{"gene":"GPR107","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2012,"finding":"GPR107 knockdown in KATOIII cells abolished neuronostatin-induced signaling responses, and siRNA-mediated knockdown of GPR107 in rat lateral cerebroventricle abolished the neuronostatin-induced increase in mean arterial pressure, identifying GPR107 as a functional receptor for neuronostatin in cardiovascular regulation.","method":"siRNA knockdown in cell line (KATOIII) and in vivo intracerebroventricular siRNA injection in rats; pharmacological response assay (MAP measurement, baroreflex sensitivity test)","journal":"American journal of physiology. Regulatory, integrative and comparative physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (siRNA) in both cell and in vivo contexts with defined phenotypic readout, but no direct binding assay or receptor reconstitution; single lab","pmids":["22933024"],"is_preprint":false},{"year":2014,"finding":"GPR107 localizes to the trans-Golgi network and is essential for retrograde transport; it is cleaved by the endoprotease furin, and a disulfide bond connects the two cleaved fragments. Compromising this disulfide-linked association impairs GPR107 function, and the N-terminal region is critical for its biological activity in Pseudomonas aeruginosa exotoxin A (PE) intoxication.","method":"Genome-wide haploid genetic screen, CRISPR/Cas9 gene editing, subcellular localization studies, furin cleavage assay, disulfide bond disruption experiments, domain deletion analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genome-wide screen confirmed by CRISPR in second cell type, subcellular localization, biochemical cleavage assay, and functional domain mutagenesis in a single rigorous study","pmids":["25031321"],"is_preprint":false},{"year":2014,"finding":"Deletion of Gpr107 in mice causes embryonic lethality and reduces cubilin transcript abundance; Gpr107-null fibroblasts show reduced transferrin internalization, decreased LRP1 cargo uptake, and resistance to toxins. Proteomic and colocalization analyses reveal GPR107 associates with clathrin and the retromer protein VPS35, implicating GPR107 in receptor recycling from endocytic compartments to the plasma membrane.","method":"Gpr107 knockout mouse (embryonic lethal phenotype), transferrin/LDL receptor uptake assays, toxin resistance assays, colocalization microscopy, proteomic analysis (VPS35/clathrin association)","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with multiple functional readouts and proteomic interaction data, but association with clathrin/VPS35 based on colocalization and proteomics without direct biochemical reconstitution; single lab","pmids":["24849652"],"is_preprint":false},{"year":2007,"finding":"Human GPR107 was cloned from lung tissue and encodes a 552-residue protein with an N-terminal signal peptide, a long extracellular domain, and a C-terminal seven-transmembrane (LUSTR) domain; the 18-exon gene maps to 9q34.2-3 and spans 86.4 kb.","method":"cDNA cloning, sequence analysis, genomic mapping","journal":"DNA sequence : the journal of DNA sequencing and mapping","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cloning and structural characterization of the gene/protein; single lab, primary molecular characterization","pmids":["17454009"],"is_preprint":false},{"year":2015,"finding":"GPR107 is abundantly expressed in rodent and human pancreatic α-cells and colocalizes with neuronostatin. Knockdown of GPR107 in α-cells prevents neuronostatin-induced PKA phosphorylation and proglucagon mRNA accumulation, placing GPR107 upstream of cAMP-independent PKA activation in α-cell signaling.","method":"GPR107 knockdown (loss-of-function), PKA phosphorylation assay, proglucagon mRNA quantification, colocalization microscopy in primary rodent and human islets","journal":"American journal of physiology. Regulatory, integrative and comparative physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with two orthogonal mechanistic readouts (PKA phosphorylation and mRNA levels), plus colocalization in primary human tissue; single lab","pmids":["26561648"],"is_preprint":false},{"year":2024,"finding":"Neuronostatin directly binds GPR107 (confirmed by structural analyses), which is primarily expressed in neurons. GPR107 mediates neuronostatin-induced effects on neuronal survivability and neurite outgrowth in response to Aβ, and suppresses mitochondrial energetic metabolism via GPR107/PKA signaling.","method":"Structural binding analyses, primary neuronal cultures, GPR107 knockout cells, behavioral and