistic relationship among GGA family members in EGFR trafficking: GGA2 was shown to interact with EGFR's juxtamembrane region via VHS-GAT domains (N108-dependent), stabilize EGFR against lysosomal degradation, and oppose the degradation-promoting activities of GGA1 and GGA3.","evidence":"Pulldown assays, proximity ligation assay, VHS domain mutagenesis, RNAi epistasis, xenograft experiments","pmids":["29358589","30578931"],"confidence":"High","gaps":["Molecular basis for why GGA2 stabilizes EGFR while GGA1/GGA3 promote its degradation not resolved","Whether this extends to other receptor tyrosine kinases beyond EGFR not systematically tested at this stage"]},{"year":2019,"claim":"Revealing a recycling endosome function for GGA2: GGA2 was found to associate selectively with active (not inactive) β1-integrin and to promote its recycling to focal adhesions via a RAB13-dependent pathway, with BioID identifying RAB13 and RAB10 as novel GGA2 proximity partners and RAB13 silencing phenocopying GGA2 loss.","evidence":"RNAi screen, co-immunoprecipitation, BioID proximity labeling, focal adhesion imaging, migration/invasion assays","pmids":["31076515"],"confidence":"High","gaps":["Whether GGA2 directly bridges integrin to RAB13 or acts through intermediate effectors unknown","Structural basis for selectivity toward active integrin conformation not determined"]},{"year":2021,"claim":"Consolidating GGA2's role at recycling endosomes: GGA2 and AP-1 were found to colocalize at Rab11-positive recycling endosomes where they function to retrieve EGFR to the plasma membrane, with GGA2 depletion reducing steady-state levels of EGFR, MET, and ErbB4.","evidence":"Triple immunofluorescence, proximity ligation assay, biochemical EGFR recycling assay, RNAi knockdown, xenograft model","pmids":["34799560"],"confidence":"High","gaps":["Whether GGA2 and AP-1 form a stable complex or act sequentially at recycling endosomes not resolved","Whether GGA2's recycling function requires clathrin not tested"]},{"year":null,"claim":"Major open questions include: the specific cargo or tissue defect responsible for embryonic lethality in Gga2 knockout mice; the structural basis for GGA2's selective stabilization of EGFR in opposition to GGA1/GGA3; how GGA2 distinguishes active from inactive integrin; and the full spectrum of GGA2 cargo at recycling endosomes versus TGN.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of GGA2 in complex with any full-length cargo","Mechanism by which GGA2 opposes GGA1/GGA3 in EGFR degradation undefined","Tissue-specific essential function underlying knockout lethality unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3,6,7,8]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,1,6]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[2,4]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[5,9]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[7,9]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,4,5,7,9]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1,4,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,8,11]}],"complexes":[],"partners":["CI-MPR","SORT1","EGFR","BACE1","ADRA2B","RAB13","ITGB1","CLTC"],"other_free_text":[]},"mechanistic_narrative":"GGA2 is a clathrin-associated sorting adaptor that directs transmembrane cargo between the trans-Golgi network (TGN), endosomes, and the plasma membrane, functioning non-redundantly from the other GGA family members as demonstrated by embryonic/neonatal lethality of Gga2 knockout mice [PMID:22291915]. Its VHS domain recognizes acidic cluster-dileucine motifs in the cytoplasmic tails of cargo proteins including CI-MPR, sortilin, β-secretase, and EGFR, while its hinge domain recruits clathrin and its GAE domain mediates additional cargo interactions such as with α2B-adrenergic receptor [PMID:11387476, PMID:11331584, PMID:12135764, PMID:27901063]. GGA2 is required for proper sorting of lysosomal enzymes (cathepsin D) at the TGN, preventing their mis-secretion [PMID:18431031], and functions at Rab11-positive recycling endosomes together with AP-1 to recycle EGFR and active β1-integrin back to the plasma membrane via a RAB13-dependent pathway, thereby sustaining receptor tyrosine kinase signaling and integrin-mediated cell migration [PMID:34799560, PMID:31076515, PMID:29358589]."