{"gene":"GLIPR2","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2004,"finding":"GAPR-1 (GLIPR2) forms homodimers both in vitro and in vivo, as determined by yeast two-hybrid screening, biochemical and biophysical assays. The 1.55 Å crystal structure shows GAPR-1 is structurally homologous to PR-1 family members (p14a and Ves V 5). Mutagenesis of conserved residues at the dimer interface leads to a greatly increased dimer population. A potential catalytic triad similar to serine proteases was identified across the dimer interface.","method":"Yeast two-hybrid, biochemical/biophysical assays, X-ray crystallography (1.55 Å), site-directed mutagenesis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus multiple orthogonal biochemical methods in one study","pmids":["15123429"],"is_preprint":false},{"year":2010,"finding":"GAPR-1 (GLIPR2) binds negatively charged phospholipid membranes (phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, phosphatidic acid) via electrostatic interactions; N-terminal myristoylation contributes to but is insufficient for stable membrane anchorage. GAPR-1 shows highest preference for phosphatidic acid. Phosphatidylinositol binds with unusual characteristics — it remains associated after denaturation or organic extraction, and mass spectrometry showed up to 3 PI molecules per GAPR-1 monomer.","method":"Liposome binding assay, SDS-PAGE gel-shift, mass spectrometry","journal":"Molecular membrane biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical methods (liposome binding, MS, gel-shift), single lab","pmids":["20095951"],"is_preprint":false},{"year":2012,"finding":"Phytic acid (inositol hexakisphosphate) induces an alternative GAPR-1 dimer conformation distinct from the previously solved dimer (one subunit rotated by 28.5°). In the presence of negatively charged lipids, GAPR-1 causes stable liposome tethering. The [D81K] mutant (stabilizing IP6-induced dimer) also causes tethering, while [A68K] mutant (stabilizing non-rotated dimer) binds but does not tether liposomes, demonstrating that alternative dimerization regulates GAPR-1 membrane interactions.","method":"X-ray crystallography, light scattering assay, flow cytometry, site-directed mutagenesis","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with phytic acid, functional mutagenesis, and two independent liposome assays","pmids":["22560898"],"is_preprint":false},{"year":2006,"finding":"GLIPR-2 protein is upregulated in fibrotic kidney and is expressed in epithelial cells. In vitro experiments showed that GLIPR-2 can induce epithelial-to-mesenchymal transition (EMT) in a renal epithelial cell line.","method":"Transcript profiling in COL4A3 knockout mouse, immunofluorescence co-staining, in vitro EMT assay in renal epithelial cells","journal":"Matrix biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — in vitro overexpression EMT assay plus in vivo expression data, single lab","pmids":["17055234"],"is_preprint":false},{"year":2013,"finding":"GLIPR-2 overexpression in HK-2 proximal renal tubular epithelial cells promotes EMT (decreased E-cadherin, increased vimentin and α-SMA) and cell migration, and activates ERK1/2 signaling; EGFR expression is also elevated in GLIPR-2-overexpressing cells.","method":"Stable transfection (pcDNA3.0-GLIPR-2), EMT PCR array, Western blot, cell migration assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — overexpression with multiple molecular readouts confirming EMT and ERK1/2 activation, single lab","pmids":["23516513"],"is_preprint":false},{"year":2013,"finding":"Hypoxia upregulates GLIPR-2 expression in hepatocellular carcinoma cells (HepG2 and PLC/PRF/5). GLIPR-2 overexpression promotes migration and invasion via EMT and positively regulates ERK1/2; knockdown of GLIPR-2 attenuates hypoxia-induced migration and invasion.","method":"Hypoxia cell culture model, overexpression and siRNA knockdown, migration/invasion assays, Western blot for ERK1/2","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — both gain- and loss-of-function in two cell lines with multiple readouts, single lab","pmids":["24204846"],"is_preprint":false},{"year":2014,"finding":"GAPR-1 (GLIPR2) forms amyloid-like fibrils in the presence of liposomes containing negatively charged lipids, as shown by electron microscopy, Thioflavin T fluorescence, and circular dichroism. GAPR-1 binds the amyloid-oligomer-specific antibody A11 even without lipids, indicating intrinsic oligomerization tendency. GAPR-1 inhibits Aβ(1-40) aggregation and binds to prefibrillar oligomeric Aβ structures during early fibril formation.","method":"Electron microscopy, Thioflavin T fluorescence, circular dichroism, immuno-dot blot with A11 antibody","journal":"Amyloid","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biophysical methods, single lab","pmids":["24471790"],"is_preprint":false},{"year":2016,"finding":"GAPR-1 (GLIPR2) is phosphorylated at Serine 58 by IRAK1 (the MyD88-dependent TLR4 kinase). This phosphorylation promotes GAPR-1 interaction with TMED7 (a TRAM-TRIF-dependent inhibitor), impairing TMED7-mediated disruption of the TRAM-TRIF complex and thereby enhancing IFN-β and IL-10 secretion downstream of TLR4.","method":"Kinase assay (IRAK1-mediated phosphorylation), co-immunoprecipitation, reporter/cytokine assays","journal":"Inflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — identified specific phosphorylation site and binding partner with functional downstream readout, single lab","pmids":["26678074"],"is_preprint":false},{"year":2017,"finding":"GAPR-1 (GLIPR2) binds Beclin 1 residues 267–284 via a conserved equatorial surface groove on GAPR-1. Mutagenesis of five conserved groove-lining residues (H54A/E86A/G102K/H103A/N138G) abrogates Beclin 1 binding. The 1.27 Å crystal structure of the pentad mutant shows the groove is shallower and more positively charged. SAXS analysis reveals that WT GAPR-1 is monomeric in solution while the pentad mutant is primarily dimeric, and dimeric GAPR-1 is unlikely to bind Beclin 1 because the groove is partially occluded.","method":"X-ray crystallography (1.27 Å), SAXS, mutagenesis, pull-down assays, structural modeling","journal":"Acta crystallographica. Section D, Structural biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus SAXS plus mutagenesis-validated binding interface, multiple orthogonal methods","pmids":["28876241"],"is_preprint":false},{"year":2019,"finding":"GAPR-1 (GLIPR2) binds zinc ions (demonstrated by ITC). Zn2+ binding causes a conformational change (shown by CD, tryptophan