histopathological assessment, PKA pathway assays, ROS and mitochondrial membrane potential measurements","journal":"Neuropharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by structural analyses plus knockout cell functional assays; single lab, multiple orthogonal methods","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, increasing MMP2 production, and suppressing COL4 gene transcription. Mechanistically, GPR107 activates the ERK/STAT3 pathway through β-arrestin, driving MMP2 upregulation.","method":"Loss-of-function and gain-of-function assays in breast cancer cells, clathrin-mediated endocytosis assays, MMP2 and COL4 expression analysis, ERK/STAT3 pathway inhibition, β-arrestin pathway studies","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic readouts (endocytosis, MMP2, COL4, ERK/STAT3, β-arrestin) in single lab study; no replication by independent lab","pmids":["41073571"],"is_preprint":false},{"year":2026,"finding":"Cyclic neuronostatin acts as a GPR107 agonist and promotes PKA activation. GPR107 undergoes phosphorylation-dependent Golgi retention, with Tyr315 identified as a critical phosphorylation site required for maintaining mitochondrial protein expression and regulating ROS in the context of glucose metabolism.","method":"Cyclic peptide pharmacology (agonist assay), GPR107 phosphorylation assays, site-directed mutagenesis (Tyr315), Golgi retention studies, mitochondrial function assays in zebrafish and mice","journal":"Neuropharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-directed mutagenesis identifies Tyr315 as functional phosphorylation site with defined cellular consequences; single lab, multiple model systems","pmids":["42208758"],"is_preprint":false}],"current_model":"GPR107 is a type III integral membrane protein with a GPCR-like seven-transmembrane domain that localizes primarily to the trans-Golgi network, where it is proteolytically processed by furin and held together by a disulfide bond; it functions as a receptor for the peptide neuronostatin (activating cAMP-independent PKA signaling), is essential for retrograde vesicular transport and clathrin/retromer-dependent receptor recycling, undergoes phosphorylation-dependent Golgi retention (with Tyr315 as a key site), and in cancer contexts activates β-arrestin/ERK/STAT3 signaling to promote invasion."},"narrative":{"mechanistic_narrative":"GPR107 is a type III integral membrane protein with a C-terminal seven-transmembrane (LUSTR) domain and a long luminal/extracellular region that localizes to the trans-Golgi network and is essential for retrograde vesicular transport [PMID:25031321, PMID:17454009]. In the secretory pathway it is proteolytically cleaved by furin, with the two resulting fragments held together by a disulfide bond whose disruption impairs function; the N-terminal region is critical for its activity in Pseudomonas exotoxin A intoxication [PMID:25031321]. Beyond Golgi-based transport, GPR107 supports clathrin- and retromer-dependent receptor recycling: its loss reduces transferrin internalization and LRP1 cargo uptake, confers toxin resistance, and it associates with clathrin and the retromer subunit VPS35 [PMID:24849652]. GPR107 also functions as a receptor for the peptide neuronostatin, which binds it directly and drives cAMP-independent PKA activation that controls downstream outputs including proglucagon expression, neuronal survival and neurite outgrowth, and mitochondrial energetics [PMID:26561648, PMID:39048031]. GPR107 undergoes phosphorylation-dependent Golgi retention, with Tyr315 required for maintaining mitochondrial protein expression and ROS regulation during glucose metabolism [PMID:42208758]. In breast cancer it promotes invasion by mediating clathrin-dependent endocytosis of collagen IV, suppressing COL4 transcription, and activating an ERK/STAT3 axis through β-arrestin to upregulate MMP2 [PMID:41073571]. Loss of Gpr107 in mice is embryonic lethal [PMID:24849652].","teleology":[{"year":2007,"claim":"Establishing the primary molecular identity of GPR107 was needed before any functional role could be assigned; cloning defined it as a multi-domain seven-transmembrane protein.","evidence":"cDNA cloning, sequence and genomic mapping of human GPR107 from lung tissue","pmids":["17454009"],"confidence":"Medium","gaps":["No functional or signaling role assigned","No subcellular localization determined","No ligand identified"]},{"year":2012,"claim":"Whether GPR107 acts as a functional receptor was unknown; loss-of-function in cells and brain showed it is required for