},"prefetch_data":{"uniprot":{"accession":"Q9UJY4","full_name":"ADP-ribosylation factor-binding protein GGA2","aliases":["Gamma-adaptin-related protein 2","Golgi-localized, gamma ear-containing, ARF-binding protein 2","VHS domain and ear domain of gamma-adaptin","Vear"],"length_aa":613,"mass_kda":67.2,"function":"Plays a role in protein sorting and trafficking between the trans-Golgi network (TGN) and endosomes. Mediates the ARF-dependent recruitment of clathrin to the TGN and binds ubiquitinated proteins and membrane cargo molecules with a cytosolic acidic cluster-dileucine (DXXLL) motif (PubMed:10747088). Mediates export of the GPCR receptor ADRA2B to the cell surface (PubMed:27901063). Regulates retrograde transport of phosphorylated form of BACE1 from endosomes to the trans-Golgi network (PubMed:15615712)","subcellular_location":"Golgi apparatus, trans-Golgi network membrane; Endosome membrane; Early endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q9UJY4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GGA2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GGA2","total_profiled":1310},"omim":[{"mim_id":"617366","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 91; CCDC91","url":"https://www.omim.org/entry/617366"},{"mim_id":"613439","title":"CONSORTIN; CNST","url":"https://www.omim.org/entry/613439"},{"mim_id":"607265","title":"CLATHRIN INTERACTOR 1; CLINT1","url":"https://www.omim.org/entry/607265"},{"mim_id":"606006","title":"GOLGI-ASSOCIATED, GAMMA-ADAPTIN EAR-CONTAINING, ARF-BINDING PROTEIN 3; GGA3","url":"https://www.omim.org/entry/606006"},{"mim_id":"606005","title":"GOLGI-ASSOCIATED, GAMMA-ADAPTIN EAR-CONTAINING, ARF-BINDING PROTEIN 2; GGA2","url":"https://www.omim.org/entry/606005"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Golgi apparatus","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GGA2"},"hgnc":{"alias_symbol":["VEAR","KIAA1080"],"prev_symbol":[]},"alphafold":{"accession":"Q9UJY4","domains":[{"cath_id":"1.25.40.90","chopping":"23-172","consensus_level":"high","plddt":88.8617,"start":23,"end":172},{"cath_id":"1.20.58.160","chopping":"182-313","consensus_level":"medium","plddt":86.0533,"start":182,"end":313},{"cath_id":"2.60.40.1230","chopping":"481-612","consensus_level":"high","plddt":87.6536,"start":481,"end":612}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UJY4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UJY4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UJY4-F1-predicted_aligned_error_v6.png","plddt_mean":71.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GGA2","jax_strain_url":"https://www.jax.org/strain/search?query=GGA2"},"sequence":{"accession":"Q9UJY4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UJY4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UJY4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UJY4"}},"corpus_meta":[{"pmid":"11331584","id":"PMC_11331584","title":"The sortilin cytoplasmic tail conveys Golgi-endosome transport and binds the VHS domain of the GGA2 sorting protein.","date":"2001","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11331584","citation_count":370,"is_preprint":false},{"pmid":"11387476","id":"PMC_11387476","title":"Binding of GGA2 to the lysosomal enzyme sorting motif of the mannose 6-phosphate receptor.","date":"2001","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/11387476","citation_count":229,"is_preprint":false},{"pmid":"12135764","id":"PMC_12135764","title":"Memapsin 2 (beta-secretase) cytosolic domain binds to the VHS domains of GGA1 and GGA2: implications on the endocytosis mechanism of memapsin 2.","date":"2002","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/12135764","citation_count":101,"is_preprint":false},{"pmid":"10702286","id":"PMC_10702286","title":"Vear, a novel Golgi-associated protein with VHS and gamma-adaptin \"ear\" domains.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10702286","citation_count":91,"is_preprint":false},{"pmid":"7966337","id":"PMC_7966337","title":"The unusual structure of the human centromere (GGA)2 motif. Unpaired guanosine residues stacked between sheared G.A pairs.","date":"1994","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/7966337","citation_count":53,"is_preprint":false},{"pmid":"31076515","id":"PMC_31076515","title":"GGA2 and RAB13 promote activity-dependent β1-integrin recycling.","date":"2019","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/31076515","citation_count":39,"is_preprint":false},{"pmid":"19574226","id":"PMC_19574226","title":"Gga2 mediates sequential ubiquitin-independent and ubiquitin-dependent steps in the trafficking of ARN1 from the trans-Golgi network to the vacuole.