fluorescence, trypsin digestion) required for oligomerization and amyloid-like assembly in the presence of heparin. Molecular dynamics simulations place Zn2+ binding at His54 and His103; mutation of these residues strongly diminishes amyloid-like aggregation.","method":"Isothermal titration calorimetry, circular dichroism, tryptophan fluorescence, trypsin digestion, Thioflavin T fluorescence, TEM, molecular dynamics simulations, site-directed mutagenesis","journal":"Bioscience reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — ITC binding assay, mutagenesis, multiple structural probes, and functional aggregation readout in one study","pmids":["30700571"],"is_preprint":false},{"year":2019,"finding":"Copper ions induce a distinct amyloid-like aggregation pathway of GAPR-1 in the presence of heparin, independent of the conserved Zn2+-binding site (His54/His103), involving disulfide bond formation and distinct nucleation/elongation phases. The Zn2+-dependent aggregation pathway is cysteine-independent and reversible upon Zn2+ removal. These two pathways are mechanistically distinct.","method":"Thioflavin T fluorescence, TEM, site-directed mutagenesis (cysteine mutants, His54/His103 mutants), redox manipulation","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biophysical methods with mutagenesis, single lab","pmids":["31636315"],"is_preprint":false},{"year":2020,"finding":"GLIPR2 is a negative regulator of the PtdIns3K-C1 autophagy complex and basal autophagy. GLIPR2 was identified as binding to BECN1 residues 267–284. CRISPR-Cas9 depletion of GLIPR2 in HeLa cells increased autophagic flux and PtdIns3P generation. Purified GLIPR2 bound to PtdIns3K-C1 and directly inhibited its in vitro lipid kinase activity. GLIPR2 KO in mice increased basal autophagic flux and WIPI2 recruitment. GLIPR2 loss also caused less compact Golgi structure.","method":"CRISPR-Cas9 knockout (cells and mice), in vitro lipid kinase assay with purified complex, autophagic flux assays, PtdIns3P detection, WIPI2 immunofluorescence","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstituted kinase inhibition assay plus in vivo CRISPR knockout with multiple orthogonal functional readouts","pmids":["33222586"],"is_preprint":false},{"year":2021,"finding":"N-myristoylation of GAPR-1 is an important determinant of early-stage cytosolic inclusion formation in yeast. Mutations in conserved metal-binding site residues (His54, His103) enhanced inclusion formation, and Zn2+ addition promotes inclusion formation while reducing GAPR-1 degradation, suggesting stabilization in inclusions.","method":"Yeast overexpression, fluorescence microscopy, FRAP (dynamic/reversible inclusions), mutagenesis, metal ion treatment","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging with functional mutagenesis in yeast model, single lab","pmids":["34298062"],"is_preprint":false},{"year":2022,"finding":"GAPR-1 (GLIPR2) interferes with Beclin 1 condensate formation in yeast through direct protein–protein interaction at the same binding interface previously characterized in mammalian cells. Mutations of the GAPR-1/Beclin 1 interaction site and the B18 Beclin 1-derived peptide (which binds GAPR-1) abolish the reduction of Beclin 1 condensates. Amyloidogenic properties of the B18 peptide are important for interaction with GAPR-1.","method":"Yeast co-expression system, fluorescence microscopy, mutagenesis of interaction surfaces, peptide competition assay","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast model with mutagenesis and peptide competition confirms interaction interface, single lab","pmids":["36586462"],"is_preprint":false},{"year":2024,"finding":"SMYD2 methylates GLIPR2 to stabilize it; SMYD2 inhibition decreases GLIPR2 methylation and facilitates GLIPR2 ubiquitination, leading to GLIPR2 destabilization. GLIPR2 mediates EMT downstream of SMYD2 through the ERK/p38 pathway; GLIPR2 overexpression rescued the inhibitory effect of SMYD2 inhibition on ERK/p38 and EMT.","method":"In vivo PQ-mouse model (western blot, immunofluorescence), in vitro MLE-12 cell model, SMYD2 inhibitor AZ505, GLIPR2 overexpression rescue experiments","journal":"Pesticide biochemistry and physiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — in vivo and in vitro rescue experiments identify methylation/ubiquitination regulation and downstream ERK/p38 pathway, single lab","pmids":["38879290"],"is_preprint":false},{"year":2025,"finding":"GLIPR2 promotes endothelial-to-mesenchymal transition (EndoMT) and cardiac fibrosis after AMI through the PDGFRL/AKT/mTOR signaling pathway. AAV-mediated knockdown of GLIPR2 in mice reversed EndoMT and attenuated cardiac fibrosis. Transcriptome sequencing and rescue experiments identified PDGFRL/AKT/mTOR as the critical downstream pathway.","method":"AAV-targeted knockdown in AMI mouse model, lentiviral overexpression/knockdown in HCMECs, transcriptome sequencing, rescue experiments","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KD and in vitro gain/loss-of-function with transcriptome pathway identification and rescue, single lab","pmids":["40543810"],"is_preprint":false},{"year":2026,"finding":"GLIPR2 is N-myristoylated, and this modification is required for its pro-ferroptotic activity in NSCLC cells. A myristoylation-deficient mutant (G2A) failed to restore ferroptosis sensitivity, establishing that N-myristoylation is functionally necessary for GLIPR2's role in ferroptosis. NMT1/NMT2 inhibition attenuated ferroptosis, and the NMT1/NMT2-GLIPR2 axis was identified as a regulator of ferroptosis.","method":"Quantitative myristoylproteomics (click chemistry), genetic/pharmacological NMT inhibition, GLIPR2 overexpression/KD, G2A myristoylation-deficient mutant functional rescue assay","journal":"Materials today. Bio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — myristoylation-deficient mutant rescue experiment plus proteomics identification, single lab","pmids":["41782991"],"is_preprint":false}],"current_model":"GLIPR2 (GAPR-1) is an N-myristoylated, peripheral Golgi membrane protein of the CAP/PR-1 superfamily that functions as a negative regulator of autophagy by directly binding BECN1 residues 267–284 through a conserved equatorial groove and inhibiting the PtdIns3K-C1 (VPS34) complex lipid kinase activity; dimerization occludes the BECN1-binding groove and may regulate this inhibitory function; GLIPR2 additionally promotes EMT via ERK1/2 and ERK/p38 signaling in epithelial cells, modulates TLR4-dependent type I interferon signaling through IRAK1-mediated phosphorylation at Ser58 and subsequent interaction with TMED7, promotes EndoMT through PDGFRL/AKT/mTOR, and its N-myristoylation is required for pro-ferroptotic activity; the protein also binds negatively charged phospholipids and zinc ions, and can form amyloid-like structures regulated by metal ions and redox state."