{"gene":"GPR107","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2012,"finding":"GPR107 is a candidate receptor for neuronostatin (NST): siRNA knockdown of GPR107 in KATOIII cells abolished neuronostatin-induced signaling, and intracerebroventricular GPR107 siRNA in rats blocked NST-induced increases in mean arterial pressure and blunted baroreflex sensitivity, indicating GPR107 mediates NST cardiovascular signaling via a PKA-dependent mechanism.","method":"siRNA knockdown in KATOIII cells; intracerebroventricular siRNA injection in rats with physiological readouts (MAP, baroreflex)","journal":"American journal of physiology. Regulatory, integrative and comparative physiology","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined cellular/physiological phenotype; single lab, two systems","pmids":["22933024"],"is_preprint":false},{"year":2014,"finding":"GPR107 localizes to the trans-Golgi network, is cleaved by the endoprotease furin, and the two resulting fragments are held together by a disulfide bond; disruption of this disulfide association impairs GPR107 function. GPR107 is essential for retrograde transport and intoxication by Pseudomonas aeruginosa exotoxin A, identified via a genome-wide genetic screen confirmed by CRISPR/Cas9 editing.","method":"Genome-wide haploid genetic screen; CRISPR/Cas9 knockout; subcellular localization (Golgi markers); furin cleavage assay; disulfide bond disruption mutagenesis; toxin intoxication assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (genetic screen, CRISPR validation, biochemical cleavage assay, mutagenesis, localization) in a single rigorous study","pmids":["25031321"],"is_preprint":false},{"year":2014,"finding":"Deletion of Gpr107 in mice causes embryonic lethality associated with reduced cubilin transcript abundance and defects in the cubilin-megalin endocytic complex; Gpr107-null fibroblasts show reduced transferrin internalization, decreased LRP1 cargo uptake, and resistance to toxins. Proteomic and colocalization analyses indicate GPR107 associates with clathrin and the retromer protein VPS35, suggesting a role in recycling receptors from endocytic compartments back to the plasma membrane.","method":"Gpr107 knockout mouse (embryonic lethal phenotype); transferrin/LDL internalization assays; toxin resistance assay; colocalization microscopy; proteomic analysis (co-purification with clathrin and VPS35)","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with defined cellular phenotypes plus proteomic identification of interactors, multiple orthogonal methods","pmids":["24849652"],"is_preprint":false},{"year":2007,"finding":"Human GPR107 was cloned from lung and shown to encode a 552-residue protein with an N-terminal hydrophobic signal peptide, a long extracellular domain, and a C-terminal seven-transmembrane (LUSTR) domain, placing it in a novel LUSTR family distinct from classical GPCRs; the gene spans 86.4 kb at 9q34.2-3 and contains 18 exons.","method":"cDNA cloning, sequence analysis, genomic mapping","journal":"DNA sequence : the journal of DNA sequencing and mapping","confidence":"Medium","confidence_rationale":"Tier 3 — molecular cloning with structural inference; foundational domain architecture determination","pmids":["17454009"],"is_preprint":false},{"year":2015,"finding":"GPR107 is abundantly expressed in pancreatic α-cells; neuronostatin acting through GPR107 increases cAMP-independent PKA phosphorylation and proglucagon mRNA accumulation. Knockdown of GPR107 in α-cells abolishes NST-induced PKA phosphorylation and proglucagon mRNA elevation. GPR107 and NST colocalize in mouse and human pancreatic α-cells.","method":"GPR107 knockdown in pancreatic α-cells; PKA phosphorylation assay; proglucagon mRNA quantification; immunofluorescence colocalization","journal":"American journal of physiology. Regulatory, integrative and comparative physiology","confidence":"Medium","confidence_rationale":"Tier 2 — KD with multiple cellular readouts (PKA phosphorylation, mRNA), colocalization; single lab","pmids":["26561648"],"is_preprint":false},{"year":2018,"finding":"Expression of GPR107 in liver tumor-initiating cells (TICs) is transcriptionally activated by the lncRNA lncGPR107, which recruits the SRCAP chromatin-remodeling complex to the GPR107 promoter; depletion of lncGPR107 reduces SRCAP binding to the GPR107 promoter and suppresses GPR107 expression and TIC self-renewal.","method":"RNA pulldown, RNA immunoprecipitation, ChIP, FACS sorting, oncosphere formation assay, tumor initiation assay, western blot, double FISH","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP, RIP, pulldown) establishing transcriptional regulatory mechanism; single lab","pmids":["29925408"],"is_preprint":false},{"year":2024,"finding":"NST directly binds GPR107 (structural analyses); GPR107 is primarily expressed in neurons; NST modulates neuronal survival and neurite outgrowth in response to Aβ via GPR107; NST regulates mitochondrial function and ATP levels through a GPR107/PKA signaling pathway.","method":"Structural binding analyses; primary neuronal cultures; GPR107 knockout cells; mitochondrial membrane potential and ROS assays; PKA signaling readouts; intracerebroventricular NST administration in APP/PS1 mice","journal":"Neuropharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding shown by structural analyses, KO cells used to establish GPR107 dependence, multiple cellular assays; single lab","pmids":["39048031"],"is_preprint":false},{"year":2025,"finding":"GPR107 promotes breast cancer invasion and metastasis by mediating clathrin-dependent endocytosis of collagen IV (COL4) from the ECM, upregulating MMP2 production to degrade COL4, and suppressing COL4 gene transcription; mechanistically, GPR107 activates the ERK/STAT3 pathway through β-arrestin, increasing MMP2 expression and reducing COL4.","method":"Loss-of-function/gain-of-function in breast cancer cells; invasion/metastasis assays; clathrin-mediated endocytosis assay; ERK/STAT3 pathway analysis; MMP2 and COL4 quantification; β-arrestin interaction studies","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 — multiple cellular assays with defined pathway readouts; single lab, no independent replication yet","pmids":["41073571"],"is_preprint":false}],"current_model":"GPR107 is a LUSTR-family integral membrane protein that localizes to the trans-Golgi network, is proteolytically processed by furin (held together by a disulfide bond), associates with clathrin and the retromer component VPS35 to mediate retrograde vesicular transport and receptor recycling, serves as a functional receptor for the peptide neuronostatin (signaling via cAMP-independent PKA phosphorylation), and in cancer contexts activates ERK/STAT3 via β-arrestin to regulate extracellular matrix remodeling."},"narrative":{"teleology":[{"year":2007,"claim":"Cloning of GPR107 established its domain architecture — a long extracellular domain followed by a seven-transmembrane LUSTR domain distinct from classical GPCRs — defining the gene product as a novel class of membrane protein.","evidence":"cDNA cloning and sequence analysis from human lung","pmids":["17454009"],"confidence":"Medium","gaps":["No ligand or cellular function identified at this stage","LUSTR domain function not characterized beyond sequence homology","Protein expression and localization not experimentally determined"]},{"year":2012,"claim":"Identification of GPR107 as a candidate receptor for neuronostatin answered the question of what ligand activates this orphan receptor and linked it to cardiovascular regulation via PKA signaling.","evidence":"siRNA knockdown in KATOIII cells abolished NST signaling; intracerebroventricular siRNA in rats blocked NST-induced cardiovascular responses","pmids":["22933024"],"confidence":"Medium","gaps":["Direct physical binding of NST to GPR107 not demonstrated at this stage","Mechanism of cAMP-independent PKA activation unclear","Single-lab finding without independent replication"]},{"year":2014,"claim":"Two independent studies converged to define GPR107's core cell-biological role: it localizes to the trans-Golgi network, undergoes furin-mediated cleavage held by a disulfide bond, and is essential for retrograde transport and receptor recycling, as shown by its association with clathrin and VPS35 and by embryonic lethality upon knockout.","evidence":"Genome-wide haploid screen with CRISPR validation, furin cleavage and mutagenesis assays, toxin intoxication (PMID:25031321); Gpr107 knockout mouse, transferrin/LRP1 uptake assays, co-purification with clathrin and VPS35 (PMID:24849652)","pmids":["25031321","24849652"],"confidence":"High","gaps":["Structural basis of GPR107-retromer and GPR107-clathrin interactions not resolved","Specific cargo repertoire beyond cubilin/LRP1/transferrin receptor unknown","Relationship between furin cleavage and trafficking function not fully delineated"]},{"year":2015,"claim":"Demonstrating that GPR107 mediates neuronostatin-induced PKA phosphorylation and proglucagon expression in pancreatic α-cells extended GPR107's receptor function beyond the cardiovascular system to endocrine regulation.","evidence":"GPR107 knockdown in α-cells abolished NST-induced PKA phosphorylation and proglucagon mRNA elevation; immunofluorescence colocalization of GPR107 and NST in mouse and human α-cells","pmids":["26561648"],"confidence":"Medium","gaps":["Single-lab replication of the NST-GPR107 axis","Downstream effectors between PKA and proglucagon transcription not identified","Whether GPR107's trafficking function contributes