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19574226","citation_count":31,"is_preprint":false},{"pmid":"29358589","id":"PMC_29358589","title":"GGA2 interacts with EGFR cytoplasmic domain to stabilize the receptor expression and promote cell growth.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29358589","citation_count":22,"is_preprint":false},{"pmid":"22291915","id":"PMC_22291915","title":"Analysis of Gga null mice demonstrates a non-redundant role for mammalian GGA2 during development.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22291915","citation_count":22,"is_preprint":false},{"pmid":"30578931","id":"PMC_30578931","title":"Integrative Genomic Analyses Identifies GGA2 as a Cooperative Driver of EGFR-Mediated Lung Tumorigenesis.","date":"2018","source":"Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30578931","citation_count":19,"is_preprint":false},{"pmid":"27901063","id":"PMC_27901063","title":"Regulation of α2B-Adrenergic Receptor Cell Surface Transport by GGA1 and GGA2.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27901063","citation_count":17,"is_preprint":false},{"pmid":"34799560","id":"PMC_34799560","title":"Clathrin adapters AP-1 and GGA2 support expression of epidermal growth factor receptor for cell growth.","date":"2021","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/34799560","citation_count":13,"is_preprint":false},{"pmid":"32761633","id":"PMC_32761633","title":"Plasma membrane to vacuole traffic induced by glucose starvation requires Gga2-dependent sorting at the trans-Golgi network.","date":"2020","source":"Biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/32761633","citation_count":12,"is_preprint":false},{"pmid":"24637350","id":"PMC_24637350","title":"Impact of genetic background on neonatal lethality of Gga2 gene-trap mice.","date":"2014","source":"G3 (Bethesda, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/24637350","citation_count":7,"is_preprint":false},{"pmid":"18431031","id":"PMC_18431031","title":"Specific depletion of GGA2 causes cathepsin D missorting in HeLa cells.","date":"2007","source":"Archives of histology and cytology","url":"https://pubmed.ncbi.nlm.nih.gov/18431031","citation_count":6,"is_preprint":false},{"pmid":"11473645","id":"PMC_11473645","title":"Podocyte-specific expression of a novel trans-Golgi protein Vear in human kidney.","date":"2001","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/11473645","citation_count":3,"is_preprint":false},{"pmid":"11150977","id":"PMC_11150977","title":"Vear, a novel Golgi-associated protein, is preferentially expressed in type I cells in skeletal muscle.","date":"2001","source":"Muscle & nerve","url":"https://pubmed.ncbi.nlm.nih.gov/11150977","citation_count":3,"is_preprint":false},{"pmid":"32355321","id":"PMC_32355321","title":"Author Correction: GGA2 interacts with EGFR cytoplasmic domain to stabilize the receptor expression and promote cell growth.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32355321","citation_count":1,"is_preprint":false},{"pmid":"41898765","id":"PMC_41898765","title":"Exploring the Role of GGA2 in Cancer Progression: Pan-Cancer Bioinformatics and Experimental Validation in Prostate Cancer.","date":"2026","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41898765","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.28.645506","title":"GGA2-depletion in beta cells by Enteroviruses causes Golgi acidification, premature activation of cathepsins and alters the MHC class I immunopeptidome","date":"2025-03-31","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.28.645506","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10042,"output_tokens":3202,"usd":0.039078},"stage2":{"model":"claude-opus-4-6","input_tokens":6608,"output_tokens":2939,"usd":0.159773},"total_usd":0.198851,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"The VHS domain of GGA2 binds directly to the acidic cluster-dileucine sorting motif in the cytoplasmic tail of the cation-independent mannose 6-phosphate receptor (CI-MPR), and the hinge domain of GGA2 binds clathrin, positioning GGA2 as a link between cargo molecules and clathrin-coated vesicle assembly for lysosomal enzyme targeting.\",\n      \"method\": \"Pulldown assays, mutagenesis of CI-MPR sorting motif, clathrin-binding assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding assay with mutagenesis, replicated across multiple labs\",\n      \"pmids\": [\"11387476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The VHS domain of GGA2 binds the cytoplasmic tail of sortilin, identifying sortilin as the first mammalian receptor targeted by the GGA family of cytosolic sorting proteins for Golgi-endosome transport.