},"narrative":{"mechanistic_narrative":"GLIPR2 (GAPR-1) is an N-myristoylated, Golgi-associated member of the CAP/PR-1 superfamily that acts as a negative regulator of autophagy and a driver of mesenchymal transition programs [PMID:15123429, PMID:33222586]. Its 1.55 Å crystal structure established structural homology to PR-1 family proteins and showed that it forms homodimers, with a potential catalytic triad across the dimer interface [PMID:15123429]. The protein binds negatively charged phospholipid membranes, preferring phosphatidic acid, and is stably anchored through combined electrostatic interactions and N-terminal myristoylation [PMID:20095951]. Mechanistically, GLIPR2 inhibits autophagy by directly binding BECN1 residues 267–284 through a conserved equatorial groove; mutagenesis of five groove-lining residues abrogates this interaction, and depletion of GLIPR2 increases autophagic flux, PtdIns3P generation, and WIPI2 recruitment, with purified GLIPR2 directly inhibiting PtdIns3K-C1 lipid kinase activity in vitro [PMID:28876241, PMID:33222586]. Dimerization occludes the BECN1-binding groove, providing a structural switch that couples oligomeric state to inhibitory function [PMID:28876241]. GLIPR2 also drives epithelial-to-mesenchymal transition in renal and hepatocellular cells via ERK1/2 signaling [PMID:23516513, PMID:24204846], drives EndoMT and cardiac fibrosis through PDGFRL/AKT/mTOR [PMID:40543810], and is stabilized by SMYD2-mediated methylation upstream of an ERK/p38 EMT program [PMID:38879290]. Additional functions include IRAK1-dependent phosphorylation at Ser58 that promotes TMED7 binding to enhance TLR4-driven IFN-β signaling [PMID:26678074], N-myristoylation-dependent pro-ferroptotic activity [PMID:41782991], and metal-ion- and redox-regulated amyloid-like assembly through zinc binding at His54/His103 versus a copper/disulfide-dependent pathway [PMID:30700571, PMID:31636315].","teleology":[{"year":2004,"claim":"Establishing the structural identity of GAPR-1 was the first step in defining its biochemical capabilities; the crystal structure placed it in the PR-1/CAP fold and revealed an intrinsic propensity to dimerize.","evidence":"Yeast two-hybrid, X-ray crystallography at 1.55 Å, and site-directed mutagenesis of the dimer interface","pmids":["15123429"],"confidence":"High","gaps":["The functional role of the putative catalytic triad was not demonstrated","No physiological binding partner identified at this stage"]},{"year":2010,"claim":"To understand how a peripheral Golgi protein engages membranes, the lipid-binding determinants were defined, showing electrostatic preference for anionic phospholipids beyond myristoylation alone.","evidence":"Liposome binding assays, gel-shift, and mass spectrometry of bound phosphoinositides","pmids":["20095951"],"confidence":"Medium","gaps":["Functional consequence of phosphatidic acid preference in cells not established","Stoichiometry of PI binding not linked to a downstream activity"]},{"year":2012,"claim":"This work connected conformational state to function by showing that an alternative inositol-phosphate-induced dimer drives membrane tethering, establishing dimerization as a regulatory switch for membrane behavior.","evidence":"X-ray crystallography with phytic acid, light scattering, flow cytometry, and conformation-locking mutants (D81K, A68K)","pmids":["22560898"],"confidence":"High","gaps":["Physiological trigger for the alternative dimer in vivo unknown","Relationship of tethering to Golgi function not tested"]},{"year":2006,"claim":"The first cellular role emerged from fibrotic kidney, linking GLIPR2 to epithelial-mesenchymal transition rather than to any structural prediction.","evidence":"Transcript profiling in COL4A3 knockout mice, immunofluorescence, and in vitro EMT assays in renal epithelial cells","pmids":["17055234"],"confidence":"Medium","gaps":["Molecular pathway driving EMT not defined","Causality versus correlation in fibrosis not resolved"]},{"year":2013,"claim":"Two studies established a mechanistic route for the EMT phenotype, implicating ERK1/2 activation in both renal epithelial and hepatocellular carcinoma contexts under overexpression and hypoxia.","evidence":"Stable overexpression and siRNA knockdown in HK-2, HepG2, and PLC/PRF/5 cells with EMT marker, migration/invasion, and ERK1/2 readouts","pmids":["23516513","24204846"],"confidence":"Medium","gaps":["Direct molecular link between GLIPR2 and ERK activation not shown","Whether membrane or Golgi localization is required for signaling untested"]},{"year":2016,"claim":"A distinct immune-signaling function was uncovered by identifying a phosphorylation event and binding partner that modulate TLR4 output.","evidence":"IRAK1 kinase assay identifying Ser58 phosphorylation, co-immunoprecipitation with TMED7, and cytokine/reporter assays","pmids":["26678074"],"confidence":"Medium","gaps":["Reciprocal validation of the TMED7 interaction limited","How phosphorylation alters GLIPR2 conformation or localization unknown"]},{"year":2017,"claim":"Structural mapping of a BECN1-binding groove defined the molecular basis for an autophagy-regulatory interaction and tied it to oligomeric state.","evidence":"1.27 Å crystal structure of a pentad groove mutant, SAXS, pull-downs, and mutagenesis of five conserved groove residues","pmids":["28876241"],"confidence":"High","gaps":["Functional autophagy consequence not yet demonstrated in this study","In vivo relevance of dimer-mediated groove occlusion untested"]},{"year":2020,"claim":"The autophagy function was causally established by showing GLIPR2 directly inhibits the PtdIns3K-C1 complex, converting the structural BECN1 interaction into a defined negative-regulatory mechanism.","evidence":"CRISPR-Cas9 knockout in HeLa cells and mice, in vitro lipid kinase assays with purified complex, PtdIns3P and WIPI2 readouts","pmids":["33222586"],"confidence":"High","gaps":["Signals that relieve GLIPR2 inhibition of PtdIns3K-C1 unknown","Connection between Golgi compaction phenotype and autophagy control unresolved"]},{"year":2019,"claim":"Metal-ion biochemistry was dissected to explain the protein's amyloidogenic behavior, defining two mechanistically distinct