to its signaling function is unknown"]},{"year":2018,"claim":"Discovery that lncGPR107 recruits the SRCAP chromatin-remodeling complex to activate GPR107 transcription in liver tumor-initiating cells revealed how GPR107 expression is epigenetically regulated in cancer.","evidence":"RNA pulldown, RIP, ChIP, and oncosphere/tumor initiation assays in liver TICs","pmids":["29925408"],"confidence":"Medium","gaps":["Functional consequence of elevated GPR107 in liver TICs not mechanistically dissected","Whether SRCAP-mediated activation is specific to liver cancer or broadly relevant is unknown","Single-lab finding"]},{"year":2024,"claim":"Structural binding analyses demonstrating direct NST-GPR107 interaction, together with evidence that GPR107 mediates NST-dependent neuronal survival, mitochondrial function, and neuroprotection against Aβ, solidified GPR107 as a bona fide NST receptor with neuroprotective roles.","evidence":"Structural binding analyses; primary neuronal cultures and GPR107 knockout cells; mitochondrial assays; in vivo NST administration in APP/PS1 mice","pmids":["39048031"],"confidence":"Medium","gaps":["High-resolution co-structure of NST-GPR107 complex not yet reported","Mechanism coupling GPR107/PKA to mitochondrial function not resolved","Single-lab study"]},{"year":2025,"claim":"Showing that GPR107 activates ERK/STAT3 via β-arrestin to promote MMP2-dependent collagen IV degradation and breast cancer metastasis revealed a signaling mode distinct from the PKA pathway and a pro-invasive oncogenic function.","evidence":"Loss/gain-of-function in breast cancer cells; clathrin-mediated endocytosis, ERK/STAT3 pathway analysis, β-arrestin interaction studies, invasion/metastasis assays","pmids":["41073571"],"confidence":"Medium","gaps":["No independent replication of the β-arrestin–ERK/STAT3 axis","Ligand that triggers GPR107/β-arrestin signaling in cancer not identified","Relationship between GPR107's trafficking and signaling functions in cancer unclear"]},{"year":null,"claim":"Key unresolved questions include the high-resolution structure of GPR107 in complex with NST, how GPR107's dual roles in vesicular trafficking and receptor signaling are mechanistically integrated, and the identity of additional ligands or cargoes.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of GPR107 or NST-GPR107 complex available","Mechanistic link between trafficking function (retromer/clathrin) and signaling function (PKA, ERK/STAT3) unresolved","Full cargo and ligand repertoire unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,4,6]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[1,2,7]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,2]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,2,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,6,7]}],"complexes":[],"partners":["VPS35","CLTC","FURIN","ARRB1"],"other_free_text":[]},"mechanistic_narrative":"GPR107 is a LUSTR-family integral membrane protein that functions in vesicular trafficking and peptide receptor signaling at the trans-Golgi network. It localizes to the trans-Golgi network, is proteolytically processed by furin into disulfide-linked fragments, and associates with clathrin and the retromer component VPS35 to mediate retrograde transport and receptor recycling; genetic ablation in mice causes embryonic lethality with defects in endocytic receptor complexes and impaired cargo internalization [PMID:25031321, PMID:24849652]. GPR107 also serves as the functional receptor for neuronostatin, transducing signals through a cAMP-independent PKA phosphorylation pathway that regulates cardiovascular tone, pancreatic proglucagon expression, and neuronal survival [PMID:22933024, PMID:26561648, PMID:39048031]. In breast cancer cells, GPR107 promotes invasion by activating ERK/STAT3 signaling through β-arrestin, driving MMP2 upregulation and collagen IV degradation [PMID:41073571]."},"prefetch_data":{"uniprot":{"accession":"Q5VW38","full_name":"Protein GPR107","aliases":["Lung seven transmembrane receptor 1"],"length_aa":600,"mass_kda":67.0,"function":"Has been proposed to act as a receptor for neuronostatin, a peptide derived from the somatostatin/SST precursor (PubMed:22933024). Involved in blood sugar regulation through the induction of glucagon in response to low glucose (By similarity) (Microbial infection) Required for intoxication by Pseudomonas aeruginosa exotoxin A and Campylobacter jejuni CDT. May contribute to the retrograde transport of bacterial toxins, including cholera toxin, from the trans-Golgi network to the endoplasmic reticulum","subcellular_location":"Cell membrane; Golgi apparatus, trans-Golgi network