neuronostatin-induced signaling and cardiovascular responses.","evidence":"siRNA knockdown in KATOIII cells and intracerebroventricular siRNA in rats with MAP/baroreflex readouts","pmids":["22933024"],"confidence":"Medium","gaps":["No direct ligand binding demonstrated","Downstream signaling cascade not defined","Single lab"]},{"year":2014,"claim":"The cell-biological function of GPR107 was undefined; a genome-wide screen placed it in TGN retrograde transport and revealed its furin cleavage and disulfide-linked architecture.","evidence":"Genome-wide haploid screen, CRISPR editing, localization, furin cleavage and disulfide disruption assays, domain deletion in toxin intoxication","pmids":["25031321"],"confidence":"High","gaps":["Molecular mechanism of retrograde transport role unresolved","Direct transport cargoes not enumerated","No structure of cleaved/disulfide-linked form"]},{"year":2014,"claim":"Extending function to endocytic recycling and organismal essentiality, knockout and proteomics linked GPR107 to clathrin/VPS35-dependent receptor recycling.","evidence":"Gpr107 knockout mouse (embryonic lethal), transferrin/LDL uptake and toxin assays, colocalization and proteomic VPS35/clathrin association","pmids":["24849652"],"confidence":"Medium","gaps":["Clathrin/VPS35 association from colocalization/proteomics without reconstitution","Direct versus indirect interaction unresolved","Cause of embryonic lethality not mechanistically defined"]},{"year":2015,"claim":"To define where neuronostatin signaling operates, GPR107 was placed upstream of cAMP-independent PKA activation in pancreatic α-cells.","evidence":"GPR107 knockdown, PKA phosphorylation and proglucagon mRNA assays, colocalization in rodent and human islets","pmids":["26561648"],"confidence":"Medium","gaps":["Mechanism coupling GPR107 to PKA without cAMP not defined","No direct binding assay","Single lab"]},{"year":2024,"claim":"Whether neuronostatin binds GPR107 directly was unresolved; structural analyses confirmed direct binding and extended function to neuronal survival and mitochondrial metabolism.","evidence":"Structural binding analyses, primary neurons, knockout cells, PKA, ROS and mitochondrial membrane potential assays","pmids":["39048031"],"confidence":"Medium","gaps":["Atomic-resolution receptor structure not reported","Link between TGN localization and surface signaling unclear","Single lab"]},{"year":2025,"claim":"A disease-relevant effector role was unknown; GPR107 was shown to drive breast cancer invasion via collagen IV endocytosis and β-arrestin/ERK/STAT3-dependent MMP2 upregulation.","evidence":"Loss- and gain-of-function in breast cancer cells, endocytosis assays, MMP2/COL4 analysis, ERK/STAT3 and β-arrestin pathway studies","pmids":["41073571"],"confidence":"Medium","gaps":["β-arrestin recruitment to GPR107 not biochemically reconstituted","In vivo metastasis contribution limited","No independent replication"]},{"year":2026,"claim":"How GPR107 trafficking is regulated and coupled to metabolism was open; phosphorylation-dependent Golgi retention with Tyr315 was identified as controlling mitochondrial protein expression and ROS.","evidence":"Cyclic neuronostatin agonist pharmacology, phosphorylation assays, Tyr315 mutagenesis, Golgi retention and mitochondrial assays in zebrafish and mice","pmids":["42208758"],"confidence":"Medium","gaps":["Kinase responsible for Tyr315 phosphorylation not identified","Mechanistic link from Golgi retention to mitochondrial outputs unclear","Single lab"]},{"year":null,"claim":"How GPR107's roles in TGN retrograde transport, endocytic recycling, and neuronostatin-evoked PKA signaling are mechanistically integrated within a single protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model reconciling transport and receptor functions","Kinase/effector coupling to cAMP-independent PKA undefined","Direct biochemical demonstration of clathrin/retromer interaction lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,5]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,7]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5]}],"complexes":[],"partners":["VPS35","CLTC","FURIN"],"other_free_text":[]}},"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},{"pmid":"42208758","id":"PMC_42208758","title":"Cyclic neuronostatin regulates glucose homeostasis and food intake through GPR107 phosphorylation.","date":"2026","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/42208758","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6853,"output_tokens":2232,"usd":0.027019,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9370,"output_tokens":2926,"usd":0.06,"stage2_stop_reason":"end_turn"},"total_usd":0.087019,"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\": 2012,\n      \"finding\": \"GPR107 knockdown in KATOIII cells abolished neuronostatin-induced signaling responses, and siRNA-mediated knockdown of GPR107 in rat lateral cerebroventricle abolished the neuronostatin-induced increase in mean arterial pressure, identifying GPR107 as a functional receptor for neuronostatin in cardiovascular regulation.