aggregation pathways governed by zinc versus copper and redox state.","evidence":"ITC, CD, tryptophan fluorescence, ThT/TEM aggregation assays, and His54/His103 and cysteine mutants","pmids":["30700571","31636315"],"confidence":"High","gaps":["Physiological role of amyloid-like assembly in cells not established","Relationship between metal binding and the BECN1/membrane functions unknown"]},{"year":2021,"claim":"Yeast modeling linked N-myristoylation and metal-binding residues to formation of reversible cytosolic inclusions, connecting the modification and metal chemistry to cellular condensate behavior.","evidence":"Yeast overexpression, fluorescence microscopy with FRAP, mutagenesis, and metal-ion treatment","pmids":["34298062"],"confidence":"Medium","gaps":["Mammalian relevance of inclusions not shown","Functional output of inclusion formation undefined"]},{"year":2022,"claim":"The BECN1-interaction mechanism was extended to condensate biology, showing GLIPR2 interferes with Beclin 1 condensate formation through the same interface and that B18 amyloidogenic properties matter.","evidence":"Yeast co-expression, fluorescence microscopy, interface mutagenesis, and B18 peptide competition","pmids":["36586462"],"confidence":"Medium","gaps":["Quantitative impact on autophagy in mammalian cells not measured","Whether condensate interference is the in vivo mode of PtdIns3K-C1 inhibition unclear"]},{"year":2024,"claim":"An upstream regulatory layer was identified, showing SMYD2 methylation stabilizes GLIPR2 against ubiquitination and drives EMT via ERK/p38.","evidence":"Paraquat mouse model, MLE-12 cells, SMYD2 inhibitor AZ505, and GLIPR2 overexpression rescue","pmids":["38879290"],"confidence":"Medium","gaps":["Methylation site on GLIPR2 not mapped","Direct versus indirect SMYD2-GLIPR2 relationship not fully resolved"]},{"year":2025,"claim":"A vascular role was defined, implicating GLIPR2 in EndoMT and cardiac fibrosis through a PDGFRL/AKT/mTOR axis distinct from its ERK-driven epithelial program.","evidence":"AAV knockdown in AMI mice, gain/loss of function in HCMECs, transcriptome sequencing, and rescue experiments","pmids":["40543810"],"confidence":"Medium","gaps":["Mechanism by which GLIPR2 engages PDGFRL not defined","Reconciliation of ERK versus AKT/mTOR pathways across cell types unknown"]},{"year":2026,"claim":"The functional necessity of N-myristoylation was extended to ferroptosis, establishing an NMT1/NMT2-GLIPR2 axis as a regulator of ferroptosis sensitivity.","evidence":"Quantitative myristoylproteomics, NMT inhibition, and a G2A myristoylation-deficient rescue assay in NSCLC cells","pmids":["41782991"],"confidence":"Medium","gaps":["Molecular mechanism by which myristoylated GLIPR2 promotes ferroptosis unknown","Link between ferroptotic activity and autophagy/Golgi functions unexplored"]},{"year":null,"claim":"How GLIPR2's distinct activities — PtdIns3K-C1 inhibition, ERK/AKT-driven mesenchymal transitions, TLR4 signaling, pro-ferroptotic activity, and metal-regulated amyloid assembly — are integrated within a single protein, and which are dominant in a given physiological context, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking the structural groove/dimer switch to the diverse signaling outputs","Tissue-specific determinants of which pathway dominates are unknown","Upstream physiological signals controlling GLIPR2 activity not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,11]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[6,9]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[11]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[16]}],"complexes":[],"partners":["BECN1","TMED7","IRAK1","SMYD2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H4G4","full_name":"Golgi-associated plant pathogenesis-related protein 1","aliases":["Glioma pathogenesis-related protein 2","GliPR 2"],"length_aa":154,"mass_kda":17.2,"function":"","subcellular_location":"Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/Q9H4G4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GLIPR2","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/GLIPR2","total_profiled":1310},"omim":[{"mim_id":"607141","title":"GLIOMA PATHOGENESIS-RELATED PROTEIN 2; GLIPR2","url":"https://www.omim.org/entry/607141"},{"mim_id":"604378","title":"BECLIN 1; BECN1","url":"https://www.omim.org/entry/604378"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"},{"location":"Microtubules","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GLIPR2"},"hgnc":{"alias_symbol":["GAPR-1"],"prev_symbol":["C9orf19"]},"alphafold":{"accession":"Q9H4G4","domains":[{"cath_id":"3.40.33.10","chopping":"4-149","consensus_level":"high","plddt":96.9003,"start":4,"end":149}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H4G4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H4G4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H4G4-F1-predicted_aligned_error_v6.png","plddt_mean":95.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GLIPR2","jax_strain_url":"https://www.jax.org/strain/search?query=GLIPR2"},"sequence":{"accession":"Q9H4G4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H4G4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H4G4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H4G4"}},"corpus_meta":[{"pmid":"22133690","id":"PMC_22133690","title":"Identification of distinct populations of prostasomes that differentially express prostate stem cell antigen, annexin A1, and GLIPR2 in humans.","date":"2012","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/22133690","citation_count":192,"is_preprint":false},{"pmid":"15123429","id":"PMC_15123429","title":"Structural analysis of the human Golgi-associated plant pathogenesis related protein GAPR-1 implicates dimerization as a regulatory mechanism.","date":"2004","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15123429","citation_count":62,"is_preprint":false},{"pmid":"33222586","id":"PMC_33222586","title":"GLIPR2 is a negative regulator of autophagy and the BECN1-ATG14-containing phosphatidylinositol 3-kinase complex.","date":"2020","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/33222586","citation_count":35,"is_preprint":false},{"pmid":"28733476","id":"PMC_28733476","title":"miR-30e targets GLIPR-2 to modulate diabetic nephropathy: in vitro and in vivo experiments.","date":"2017","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/28733476","citation_count":33,"is_preprint":false},{"pmid":"23516513","id":"PMC_23516513","title":"GLIPR-2 overexpression in HK-2 cells promotes cell EMT and migration through ERK1/2 activation.