membrane","url":"https://www.uniprot.org/uniprotkb/Q5VW38/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GPR107","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000148358","cell_line_id":"CID000816","localizations":[{"compartment":"golgi","grade":3},{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"JTB","stoichiometry":0.2},{"gene":"HTN1","stoichiometry":0.2},{"gene":"VPS35","stoichiometry":0.2},{"gene":"SCFD1","stoichiometry":0.2},{"gene":"TMEM230","stoichiometry":0.2},{"gene":"TMEM165","stoichiometry":0.2},{"gene":"ARFRP1","stoichiometry":0.2},{"gene":"SYAP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000816","total_profiled":1310},"omim":[{"mim_id":"618491","title":"G PROTEIN-COUPLED RECEPTOR 108; GPR108","url":"https://www.omim.org/entry/618491"},{"mim_id":"618490","title":"G PROTEIN-COUPLED RECEPTOR 107; GPR107","url":"https://www.omim.org/entry/618490"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GPR107"},"hgnc":{"alias_symbol":["KIAA1624","RP11-88G17","FLJ20998","LUSTR1"],"prev_symbol":[]},"alphafold":{"accession":"Q5VW38","domains":[{"cath_id":"2.60.120,2.60.120","chopping":"42-150_192-250","consensus_level":"high","plddt":78.8145,"start":42,"end":250},{"cath_id":"1.20.1070,1.20.1070","chopping":"262-436_479-573","consensus_level":"high","plddt":79.9126,"start":262,"end":573}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VW38","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VW38-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VW38-F1-predicted_aligned_error_v6.png","plddt_mean":70.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GPR107","jax_strain_url":"https://www.jax.org/strain/search?query=GPR107"},"sequence":{"accession":"Q5VW38","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5VW38.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5VW38/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VW38"}},"corpus_meta":[{"pmid":"22933024","id":"PMC_22933024","title":"Evidence for an interaction of neuronostatin with the orphan G protein-coupled receptor, GPR107.","date":"2012","source":"American journal of physiology. Regulatory, integrative and comparative physiology","url":"https://pubmed.ncbi.nlm.nih.gov/22933024","citation_count":51,"is_preprint":false},{"pmid":"25031321","id":"PMC_25031321","title":"GPR107, a G-protein-coupled receptor essential for intoxication by Pseudomonas aeruginosa exotoxin A, localizes to the Golgi and is cleaved by furin.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25031321","citation_count":43,"is_preprint":false},{"pmid":"26561648","id":"PMC_26561648","title":"Neuronostatin acts via GPR107 to increase cAMP-independent PKA phosphorylation and proglucagon mRNA accumulation in pancreatic α-cells.","date":"2015","source":"American journal of physiology. Regulatory, integrative and comparative physiology","url":"https://pubmed.ncbi.nlm.nih.gov/26561648","citation_count":33,"is_preprint":false},{"pmid":"17454009","id":"PMC_17454009","title":"Human GPR107 and murine Gpr108 are members of the LUSTR family of proteins found in both plants and animals, having similar topology to G-protein coupled receptors.","date":"2007","source":"DNA sequence : the journal of DNA sequencing and mapping","url":"https://pubmed.ncbi.nlm.nih.gov/17454009","citation_count":27,"is_preprint":false},{"pmid":"24849652","id":"PMC_24849652","title":"Deficits in receptor-mediated endocytosis and recycling in cells from mice with Gpr107 locus disruption.","date":"2014","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/24849652","citation_count":22,"is_preprint":false},{"pmid":"29925408","id":"PMC_29925408","title":"LncGPR107 drives the self-renewal of liver tumor initiating cells and liver tumorigenesis through GPR107-dependent manner.","date":"2018","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/29925408","citation_count":11,"is_preprint":false},{"pmid":"33121311","id":"PMC_33121311","title":"Changes in expression of orphan receptors GPR99 and GPR107 during the development and establishment of hypertension in spontaneously hypertensive rats.","date":"2020","source":"Journal of receptor and signal transduction research","url":"https://pubmed.ncbi.nlm.nih.gov/33121311","citation_count":6,"is_preprint":false},{"pmid":"39048031","id":"PMC_39048031","title":"Neuronostatin regulates neuronal function and energetic metabolism in Alzheimer's disease in a GPR107-dependent manner.","date":"2024","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39048031","citation_count":2,"is_preprint":false},{"pmid":"41073571","id":"PMC_41073571","title":"GPR107: A key driver of breast cancer invasion and metastasis through collagen IV modulation.","date":"2025","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/41073571","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5577,"output_tokens":2199,"usd":0.024858},"stage2":{"model":"claude-opus-4-6","input_tokens":5502,"output_tokens":2238,"usd":0.12519},"total_usd":0.150048,"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\": 2012,\n      \"finding\": \"GPR107 is a candidate receptor for neuronostatin (NST): siRNA knockdown of GPR107 in KATOIII cells abolished neuronostatin-induced signaling, and intracerebroventricular GPR107 siRNA in rats blocked NST-induced increases in mean arterial pressure and blunted baroreflex sensitivity, indicating GPR107 mediates NST cardiovascular signaling via a PKA-dependent mechanism.