\",\n      \"method\": \"Binding assays with sortilin chimeric receptors, functional sorting assays in MPR knockout cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding demonstrated with functional validation of sorting, replicated across labs\",\n      \"pmids\": [\"11331584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"GGA2 (Vear) localizes to the Golgi complex, as shown by colocalization with gamma-adaptin Golgi marker and sensitivity to brefeldin A treatment; its VHS domain shows diffuse membrane/vesicle distribution while the ear domain is sufficient for Golgi association.\",\n      \"method\": \"Immunofluorescence microscopy, brefeldin A treatment, cell fractionation, domain truncation transfection experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional domain dissection, single lab\",\n      \"pmids\": [\"10702286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The VHS domains of GGA1 and GGA2 bind the cytosolic domain of memapsin 2 (beta-secretase), with Asp496, Leu499, and Leu500 being essential residues for binding, suggesting GGA2 mediates endocytosis and intracellular transport of memapsin 2.\",\n      \"method\": \"Pulldown with gel-immobilized VHS domains, site-directed mutagenesis, binding from mammalian cell lysates\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro pulldown with mutagenesis, single lab\",\n      \"pmids\": [\"12135764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Specific depletion of GGA2 (to ~5% of normal levels) by RNAi in HeLa cells causes increased secretion of the lysosomal enzyme cathepsin D, establishing GGA2 as required for efficient sorting of lysosomal enzymes at the TGN independently of GGA1 and GGA3.\",\n      \"method\": \"Stable RNAi knockdown cell lines, cathepsin D secretion assay, immunofluorescence\",\n      \"journal\": \"Archives of histology and cytology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with specific enzymatic phenotype, single lab\",\n      \"pmids\": [\"18431031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In yeast, Gga2 mediates sequential ubiquitin-independent sorting of ARN1 from TGN to endosome and ubiquitin-dependent sorting into multivesicular bodies; a ubiquitin-binding mutant of Gga2 causes accumulation of ubiquitinated Arn1p on the vacuolar membrane.\",\n      \"method\": \"Genetic mutant analysis, subcellular fractionation, ubiquitin-binding mutant characterization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with defined mechanistic steps, single lab\",\n      \"pmids\": [\"19574226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GGA2 interacts with the cytoplasmic juxtamembrane region of EGFR through its VHS-GAT domains (dependent on N108 in VHS domain); GGA2 depletion causes enhanced lysosomal degradation of EGFR and reduced steady-state EGFR expression, while additional depletion of GGA1 or GGA3 reverses this, indicating GGA1/GGA3 promote EGFR degradation that GGA2 opposes.\",\n      \"method\": \"RNAi knockdown, pulldown assays, proximity ligation assay, VHS-GAT domain mutagenesis (N108), xenograft experiments\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding with mutagenesis, proximity ligation in situ, functional rescue, replicated in subsequent study\",\n      \"pmids\": [\"29358589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GGA2 associates with active (but not inactive) β1-integrin and promotes recycling of active β1-integrin to the plasma membrane; proximity BioID identified RAB13 and RAB10 as novel GGA2 interactors, and RAB13 silencing phenocopies GGA2 depletion in reducing active β1-integrin in focal adhesions and impairing cell migration.\",\n      \"method\": \"RNAi screen, co-immunoprecipitation, BioID proximity labeling, focal adhesion imaging, migration/invasion assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction confirmed by BioID + functional epistasis with RAB13, multiple orthogonal methods\",\n      \"pmids\": [\"31076515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GGA2 is required for anterograde cell surface transport of α2B-adrenergic receptor (α2B-AR); the GGA2 GAE domain (not hinge as for GGA1) directly interacts with multiple subdomains of the third intracellular loop of α2B-AR, and GGA2 depletion arrests the receptor in the perinuclear region and attenuates receptor-mediated ERK1/2 and cAMP signaling.