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23516513","citation_count":32,"is_preprint":false},{"pmid":"22560898","id":"PMC_22560898","title":"Interaction of GAPR-1 with lipid bilayers is regulated by alternative homodimerization.","date":"2012","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/22560898","citation_count":28,"is_preprint":false},{"pmid":"20095951","id":"PMC_20095951","title":"Binding of GAPR-1 to negatively charged phospholipid membranes: unusual binding characteristics to phosphatidylinositol.","date":"2010","source":"Molecular membrane biology","url":"https://pubmed.ncbi.nlm.nih.gov/20095951","citation_count":27,"is_preprint":false},{"pmid":"17055234","id":"PMC_17055234","title":"The plant pathogenesis related protein GLIPR-2 is highly expressed in fibrotic kidney and promotes epithelial to mesenchymal transition in vitro.","date":"2006","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/17055234","citation_count":24,"is_preprint":false},{"pmid":"24471790","id":"PMC_24471790","title":"Golgi-Associated plant Pathogenesis Related protein 1 (GAPR-1) forms amyloid-like fibrils by interaction with acidic phospholipids and inhibits Aβ aggregation.","date":"2014","source":"Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of 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Bio","url":"https://pubmed.ncbi.nlm.nih.gov/41782991","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15165,"output_tokens":4805,"usd":0.058785,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12814,"output_tokens":4593,"usd":0.089447,"stage2_stop_reason":"end_turn"},"total_usd":0.148232,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"GAPR-1 (GLIPR2) forms homodimers both in vitro and in vivo, as determined by yeast two-hybrid screening, biochemical and biophysical assays. The 1.55 Å crystal structure shows GAPR-1 is structurally homologous to PR-1 family members (p14a and Ves V 5). Mutagenesis of conserved residues at the dimer interface leads to a greatly increased dimer population. A potential catalytic triad similar to serine proteases was identified across the dimer interface.\",\n      \"method\": \"Yeast two-hybrid, biochemical/biophysical assays, X-ray crystallography (1.55 Å), site-directed mutagenesis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus multiple orthogonal biochemical methods in one study\",\n      \"pmids\": [\"15123429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"GAPR-1 (GLIPR2) binds negatively charged phospholipid membranes (phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, phosphatidic acid) via electrostatic interactions; N-terminal myristoylation contributes to but is insufficient for stable membrane anchorage. GAPR-1 shows highest preference for phosphatidic acid. Phosphatidylinositol binds with unusual characteristics — it remains associated after denaturation or organic extraction, and mass spectrometry showed up to 3 PI molecules per GAPR-1 monomer.\",\n      \"method\": \"Liposome binding assay, SDS-PAGE gel-shift, mass spectrometry\",\n      \"journal\": \"Molecular membrane biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical methods (liposome binding, MS, gel-shift), single lab\",\n      \"pmids\": [\"20095951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Phytic acid (inositol hexakisphosphate) induces an alternative GAPR-1 dimer conformation distinct from the previously solved dimer (one subunit rotated by 28.5°). In the presence of negatively charged lipids, GAPR-1 causes stable liposome tethering. The [D81K] mutant (stabilizing IP6-induced dimer) also causes tethering, while [A68K] mutant (stabilizing non-rotated dimer) binds but does not tether liposomes, demonstrating that alternative dimerization regulates GAPR-1 membrane interactions.\",\n      \"method\": \"X-ray crystallography, light scattering assay, flow cytometry, site-directed mutagenesis\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with phytic acid, functional mutagenesis, and two independent liposome assays\",\n      \"pmids\": [\"22560898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"GLIPR-2 protein is upregulated in fibrotic kidney and is expressed in epithelial cells. In vitro experiments showed that GLIPR-2 can induce epithelial-to-mesenchymal transition (EMT) in a renal epithelial cell line.\",\n      \"method\": \"Transcript profiling in COL4A3 knockout mouse, immunofluorescence co-staining, in vitro EMT assay in renal epithelial cells\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in vitro overexpression EMT assay plus in vivo expression data, single lab\",\n      \"pmids\": [\"17055234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GLIPR-2 overexpression in HK-2 proximal renal tubular epithelial cells promotes EMT (decreased E-cadherin, increased vimentin and α-SMA) and cell migration, and activates ERK1/2 signaling; EGFR expression is also elevated in GLIPR-2-overexpressing cells.\",\n      \"method\": \"Stable transfection (pcDNA3.0-GLIPR-2), EMT PCR array, Western blot, cell migration assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — overexpression with multiple molecular readouts confirming EMT and ERK1/2 activation, single lab\",\n      \"pmids\": [\"23516513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Hypoxia upregulates GLIPR-2 expression in hepatocellular carcinoma cells (HepG2 and PLC/PRF/5). GLIPR-2 overexpression promotes migration and invasion via EMT and positively regulates ERK1/2; knockdown of GLIPR-2 attenuates hypoxia-induced migration and invasion.\",\n      \"method\": \"Hypoxia cell culture model, overexpression and siRNA knockdown, migration/invasion assays, Western blot for ERK1/2\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — both gain- and loss-of-function in two cell lines with multiple readouts, single lab\",\n      \"pmids\": [\"24204846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GAPR-1 (GLIPR2) forms amyloid-like fibrils in the presence of liposomes containing negatively charged lipids, as shown by electron microscopy, Thioflavin T fluorescence, and circular dichroism. GAPR-1 binds the amyloid-oligomer-specific antibody A11 even without lipids, indicating intrinsic oligomerization tendency. GAPR-1 inhibits Aβ(1-40) aggregation and binds to prefibrillar oligomeric Aβ structures during early fibril formation.