\",\n      \"method\": \"siRNA knockdown in KATOIII cells; intracerebroventricular siRNA injection in rats with physiological readouts (MAP, baroreflex)\",\n      \"journal\": \"American journal of physiology. Regulatory, integrative and comparative physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular/physiological phenotype; single lab, two systems\",\n      \"pmids\": [\"22933024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GPR107 localizes to the trans-Golgi network, is cleaved by the endoprotease furin, and the two resulting fragments are held together by a disulfide bond; disruption of this disulfide association impairs GPR107 function. GPR107 is essential for retrograde transport and intoxication by Pseudomonas aeruginosa exotoxin A, identified via a genome-wide genetic screen confirmed by CRISPR/Cas9 editing.\",\n      \"method\": \"Genome-wide haploid genetic screen; CRISPR/Cas9 knockout; subcellular localization (Golgi markers); furin cleavage assay; disulfide bond disruption mutagenesis; toxin intoxication assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (genetic screen, CRISPR validation, biochemical cleavage assay, mutagenesis, localization) in a single rigorous study\",\n      \"pmids\": [\"25031321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Deletion of Gpr107 in mice causes embryonic lethality associated with reduced cubilin transcript abundance and defects in the cubilin-megalin endocytic complex; Gpr107-null fibroblasts show reduced transferrin internalization, decreased LRP1 cargo uptake, and resistance to toxins. Proteomic and colocalization analyses indicate GPR107 associates with clathrin and the retromer protein VPS35, suggesting a role in recycling receptors from endocytic compartments back to the plasma membrane.\",\n      \"method\": \"Gpr107 knockout mouse (embryonic lethal phenotype); transferrin/LDL internalization assays; toxin resistance assay; colocalization microscopy; proteomic analysis (co-purification with clathrin and VPS35)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined cellular phenotypes plus proteomic identification of interactors, multiple orthogonal methods\",\n      \"pmids\": [\"24849652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human GPR107 was cloned from lung and shown to encode a 552-residue protein with an N-terminal hydrophobic signal peptide, a long extracellular domain, and a C-terminal seven-transmembrane (LUSTR) domain, placing it in a novel LUSTR family distinct from classical GPCRs; the gene spans 86.4 kb at 9q34.2-3 and contains 18 exons.\",\n      \"method\": \"cDNA cloning, sequence analysis, genomic mapping\",\n      \"journal\": \"DNA sequence : the journal of DNA sequencing and mapping\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — molecular cloning with structural inference; foundational domain architecture determination\",\n      \"pmids\": [\"17454009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GPR107 is abundantly expressed in pancreatic α-cells; neuronostatin acting through GPR107 increases cAMP-independent PKA phosphorylation and proglucagon mRNA accumulation. Knockdown of GPR107 in α-cells abolishes NST-induced PKA phosphorylation and proglucagon mRNA elevation. GPR107 and NST colocalize in mouse and human pancreatic α-cells.\",\n      \"method\": \"GPR107 knockdown in pancreatic α-cells; PKA phosphorylation assay; proglucagon mRNA quantification; immunofluorescence colocalization\",\n      \"journal\": \"American journal of physiology. Regulatory, integrative and comparative physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with multiple cellular readouts (PKA phosphorylation, mRNA), colocalization; single lab\",\n      \"pmids\": [\"26561648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Expression of GPR107 in liver tumor-initiating cells (TICs) is transcriptionally activated by the lncRNA lncGPR107, which recruits the SRCAP chromatin-remodeling complex to the GPR107 promoter; depletion of lncGPR107 reduces SRCAP binding to the GPR107 promoter and suppresses GPR107 expression and TIC self-renewal.