\",\n      \"method\": \"shRNA/siRNA knockdown, co-immunoprecipitation, domain-mapping pulldown assays, ERK1/2 and cAMP signaling assays, primary cortical neuron imaging\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction domain mapping with functional signaling readout, single lab\",\n      \"pmids\": [\"27901063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GGA2 and AP-1 function in Rab11-positive recycling endosomes to retrieve endocytosed EGFR back to the plasma membrane; depletion of GGA2 suppresses EGFR recycling (biochemical recycling assay) and reduces steady-state levels of EGFR, MET, and ErbB4.\",\n      \"method\": \"Triple immunofluorescence, proximity ligation assay, biochemical recycling assay, RNAi knockdown, xenograft model\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct recycling assay with colocalization evidence, multiple orthogonal methods\",\n      \"pmids\": [\"34799560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"GGA2 mediates a non-redundant essential function in vivo; Gga2 knockout mice display embryonic or neonatal lethality depending on genetic background, while loss of GGA1 or GGA3 alone is tolerated, establishing that GGA2 cannot be fully compensated by the other GGA family members.\",\n      \"method\": \"Insertional mutagenesis gene knockout in mice, genetic background analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined lethal phenotype, replicated with two alleles and confirmed in follow-up study\",\n      \"pmids\": [\"22291915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GGA2 interacts with EGFR (confirmed by co-immunoprecipitation), increases EGFR protein levels, and modifies EGFR degradation after ligand stimulation in lung adenocarcinoma cells; GGA2 overexpression enhances EGFR-mediated transformation.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, RNAi knockdown, overexpression, colony and tumor forming assays\",\n      \"journal\": \"Journal of thoracic oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with functional overexpression/KD phenotype, single lab\",\n      \"pmids\": [\"30578931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In yeast, Gga2 is required for vacuolar delivery of amino acid permeases (including Mup1 and Can1) during glucose starvation, acting at the TGN as a clathrin adaptor; ectopic de-ubiquitination at the TGN redirects permeases to recycling, confirming active Gga2-dependent ubiquitin-recognition sorting.\",\n      \"method\": \"Genetic deletion analysis, fluorescence microscopy trafficking assays, engineered de-ubiquitination at TGN\",\n      \"journal\": \"Biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with mechanistic de-ubiquitination rescue experiment, single lab\",\n      \"pmids\": [\"32761633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Enterovirus (CVB5) protease 2A rapidly depletes GGA2 in beta cells due to GGA2's short half-life; GGA2 depletion impairs insulin secretory granule biogenesis at the TGN, disrupts vacuolar ATPase and cathepsin sorting, causes TGN acidification, and leads to premature lysosomal hydrolase activation and altered MHC class I immunopeptidome.\",\n      \"method\": \"Immunostaining of patient pancreas sections, viral infection experiments, siRNA depletion, proteomics of immunopeptidome\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, multiple phenotypic readouts but mechanistic pathway placement partially indirect\",\n      \"pmids\": [\"bio_10.1101_2025.03.28.645506\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"GGA2 is a multidomain Golgi/endosome-localized clathrin adaptor whose VHS domain recognizes acidic cluster-dileucine sorting motifs on cargo proteins (CI-MPR, sortilin, EGFR, β-secretase, α2B-AR), whose hinge domain binds clathrin and whose GAE domain mediates additional cargo interactions, collectively enabling GGA2 to direct cargo from the TGN to endosomes/lysosomes, mediate recycling of active β1-integrin and EGFR from recycling endosomes back to the plasma membrane via RAB13, and sort lysosomal enzymes (cathepsin D) to prevent their mis-secretion.