\",\n      \"method\": \"Electron microscopy, Thioflavin T fluorescence, circular dichroism, immuno-dot blot with A11 antibody\",\n      \"journal\": \"Amyloid\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biophysical methods, single lab\",\n      \"pmids\": [\"24471790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GAPR-1 (GLIPR2) is phosphorylated at Serine 58 by IRAK1 (the MyD88-dependent TLR4 kinase). This phosphorylation promotes GAPR-1 interaction with TMED7 (a TRAM-TRIF-dependent inhibitor), impairing TMED7-mediated disruption of the TRAM-TRIF complex and thereby enhancing IFN-β and IL-10 secretion downstream of TLR4.\",\n      \"method\": \"Kinase assay (IRAK1-mediated phosphorylation), co-immunoprecipitation, reporter/cytokine assays\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — identified specific phosphorylation site and binding partner with functional downstream readout, single lab\",\n      \"pmids\": [\"26678074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GAPR-1 (GLIPR2) binds Beclin 1 residues 267–284 via a conserved equatorial surface groove on GAPR-1. Mutagenesis of five conserved groove-lining residues (H54A/E86A/G102K/H103A/N138G) abrogates Beclin 1 binding. The 1.27 Å crystal structure of the pentad mutant shows the groove is shallower and more positively charged. SAXS analysis reveals that WT GAPR-1 is monomeric in solution while the pentad mutant is primarily dimeric, and dimeric GAPR-1 is unlikely to bind Beclin 1 because the groove is partially occluded.\",\n      \"method\": \"X-ray crystallography (1.27 Å), SAXS, mutagenesis, pull-down assays, structural modeling\",\n      \"journal\": \"Acta crystallographica. Section D, Structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus SAXS plus mutagenesis-validated binding interface, multiple orthogonal methods\",\n      \"pmids\": [\"28876241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GAPR-1 (GLIPR2) binds zinc ions (demonstrated by ITC). Zn2+ binding causes a conformational change (shown by CD, tryptophan fluorescence, trypsin digestion) required for oligomerization and amyloid-like assembly in the presence of heparin. Molecular dynamics simulations place Zn2+ binding at His54 and His103; mutation of these residues strongly diminishes amyloid-like aggregation.\",\n      \"method\": \"Isothermal titration calorimetry, circular dichroism, tryptophan fluorescence, trypsin digestion, Thioflavin T fluorescence, TEM, molecular dynamics simulations, site-directed mutagenesis\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ITC binding assay, mutagenesis, multiple structural probes, and functional aggregation readout in one study\",\n      \"pmids\": [\"30700571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Copper ions induce a distinct amyloid-like aggregation pathway of GAPR-1 in the presence of heparin, independent of the conserved Zn2+-binding site (His54/His103), involving disulfide bond formation and distinct nucleation/elongation phases. The Zn2+-dependent aggregation pathway is cysteine-independent and reversible upon Zn2+ removal. These two pathways are mechanistically distinct.\",\n      \"method\": \"Thioflavin T fluorescence, TEM, site-directed mutagenesis (cysteine mutants, His54/His103 mutants), redox manipulation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biophysical methods with mutagenesis, single lab\",\n      \"pmids\": [\"31636315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GLIPR2 is a negative regulator of the PtdIns3K-C1 autophagy complex and basal autophagy. GLIPR2 was identified as binding to BECN1 residues 267–284. CRISPR-Cas9 depletion of GLIPR2 in HeLa cells increased autophagic flux and PtdIns3P generation. Purified GLIPR2 bound to PtdIns3K-C1 and directly inhibited its in vitro lipid kinase activity. GLIPR2 KO in mice increased basal autophagic flux and WIPI2 recruitment. GLIPR2 loss also caused less compact Golgi structure.\",\n      \"method\": \"CRISPR-Cas9 knockout (cells and mice), in vitro lipid kinase assay with purified complex, autophagic flux assays, PtdIns3P detection, WIPI2 immunofluorescence\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstituted kinase inhibition assay plus in vivo CRISPR knockout with multiple orthogonal functional readouts\",\n      \"pmids\": [\"33222586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"N-myristoylation of GAPR-1 is an important determinant of early-stage cytosolic inclusion formation in yeast. Mutations in conserved metal-binding site residues (His54, His103) enhanced inclusion formation, and Zn2+ addition promotes inclusion formation while reducing GAPR-1 degradation, suggesting stabilization in inclusions.\",\n      \"method\": \"Yeast overexpression, fluorescence microscopy, FRAP (dynamic/reversible inclusions), mutagenesis, metal ion treatment\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging with functional mutagenesis in yeast model, single lab\",\n      \"pmids\": [\"34298062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GAPR-1 (GLIPR2) interferes with Beclin 1 condensate formation in yeast through direct protein–protein interaction at the same binding interface previously characterized in mammalian cells. Mutations of the GAPR-1/Beclin 1 interaction site and the B18 Beclin 1-derived peptide (which binds GAPR-1) abolish the reduction of Beclin 1 condensates. Amyloidogenic properties of the B18 peptide are important for interaction with GAPR-1.\",\n      \"method\": \"Yeast co-expression system, fluorescence microscopy, mutagenesis of interaction surfaces, peptide competition assay\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast model with mutagenesis and peptide competition confirms interaction interface, single lab\",\n      \"pmids\": [\"36586462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SMYD2 methylates GLIPR2 to stabilize it; SMYD2 inhibition decreases GLIPR2 methylation and facilitates GLIPR2 ubiquitination, leading to GLIPR2 destabilization. GLIPR2 mediates EMT downstream of SMYD2 through the ERK/p38 pathway; GLIPR2 overexpression rescued the inhibitory effect of SMYD2 inhibition on ERK/p38 and EMT.\",\n      \"method\": \"In vivo PQ-mouse model (western blot, immunofluorescence), in vitro MLE-12 cell model, SMYD2 inhibitor AZ505, GLIPR2 overexpression rescue experiments\",\n      \"journal\": \"Pesticide biochemistry and physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in vivo and in vitro rescue experiments identify methylation/ubiquitination regulation and downstream ERK/p38 pathway, single lab\",\n      \"pmids\": [\"38879290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GLIPR2 promotes endothelial-to-mesenchymal transition (EndoMT) and cardiac fibrosis after AMI through the PDGFRL/AKT/mTOR signaling pathway. AAV-mediated knockdown of GLIPR2 in mice reversed EndoMT and attenuated cardiac fibrosis. Transcriptome sequencing and rescue experiments identified PDGFRL/AKT/mTOR as the critical downstream pathway.