\",\n      \"method\": \"RNA pulldown, RNA immunoprecipitation, ChIP, FACS sorting, oncosphere formation assay, tumor initiation assay, western blot, double FISH\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, RIP, pulldown) establishing transcriptional regulatory mechanism; single lab\",\n      \"pmids\": [\"29925408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NST directly binds GPR107 (structural analyses); GPR107 is primarily expressed in neurons; NST modulates neuronal survival and neurite outgrowth in response to Aβ via GPR107; NST regulates mitochondrial function and ATP levels through a GPR107/PKA signaling pathway.\",\n      \"method\": \"Structural binding analyses; primary neuronal cultures; GPR107 knockout cells; mitochondrial membrane potential and ROS assays; PKA signaling readouts; intracerebroventricular NST administration in APP/PS1 mice\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding shown by structural analyses, KO cells used to establish GPR107 dependence, multiple cellular assays; single lab\",\n      \"pmids\": [\"39048031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GPR107 promotes breast cancer invasion and metastasis by mediating clathrin-dependent endocytosis of collagen IV (COL4) from the ECM, upregulating MMP2 production to degrade COL4, and suppressing COL4 gene transcription; mechanistically, GPR107 activates the ERK/STAT3 pathway through β-arrestin, increasing MMP2 expression and reducing COL4.\",\n      \"method\": \"Loss-of-function/gain-of-function in breast cancer cells; invasion/metastasis assays; clathrin-mediated endocytosis assay; ERK/STAT3 pathway analysis; MMP2 and COL4 quantification; β-arrestin interaction studies\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple cellular assays with defined pathway readouts; single lab, no independent replication yet\",\n      \"pmids\": [\"41073571\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GPR107 is a LUSTR-family integral membrane protein that localizes to the trans-Golgi network, is proteolytically processed by furin (held together by a disulfide bond), associates with clathrin and the retromer component VPS35 to mediate retrograde vesicular transport and receptor recycling, serves as a functional receptor for the peptide neuronostatin (signaling via cAMP-independent PKA phosphorylation), and in cancer contexts activates ERK/STAT3 via β-arrestin to regulate extracellular matrix remodeling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"GPR107 is a LUSTR-family integral membrane protein that functions in vesicular trafficking and peptide receptor signaling at the trans-Golgi network. It localizes to the trans-Golgi network, is proteolytically processed by furin into disulfide-linked fragments, and associates with clathrin and the retromer component VPS35 to mediate retrograde transport and receptor recycling; genetic ablation in mice causes embryonic lethality with defects in endocytic receptor complexes and impaired cargo internalization [PMID:25031321, PMID:24849652]. GPR107 also serves as the functional receptor for neuronostatin, transducing signals through a cAMP-independent PKA phosphorylation pathway that regulates cardiovascular tone, pancreatic proglucagon expression, and neuronal survival [PMID:22933024, PMID:26561648, PMID:39048031]. In breast cancer cells, GPR107 promotes invasion by activating ERK/STAT3 signaling through β-arrestin, driving MMP2 upregulation and collagen IV degradation [PMID:41073571].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Cloning of GPR107 established its domain architecture — a long extracellular domain followed by a seven-transmembrane LUSTR domain distinct from classical GPCRs — defining the gene product as a novel class of membrane protein.\",\n      \"evidence\": \"cDNA cloning and sequence analysis from human lung\",\n      \"pmids\": [\"17454009\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No ligand or cellular function identified at this stage\",\n        \"LUSTR domain function not characterized beyond sequence homology\",\n        \"Protein expression and localization not experimentally determined\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of GPR107 as a candidate receptor for neuronostatin answered the question of what ligand activates this orphan receptor and linked it to cardiovascular regulation via PKA signaling.\",\n      \"evidence\": \"siRNA knockdown in KATOIII cells abolished NST signaling; intracerebroventricular siRNA in rats blocked NST-induced cardiovascular responses\",\n      \"pmids\": [\"22933024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct physical binding of NST to GPR107 not demonstrated at this stage\",\n        \"Mechanism of cAMP-independent PKA activation unclear\",\n        \"Single-lab finding without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Two independent studies converged to define GPR107's core cell-biological role: it localizes to the trans-Golgi network, undergoes furin-mediated cleavage held by a disulfide bond, and is essential for retrograde transport and receptor recycling, as shown by its association with clathrin and VPS35 and by embryonic lethality upon knockout.