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"GGA2 is a clathrin-associated sorting adaptor that directs transmembrane cargo between the trans-Golgi network (TGN), endosomes, and the plasma membrane, functioning non-redundantly from the other GGA family members as demonstrated by embryonic/neonatal lethality of Gga2 knockout mice [PMID:22291915]. Its VHS domain recognizes acidic cluster-dileucine motifs in the cytoplasmic tails of cargo proteins including CI-MPR, sortilin, β-secretase, and EGFR, while its hinge domain recruits clathrin and its GAE domain mediates additional cargo interactions such as with α2B-adrenergic receptor [PMID:11387476, PMID:11331584, PMID:12135764, PMID:27901063]. GGA2 is required for proper sorting of lysosomal enzymes (cathepsin D) at the TGN, preventing their mis-secretion [PMID:18431031], and functions at Rab11-positive recycling endosomes together with AP-1 to recycle EGFR and active β1-integrin back to the plasma membrane via a RAB13-dependent pathway, thereby sustaining receptor tyrosine kinase signaling and integrin-mediated cell migration [PMID:34799560, PMID:31076515, PMID:29358589].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing where GGA2 operates: GGA2 was localized to the Golgi complex, with domain dissection showing that the ear (GAE) domain was sufficient for Golgi targeting while the VHS domain distributed to membranes/vesicles, providing the first spatial framework for its sorting function.\",\n      \"evidence\": \"Immunofluorescence with Golgi markers, brefeldin A sensitivity, and truncation constructs in transfected cells\",\n      \"pmids\": [\"10702286\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; no endosomal or plasma membrane localization assessed at this stage\", \"Mechanism of Golgi recruitment via ear domain not defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identifying the molecular logic of cargo recognition: the VHS domain of GGA2 was shown to bind directly to acidic cluster-dileucine motifs in CI-MPR and sortilin cytoplasmic tails, and the hinge domain was shown to bind clathrin, establishing GGA2 as a bridging adaptor between sorting signals and coat assembly for TGN-to-endosome transport.\",\n      \"evidence\": \"Pulldown assays with mutagenesis of CI-MPR sorting motif; sortilin chimeric receptor binding and sorting assays in MPR-knockout cells; clathrin-binding assays\",\n      \"pmids\": [\"11387476\", \"11331584\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GGA2 is functionally non-redundant with GGA1/GGA3 not yet tested\", \"In vivo physiological relevance not established\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Expanding the cargo repertoire to disease-relevant substrates: the VHS domain of GGA2 was found to bind β-secretase (memapsin 2) via D496/L499/L500 in its cytoplasmic tail, implicating GGA2 in the intracellular trafficking of the Alzheimer's-associated protease.\",\n      \"evidence\": \"Pulldown with immobilized VHS domains and site-directed mutagenesis from mammalian cell lysates\",\n      \"pmids\": [\"12135764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of GGA2-β-secretase interaction on amyloid processing not demonstrated\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating a non-redundant requirement for GGA2 in lysosomal enzyme sorting: specific depletion of GGA2 to ~5% caused increased secretion of cathepsin D, establishing that GGA2 independently ensures efficient TGN-to-lysosome targeting of soluble hydrolases.\",\n      \"evidence\": \"Stable RNAi knockdown in HeLa cells with cathepsin D secretion assay\",\n      \"pmids\": [\"18431031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; cargo receptor (MPR) trafficking kinetics not directly measured\", \"Whether phenotype reflects direct or indirect sorting defect not fully resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealing a dual sorting mechanism in yeast: Gga2 was shown to mediate sequential ubiquitin-independent sorting of Arn1 from TGN to endosome and ubiquitin-dependent sorting into multivesicular bodies, demonstrating that GGA2 family members can read both dileucine and ubiquitin signals at distinct trafficking steps.\",\n      \"evidence\": \"Genetic mutant analysis with ubiquitin-binding mutant Gga2 and subcellular fractionation in S. cerevisiae\",\n      \"pmids\": [\"19574226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether mammalian GGA2 similarly performs dual ubiquitin-dependent/independent sorting not tested\", \"Structural basis for ubiquitin recognition by Gga2 not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Establishing essential in vivo function: Gga2 knockout mice exhibited embryonic or neonatal lethality depending on genetic background, while GGA1 and GGA3 knockouts were viable, proving that GGA2 performs a unique essential function that cannot be compensated by its paralogs.