\",\n      \"method\": \"AAV-targeted knockdown in AMI mouse model, lentiviral overexpression/knockdown in HCMECs, transcriptome sequencing, rescue experiments\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KD and in vitro gain/loss-of-function with transcriptome pathway identification and rescue, single lab\",\n      \"pmids\": [\"40543810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"GLIPR2 is N-myristoylated, and this modification is required for its pro-ferroptotic activity in NSCLC cells. A myristoylation-deficient mutant (G2A) failed to restore ferroptosis sensitivity, establishing that N-myristoylation is functionally necessary for GLIPR2's role in ferroptosis. NMT1/NMT2 inhibition attenuated ferroptosis, and the NMT1/NMT2-GLIPR2 axis was identified as a regulator of ferroptosis.\",\n      \"method\": \"Quantitative myristoylproteomics (click chemistry), genetic/pharmacological NMT inhibition, GLIPR2 overexpression/KD, G2A myristoylation-deficient mutant functional rescue assay\",\n      \"journal\": \"Materials today. Bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — myristoylation-deficient mutant rescue experiment plus proteomics identification, single lab\",\n      \"pmids\": [\"41782991\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GLIPR2 (GAPR-1) is an N-myristoylated, peripheral Golgi membrane protein of the CAP/PR-1 superfamily that functions as a negative regulator of autophagy by directly binding BECN1 residues 267–284 through a conserved equatorial groove and inhibiting the PtdIns3K-C1 (VPS34) complex lipid kinase activity; dimerization occludes the BECN1-binding groove and may regulate this inhibitory function; GLIPR2 additionally promotes EMT via ERK1/2 and ERK/p38 signaling in epithelial cells, modulates TLR4-dependent type I interferon signaling through IRAK1-mediated phosphorylation at Ser58 and subsequent interaction with TMED7, promotes EndoMT through PDGFRL/AKT/mTOR, and its N-myristoylation is required for pro-ferroptotic activity; the protein also binds negatively charged phospholipids and zinc ions, and can form amyloid-like structures regulated by metal ions and redox state.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GLIPR2 (GAPR-1) is an N-myristoylated, Golgi-associated member of the CAP/PR-1 superfamily that acts as a negative regulator of autophagy and a driver of mesenchymal transition programs [#0, #11]. Its 1.55 Å crystal structure established structural homology to PR-1 family proteins and showed that it forms homodimers, with a potential catalytic triad across the dimer interface [#0]. The protein binds negatively charged phospholipid membranes, preferring phosphatidic acid, and is stably anchored through combined electrostatic interactions and N-terminal myristoylation [#1]. Mechanistically, GLIPR2 inhibits autophagy by directly binding BECN1 residues 267–284 through a conserved equatorial groove; mutagenesis of five groove-lining residues abrogates this interaction, and depletion of GLIPR2 increases autophagic flux, PtdIns3P generation, and WIPI2 recruitment, with purified GLIPR2 directly inhibiting PtdIns3K-C1 lipid kinase activity in vitro [#8, #11]. Dimerization occludes the BECN1-binding groove, providing a structural switch that couples oligomeric state to inhibitory function [#8]. GLIPR2 also drives epithelial-to-mesenchymal transition in renal and hepatocellular cells via ERK1/2 signaling [#4, #5], drives EndoMT and cardiac fibrosis through PDGFRL/AKT/mTOR [#15], and is stabilized by SMYD2-mediated methylation upstream of an ERK/p38 EMT program [#14]. Additional functions include IRAK1-dependent phosphorylation at Ser58 that promotes TMED7 binding to enhance TLR4-driven IFN-β signaling [#7], N-myristoylation-dependent pro-ferroptotic activity [#16], and metal-ion- and redox-regulated amyloid-like assembly through zinc binding at His54/His103 versus a copper/disulfide-dependent pathway [#9, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing the structural identity of GAPR-1 was the first step in defining its biochemical capabilities; the crystal structure placed it in the PR-1/CAP fold and revealed an intrinsic propensity to dimerize.\",\n      \"evidence\": \"Yeast two-hybrid, X-ray crystallography at 1.55 Å, and site-directed mutagenesis of the dimer interface\",\n      \"pmids\": [\"15123429\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The functional role of the putative catalytic triad was not demonstrated\", \"No physiological binding partner identified at this stage\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"To understand how a peripheral Golgi protein engages membranes, the lipid-binding determinants were defined, showing electrostatic preference for anionic phospholipids beyond myristoylation alone.\",\n      \"evidence\": \"Liposome binding assays, gel-shift, and mass spectrometry of bound phosphoinositides\",\n      \"pmids\": [\"20095951\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of phosphatidic acid preference in cells not established\", \"Stoichiometry of PI binding not linked to a downstream activity\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"This work connected conformational state to function by showing that an alternative inositol-phosphate-induced dimer drives membrane tethering, establishing dimerization as a regulatory switch for membrane behavior.\",\n      \"evidence\": \"X-ray crystallography with phytic acid, light scattering, flow cytometry, and conformation-locking mutants (D81K, A68K)\",\n      \"pmids\": [\"22560898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological trigger for the alternative dimer in vivo unknown\", \"Relationship of tethering to Golgi function not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The first cellular role emerged from fibrotic kidney, linking GLIPR2 to epithelial-mesenchymal transition rather than to any structural prediction.\",\n      \"evidence\": \"Transcript profiling in COL4A3 knockout mice, immunofluorescence, and in vitro EMT assays in renal epithelial cells\",\n      \"pmids\": [\"17055234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway driving EMT not defined\", \"Causality versus correlation in fibrosis not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two studies established a mechanistic route for the EMT phenotype, implicating ERK1/2 activation in both renal epithelial and hepatocellular carcinoma contexts under overexpression and hypoxia.