\",\n      \"evidence\": \"Genome-wide haploid screen with CRISPR validation, furin cleavage and mutagenesis assays, toxin intoxication (PMID:25031321); Gpr107 knockout mouse, transferrin/LRP1 uptake assays, co-purification with clathrin and VPS35 (PMID:24849652)\",\n      \"pmids\": [\"25031321\", \"24849652\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of GPR107-retromer and GPR107-clathrin interactions not resolved\",\n        \"Specific cargo repertoire beyond cubilin/LRP1/transferrin receptor unknown\",\n        \"Relationship between furin cleavage and trafficking function not fully delineated\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrating that GPR107 mediates neuronostatin-induced PKA phosphorylation and proglucagon expression in pancreatic α-cells extended GPR107's receptor function beyond the cardiovascular system to endocrine regulation.\",\n      \"evidence\": \"GPR107 knockdown in α-cells abolished NST-induced PKA phosphorylation and proglucagon mRNA elevation; immunofluorescence colocalization of GPR107 and NST in mouse and human α-cells\",\n      \"pmids\": [\"26561648\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab replication of the NST-GPR107 axis\",\n        \"Downstream effectors between PKA and proglucagon transcription not identified\",\n        \"Whether GPR107's trafficking function contributes to its signaling function is unknown\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that lncGPR107 recruits the SRCAP chromatin-remodeling complex to activate GPR107 transcription in liver tumor-initiating cells revealed how GPR107 expression is epigenetically regulated in cancer.\",\n      \"evidence\": \"RNA pulldown, RIP, ChIP, and oncosphere/tumor initiation assays in liver TICs\",\n      \"pmids\": [\"29925408\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of elevated GPR107 in liver TICs not mechanistically dissected\",\n        \"Whether SRCAP-mediated activation is specific to liver cancer or broadly relevant is unknown\",\n        \"Single-lab finding\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Structural binding analyses demonstrating direct NST-GPR107 interaction, together with evidence that GPR107 mediates NST-dependent neuronal survival, mitochondrial function, and neuroprotection against Aβ, solidified GPR107 as a bona fide NST receptor with neuroprotective roles.\",\n      \"evidence\": \"Structural binding analyses; primary neuronal cultures and GPR107 knockout cells; mitochondrial assays; in vivo NST administration in APP/PS1 mice\",\n      \"pmids\": [\"39048031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"High-resolution co-structure of NST-GPR107 complex not yet reported\",\n        \"Mechanism coupling GPR107/PKA to mitochondrial function not resolved\",\n        \"Single-lab study\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showing that GPR107 activates ERK/STAT3 via β-arrestin to promote MMP2-dependent collagen IV degradation and breast cancer metastasis revealed a signaling mode distinct from the PKA pathway and a pro-invasive oncogenic function.\",\n      \"evidence\": \"Loss/gain-of-function in breast cancer cells; clathrin-mediated endocytosis, ERK/STAT3 pathway analysis, β-arrestin interaction studies, invasion/metastasis assays\",\n      \"pmids\": [\"41073571\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No independent replication of the β-arrestin–ERK/STAT3 axis\",\n        \"Ligand that triggers GPR107/β-arrestin signaling in cancer not identified\",\n        \"Relationship between GPR107's trafficking and signaling functions in cancer unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the high-resolution structure of GPR107 in complex with NST, how GPR107's dual roles in vesicular trafficking and receptor signaling are mechanistically integrated, and the identity of additional ligands or cargoes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of GPR107 or NST-GPR107 complex available\",\n        \"Mechanistic link between trafficking function (retromer/clathrin) and signaling function (PKA, ERK/STAT3) unresolved\",\n        \"Full cargo and ligand repertoire unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 4, 6]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [1, 2, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 2, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 6, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"VPS35\",\n      \"CLTC\",\n      \"FURIN\",\n      \"ARRB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}