\",\n      \"method\": \"siRNA knockdown in cell line (KATOIII) and in vivo intracerebroventricular siRNA injection in rats; pharmacological response assay (MAP measurement, baroreflex sensitivity test)\",\n      \"journal\": \"American journal of physiology. Regulatory, integrative and comparative physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (siRNA) in both cell and in vivo contexts with defined phenotypic readout, but no direct binding assay or receptor reconstitution; single lab\",\n      \"pmids\": [\"22933024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GPR107 localizes to the trans-Golgi network and is essential for retrograde transport; it is cleaved by the endoprotease furin, and a disulfide bond connects the two cleaved fragments. Compromising this disulfide-linked association impairs GPR107 function, and the N-terminal region is critical for its biological activity in Pseudomonas aeruginosa exotoxin A (PE) intoxication.\",\n      \"method\": \"Genome-wide haploid genetic screen, CRISPR/Cas9 gene editing, subcellular localization studies, furin cleavage assay, disulfide bond disruption experiments, domain deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genome-wide screen confirmed by CRISPR in second cell type, subcellular localization, biochemical cleavage assay, and functional domain mutagenesis 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 and reduces cubilin transcript abundance; Gpr107-null fibroblasts show reduced transferrin internalization, decreased LRP1 cargo uptake, and resistance to toxins. Proteomic and colocalization analyses reveal GPR107 associates with clathrin and the retromer protein VPS35, implicating GPR107 in receptor recycling from endocytic compartments to the plasma membrane.\",\n      \"method\": \"Gpr107 knockout mouse (embryonic lethal phenotype), transferrin/LDL receptor uptake assays, toxin resistance assays, colocalization microscopy, proteomic analysis (VPS35/clathrin association)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with multiple functional readouts and proteomic interaction data, but association with clathrin/VPS35 based on colocalization and proteomics without direct biochemical reconstitution; single lab\",\n      \"pmids\": [\"24849652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human GPR107 was cloned from lung tissue and encodes a 552-residue protein with an N-terminal signal peptide, a long extracellular domain, and a C-terminal seven-transmembrane (LUSTR) domain; the 18-exon gene maps to 9q34.2-3 and spans 86.4 kb.\",\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 2 / Moderate — direct cloning and structural characterization of the gene/protein; single lab, primary molecular characterization\",\n      \"pmids\": [\"17454009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GPR107 is abundantly expressed in rodent and human pancreatic α-cells and colocalizes with neuronostatin. Knockdown of GPR107 in α-cells prevents neuronostatin-induced PKA phosphorylation and proglucagon mRNA accumulation, placing GPR107 upstream of cAMP-independent PKA activation in α-cell signaling.\",\n      \"method\": \"GPR107 knockdown (loss-of-function), PKA phosphorylation assay, proglucagon mRNA quantification, colocalization microscopy in primary rodent and human islets\",\n      \"journal\": \"American journal of physiology. Regulatory, integrative and comparative physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with two orthogonal mechanistic readouts (PKA phosphorylation and mRNA levels), plus colocalization in primary human tissue; single lab\",\n      \"pmids\": [\"26561648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Neuronostatin directly binds GPR107 (confirmed by structural analyses), which is primarily expressed in neurons. GPR107 mediates neuronostatin-induced effects on neuronal survivability and neurite outgrowth in response to Aβ, and suppresses mitochondrial energetic metabolism via GPR107/PKA signaling.