\",\n      \"evidence\": \"Insertional mutagenesis gene knockout in mice across multiple genetic backgrounds\",\n      \"pmids\": [\"22291915\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific cargo or tissue responsible for lethality not identified\", \"Conditional knockout to resolve tissue-specific requirements not performed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Uncovering a role in anterograde receptor transport and signaling: GGA2 was found to be required for cell-surface delivery of α2B-adrenergic receptor via a GAE domain interaction (distinct from the VHS-mediated cargo interactions), with GGA2 depletion trapping the receptor perinuclearly and attenuating ERK1/2 and cAMP signaling.\",\n      \"evidence\": \"shRNA/siRNA knockdown, co-immunoprecipitation with domain mapping, signaling assays, and primary cortical neuron imaging\",\n      \"pmids\": [\"27901063\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GAE-mediated cargo interactions represent a general anterograde sorting mechanism not addressed\", \"Single lab observation\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defining an antagonistic relationship among GGA family members in EGFR trafficking: GGA2 was shown to interact with EGFR's juxtamembrane region via VHS-GAT domains (N108-dependent), stabilize EGFR against lysosomal degradation, and oppose the degradation-promoting activities of GGA1 and GGA3.\",\n      \"evidence\": \"Pulldown assays, proximity ligation assay, VHS domain mutagenesis, RNAi epistasis, xenograft experiments\",\n      \"pmids\": [\"29358589\", \"30578931\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for why GGA2 stabilizes EGFR while GGA1/GGA3 promote its degradation not resolved\", \"Whether this extends to other receptor tyrosine kinases beyond EGFR not systematically tested at this stage\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealing a recycling endosome function for GGA2: GGA2 was found to associate selectively with active (not inactive) β1-integrin and to promote its recycling to focal adhesions via a RAB13-dependent pathway, with BioID identifying RAB13 and RAB10 as novel GGA2 proximity partners and RAB13 silencing phenocopying GGA2 loss.\",\n      \"evidence\": \"RNAi screen, co-immunoprecipitation, BioID proximity labeling, focal adhesion imaging, migration/invasion assays\",\n      \"pmids\": [\"31076515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GGA2 directly bridges integrin to RAB13 or acts through intermediate effectors unknown\", \"Structural basis for selectivity toward active integrin conformation not determined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Consolidating GGA2's role at recycling endosomes: GGA2 and AP-1 were found to colocalize at Rab11-positive recycling endosomes where they function to retrieve EGFR to the plasma membrane, with GGA2 depletion reducing steady-state levels of EGFR, MET, and ErbB4.\",\n      \"evidence\": \"Triple immunofluorescence, proximity ligation assay, biochemical EGFR recycling assay, RNAi knockdown, xenograft model\",\n      \"pmids\": [\"34799560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GGA2 and AP-1 form a stable complex or act sequentially at recycling endosomes not resolved\", \"Whether GGA2's recycling function requires clathrin not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open questions include: the specific cargo or tissue defect responsible for embryonic lethality in Gga2 knockout mice; the structural basis for GGA2's selective stabilization of EGFR in opposition to GGA1/GGA3; how GGA2 distinguishes active from inactive integrin; and the full spectrum of GGA2 cargo at recycling endosomes versus TGN.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of GGA2 in complex with any full-length cargo\", \"Mechanism by which GGA2 opposes GGA1/GGA3 in EGFR degradation undefined\", \"Tissue-specific essential function underlying knockout lethality unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3, 6, 7, 8]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 1, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [7, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 4, 5, 7, 9]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1, 4, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 8, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CI-MPR\", \"SORT1\", \"EGFR\", \"BACE1\", \"ADRA2B\", \"RAB13\", \"ITGB1\", \"CLTC\"],\n    \"other_free_text\": []\n  }\n}\n```"}