\",\n      \"evidence\": \"Stable overexpression and siRNA knockdown in HK-2, HepG2, and PLC/PRF/5 cells with EMT marker, migration/invasion, and ERK1/2 readouts\",\n      \"pmids\": [\"23516513\", \"24204846\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between GLIPR2 and ERK activation not shown\", \"Whether membrane or Golgi localization is required for signaling untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A distinct immune-signaling function was uncovered by identifying a phosphorylation event and binding partner that modulate TLR4 output.\",\n      \"evidence\": \"IRAK1 kinase assay identifying Ser58 phosphorylation, co-immunoprecipitation with TMED7, and cytokine/reporter assays\",\n      \"pmids\": [\"26678074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal validation of the TMED7 interaction limited\", \"How phosphorylation alters GLIPR2 conformation or localization unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Structural mapping of a BECN1-binding groove defined the molecular basis for an autophagy-regulatory interaction and tied it to oligomeric state.\",\n      \"evidence\": \"1.27 Å crystal structure of a pentad groove mutant, SAXS, pull-downs, and mutagenesis of five conserved groove residues\",\n      \"pmids\": [\"28876241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional autophagy consequence not yet demonstrated in this study\", \"In vivo relevance of dimer-mediated groove occlusion untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The autophagy function was causally established by showing GLIPR2 directly inhibits the PtdIns3K-C1 complex, converting the structural BECN1 interaction into a defined negative-regulatory mechanism.\",\n      \"evidence\": \"CRISPR-Cas9 knockout in HeLa cells and mice, in vitro lipid kinase assays with purified complex, PtdIns3P and WIPI2 readouts\",\n      \"pmids\": [\"33222586\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals that relieve GLIPR2 inhibition of PtdIns3K-C1 unknown\", \"Connection between Golgi compaction phenotype and autophagy control unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Metal-ion biochemistry was dissected to explain the protein's amyloidogenic behavior, defining two mechanistically distinct aggregation pathways governed by zinc versus copper and redox state.\",\n      \"evidence\": \"ITC, CD, tryptophan fluorescence, ThT/TEM aggregation assays, and His54/His103 and cysteine mutants\",\n      \"pmids\": [\"30700571\", \"31636315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological role of amyloid-like assembly in cells not established\", \"Relationship between metal binding and the BECN1/membrane functions unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Yeast modeling linked N-myristoylation and metal-binding residues to formation of reversible cytosolic inclusions, connecting the modification and metal chemistry to cellular condensate behavior.\",\n      \"evidence\": \"Yeast overexpression, fluorescence microscopy with FRAP, mutagenesis, and metal-ion treatment\",\n      \"pmids\": [\"34298062\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian relevance of inclusions not shown\", \"Functional output of inclusion formation undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The BECN1-interaction mechanism was extended to condensate biology, showing GLIPR2 interferes with Beclin 1 condensate formation through the same interface and that B18 amyloidogenic properties matter.\",\n      \"evidence\": \"Yeast co-expression, fluorescence microscopy, interface mutagenesis, and B18 peptide competition\",\n      \"pmids\": [\"36586462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative impact on autophagy in mammalian cells not measured\", \"Whether condensate interference is the in vivo mode of PtdIns3K-C1 inhibition unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"An upstream regulatory layer was identified, showing SMYD2 methylation stabilizes GLIPR2 against ubiquitination and drives EMT via ERK/p38.\",\n      \"evidence\": \"Paraquat mouse model, MLE-12 cells, SMYD2 inhibitor AZ505, and GLIPR2 overexpression rescue\",\n      \"pmids\": [\"38879290\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Methylation site on GLIPR2 not mapped\", \"Direct versus indirect SMYD2-GLIPR2 relationship not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A vascular role was defined, implicating GLIPR2 in EndoMT and cardiac fibrosis through a PDGFRL/AKT/mTOR axis distinct from its ERK-driven epithelial program.\",\n      \"evidence\": \"AAV knockdown in AMI mice, gain/loss of function in HCMECs, transcriptome sequencing, and rescue experiments\",\n      \"pmids\": [\"40543810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which GLIPR2 engages PDGFRL not defined\", \"Reconciliation of ERK versus AKT/mTOR pathways across cell types unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"The functional necessity of N-myristoylation was extended to ferroptosis, establishing an NMT1/NMT2-GLIPR2 axis as a regulator of ferroptosis sensitivity.\",\n      \"evidence\": \"Quantitative myristoylproteomics, NMT inhibition, and a G2A myristoylation-deficient rescue assay in NSCLC cells\",\n      \"pmids\": [\"41782991\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which myristoylated GLIPR2 promotes ferroptosis unknown\", \"Link between ferroptotic activity and autophagy/Golgi functions unexplored\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GLIPR2's distinct activities — PtdIns3K-C1 inhibition, ERK/AKT-driven mesenchymal transitions, TLR4 signaling, pro-ferroptotic activity, and metal-regulated amyloid assembly — are integrated within a single protein, and which are dominant in a given physiological context, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking the structural groove/dimer switch to the diverse signaling outputs\", \"Tissue-specific determinants of which pathway dominates are unknown\", \"Upstream physiological signals controlling GLIPR2 activity not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 11]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [6, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BECN1\", \"TMED7\", \"IRAK1\", \"SMYD2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":7,"faith_total":7,"faith_pct":100.0}}