\",\n      \"method\": \"Structural binding analyses, primary neuronal cultures, GPR107 knockout cells, behavioral and histopathological assessment, PKA pathway assays, ROS and mitochondrial membrane potential measurements\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by structural analyses plus knockout cell functional assays; single lab, multiple orthogonal methods\",\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, increasing MMP2 production, and suppressing COL4 gene transcription. Mechanistically, GPR107 activates the ERK/STAT3 pathway through β-arrestin, driving MMP2 upregulation.\",\n      \"method\": \"Loss-of-function and gain-of-function assays in breast cancer cells, clathrin-mediated endocytosis assays, MMP2 and COL4 expression analysis, ERK/STAT3 pathway inhibition, β-arrestin pathway studies\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic readouts (endocytosis, MMP2, COL4, ERK/STAT3, β-arrestin) in single lab study; no replication by independent lab\",\n      \"pmids\": [\"41073571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Cyclic neuronostatin acts as a GPR107 agonist and promotes PKA activation. GPR107 undergoes phosphorylation-dependent Golgi retention, with Tyr315 identified as a critical phosphorylation site required for maintaining mitochondrial protein expression and regulating ROS in the context of glucose metabolism.\",\n      \"method\": \"Cyclic peptide pharmacology (agonist assay), GPR107 phosphorylation assays, site-directed mutagenesis (Tyr315), Golgi retention studies, mitochondrial function assays in zebrafish and mice\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-directed mutagenesis identifies Tyr315 as functional phosphorylation site with defined cellular consequences; single lab, multiple model systems\",\n      \"pmids\": [\"42208758\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GPR107 is a type III integral membrane protein with a GPCR-like seven-transmembrane domain that localizes primarily to the trans-Golgi network, where it is proteolytically processed by furin and held together by a disulfide bond; it functions as a receptor for the peptide neuronostatin (activating cAMP-independent PKA signaling), is essential for retrograde vesicular transport and clathrin/retromer-dependent receptor recycling, undergoes phosphorylation-dependent Golgi retention (with Tyr315 as a key site), and in cancer contexts activates β-arrestin/ERK/STAT3 signaling to promote invasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GPR107 is a type III integral membrane protein with a C-terminal seven-transmembrane (LUSTR) domain and a long luminal/extracellular region that localizes to the trans-Golgi network and is essential for retrograde vesicular transport [#1, #3]. In the secretory pathway it is proteolytically cleaved by furin, with the two resulting fragments held together by a disulfide bond whose disruption impairs function; the N-terminal region is critical for its activity in Pseudomonas exotoxin A intoxication [#1]. Beyond Golgi-based transport, GPR107 supports clathrin- and retromer-dependent receptor recycling: its loss reduces transferrin internalization and LRP1 cargo uptake, confers toxin resistance, and it associates with clathrin and the retromer subunit VPS35 [#2]. GPR107 also functions as a receptor for the peptide neuronostatin, which binds it directly and drives cAMP-independent PKA activation that controls downstream outputs including proglucagon expression, neuronal survival and neurite outgrowth, and mitochondrial energetics [#4, #5]. GPR107 undergoes phosphorylation-dependent Golgi retention, with Tyr315 required for maintaining mitochondrial protein expression and ROS regulation during glucose metabolism [#7]. In breast cancer it promotes invasion by mediating clathrin-dependent endocytosis of collagen IV, suppressing COL4 transcription, and activating an ERK/STAT3 axis through \\u03b2-arrestin to upregulate MMP2 [#6]. Loss of Gpr107 in mice is embryonic lethal [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing the primary molecular identity of GPR107 was needed before any functional role could be assigned; cloning defined it as a multi-domain seven-transmembrane protein.\",\n      \"evidence\": \"cDNA cloning, sequence and genomic mapping of human GPR107 from lung tissue\",\n      \"pmids\": [\"17454009\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional or signaling role assigned\", \"No subcellular localization determined\", \"No ligand identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Whether GPR107 acts as a functional receptor was unknown; loss-of-function in cells and brain showed it is required for neuronostatin-induced signaling and cardiovascular responses.\",\n      \"evidence\": \"siRNA knockdown in KATOIII cells and intracerebroventricular siRNA in rats with MAP/baroreflex readouts\",\n      \"pmids\": [\"22933024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct ligand binding demonstrated\", \"Downstream signaling cascade not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The cell-biological function of GPR107 was undefined; a genome-wide screen placed it in TGN retrograde transport and revealed its furin cleavage and disulfide-linked architecture.\",\n      \"evidence\": \"Genome-wide haploid screen, CRISPR editing, localization, furin cleavage and disulfide disruption assays, domain deletion in toxin intoxication\",\n      \"pmids\": [\"25031321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of retrograde transport role unresolved\", \"Direct transport cargoes not enumerated\", \"No structure of cleaved/disulfide-linked form\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extending function to endocytic recycling and organismal essentiality, knockout and proteomics linked GPR107 to clathrin/VPS35-dependent receptor recycling.\",\n      \"evidence\": \"Gpr107 knockout mouse (embryonic lethal), transferrin/LDL uptake and toxin assays, colocalization and proteomic VPS35/clathrin association\",\n      \"pmids\": [\"24849652\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Clathrin/VPS35 association from colocalization/proteomics without reconstitution\", \"Direct versus indirect interaction unresolved\", \"Cause of embryonic lethality not mechanistically defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"To define where neuronostatin signaling operates, GPR107 was placed upstream of cAMP-independent PKA activation in pancreatic \\u03b1-cells.\",\n      \"evidence\": \"GPR107 knockdown, PKA phosphorylation and proglucagon mRNA assays, colocalization in rodent and human islets\",\n      \"pmids\": [\"26561648\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling GPR107 to PKA without cAMP not defined\", \"No direct binding assay\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether neuronostatin binds GPR107 directly was unresolved; structural analyses confirmed direct binding and extended function to neuronal survival and mitochondrial metabolism.\",\n      \"evidence\": \"Structural binding analyses, primary neurons, knockout cells, PKA, ROS and mitochondrial membrane potential assays\",\n      \"pmids\": [\"39048031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Atomic-resolution receptor structure not reported\", \"Link between TGN localization and surface signaling unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A disease-relevant effector role was unknown; GPR107 was shown to drive breast cancer invasion via collagen IV endocytosis and \\u03b2-arrestin/ERK/STAT3-dependent MMP2 upregulation.\",\n      \"evidence\": \"Loss- and gain-of-function in breast cancer cells, endocytosis assays, MMP2/COL4 analysis, ERK/STAT3 and \\u03b2-arrestin pathway studies\",\n      \"pmids\": [\"41073571\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"β-arrestin recruitment to GPR107 not biochemically reconstituted\", \"In vivo metastasis contribution limited\", \"No independent replication\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"How GPR107 trafficking is regulated and coupled to metabolism was open; phosphorylation-dependent Golgi retention with Tyr315 was identified as controlling mitochondrial protein expression and ROS.\",\n      \"evidence\": \"Cyclic neuronostatin agonist pharmacology, phosphorylation assays, Tyr315 mutagenesis, Golgi retention and mitochondrial assays in zebrafish and mice\",\n      \"pmids\": [\"42208758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible for Tyr315 phosphorylation not identified\", \"Mechanistic link from Golgi retention to mitochondrial outputs unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GPR107's roles in TGN retrograde transport, endocytic recycling, and neuronostatin-evoked PKA signaling are mechanistically integrated within a single protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model reconciling transport and receptor functions\", \"Kinase/effector coupling to cAMP-independent PKA undefined\", \"Direct biochemical demonstration of clathrin/retromer interaction lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VPS35\", \"CLTC\", \"FURIN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}