{"gene":"ADGRF5","run_date":"2026-06-09T22:02:41","timeline":{"discoveries":[{"year":2013,"finding":"GPR116 promotes breast cancer cell migration and invasion through the Gαq-p63RhoGEF-RhoA/Rac1 pathway, modulating lamellipodia formation and actin stress fibers in a RhoA- and Rac1-dependent manner.","method":"Knockdown in MDA-MB-231 cells, ectopic expression in MCF-7/Hs578T cells, in vivo mammary tumor metastasis mouse models, pathway dissection via Gαq-p63RhoGEF-RhoA/Rac1 signaling analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD/KO with defined cellular phenotype plus pathway placement, single lab but multiple orthogonal methods (in vitro and in vivo)","pmids":["24008316"],"is_preprint":false},{"year":2013,"finding":"GPR116 expression in alveolar type II (ATII) cells is required for maintaining normal pulmonary surfactant homeostasis; global and conditional knockout mice show progressive surfactant lipid and protein accumulation, labored breathing, and reduced lifespan.","method":"Global Gpr116 gene disruption in mice, bone marrow transplantation studies, conditional knockout mice with cell-type-specific deletion, surfactant structure/function analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — independently replicated across multiple labs using genetic KO models with clear cellular and molecular phenotypic readout","pmids":["23684610"],"is_preprint":false},{"year":2013,"finding":"Surfactant protein D (SP-D) was identified as a ligand of Ig-Hepta/GPR116; GPR116 on alveolar type II cells senses surfactant levels by monitoring SP-D concentration, and its signaling attenuates surfactant lipid/protein synthesis and secretion while stimulating surfactant recycling/uptake.","method":"Co-expression of SP-D and extracellular region of Ig-Hepta/GPR116 followed by immunoprecipitation; radioactive tracer studies of surfactant metabolism in wildtype vs knockout mice","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ligand identification by co-IP plus in vivo metabolic tracing, single lab with two orthogonal methods","pmids":["23922714"],"is_preprint":false},{"year":2013,"finding":"GPR116 functions as a molecular sensor of alveolar surfactant lipid pool sizes by regulating surfactant secretion; knockout mice show 12–30-fold accumulation of alveolar surfactant phospholipids with increased saturated phosphatidylcholine synthesis; P2RY2 purinergic receptor is induced in knockout type II cells.","method":"Targeted mutation of Gpr116 locus (Gpr116Δexon17) in mice, mRNA microarray analyses, lipid quantification","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated genetic KO model with quantitative molecular phenotype across multiple labs","pmids":["23590306"],"is_preprint":false},{"year":2006,"finding":"Ig-Hepta/GPR116 undergoes multiple proteolytic processing events yielding four fragments (presequence, proEGF2/alpha, Ig repeats/beta-chain, TM7/gamma-chain); the proEGF2 region is cleaved by furin to generate EGF2 and the alpha-fragment influences expression of some mRNA species.","method":"Biochemical characterization of processing fragments, furin inhibitor experiments, mRNA expression analysis","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro biochemical identification of cleavage sites and processing enzyme (furin), single lab","pmids":["16882675"],"is_preprint":false},{"year":2017,"finding":"GPR116/ADGRF5 controls surfactant secretion and reuptake in alveolar type II cells via Gq/11 signaling; synthetic agonist peptides derived from the GPR116 ectodomain activated Gq/11-dependent inositol phosphate conversion, calcium mobilization, and cortical F-actin stabilization to inhibit surfactant secretion; AT2 cell-specific deletion of Gnaq and Gna11 phenocopied GPR116 knockout surfactant accumulation.","method":"Synthetic tethered agonist peptides, inositol phosphate conversion assay, calcium mobilization assay, F-actin imaging, AT2 cell-specific Gnaq/Gna11 double knockout mice","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal in vitro and in vivo methods (biochemical signaling assays + epistatic genetic rescue), mechanistic pathway established","pmids":["28570277"],"is_preprint":false},{"year":2015,"finding":"Loss of Gpr116 in mice causes cerebral vascular leakage beginning at ~1.5 months; endothelial-specific deletion of Gpr116 results in significant increase of brain vascular leakage, and Gpr116 knockout mice show attenuated pathological retinal vascular response in oxygen-induced retinopathy, indicating Gpr116 modulates endothelial barrier properties.","method":"Constitutive Gpr116 knockout mouse model (exon 4–21 deletion), endothelial-specific conditional knockout, oxygen-induced retinopathy model, vascular permeability assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endothelial-specific KO with defined vascular permeability phenotype, single lab","pmids":["26394398"],"is_preprint":false},{"year":2015,"finding":"Ig-Hepta/GPR116 deficiency leads to activation of alveolar macrophages producing reactive oxygen species, NF-κB activation and nuclear translocation in alveolar macrophages, and release of MMP-2 and MMP-9; monocyte chemotactic protein-1 (MCP-1) is elevated in embryonic lungs of knockout mice, suggesting GPR116 regulates macrophage immune responses.","method":"Analysis of bronchoalveolar lavage fluid from knockout mice, ROS detection, NF-κB immunofluorescence, MMP inhibitor experiments, MCP-1 ELISA","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with multiple downstream molecular readouts, single lab","pmids":["25778400"],"is_preprint":false},{"year":2017,"finding":"Loss of both GPR116 and ELTD1 (but not either alone) in mice causes aortic arch artery and cardiac outflow tract malformations, renal thrombotic microangiopathy, hemolysis, and splenomegaly; these phenotypes are not recapitulated by endothelial- or neural crest-specific double deletions, indicating expression in non-endothelial, non-neural crest cells accounts for these defects.","method":"Double knockout mouse model, endothelial-specific and neural crest-specific conditional double knockouts, histological and cardiovascular analyses","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via double KO and cell-type-specific conditional KO, single lab","pmids":["28806758"],"is_preprint":false},{"year":2012,"finding":"Adipose tissue-specific deletion of Gpr116 in mice causes glucose intolerance and insulin resistance, hepatosteatosis, reduced circulating adiponectin, and increased serum resistin, indicating GPR116 controls adipocyte biology and systemic energy homeostasis.","method":"Adipose tissue-specific conditional Gpr116 knockout mice on standard chow and high-fat diet, glucose tolerance tests, insulin tolerance tests, serum adipokine measurements","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with defined metabolic phenotype, single lab","pmids":["22971422"],"is_preprint":false},{"year":2021,"finding":"FNDC4 (a hepatokine) directly binds GPR116 in white adipose tissue with high affinity; sFNDC4 binding to GPR116 promotes insulin signaling and insulin-mediated glucose uptake in white adipocytes; GPR116 mediates the insulin-sensitizing effects of FNDC4 in a white-adipocyte-selective manner.","method":"Direct binding assay (high-affinity binding of sFNDC4 to GPR116), GPR116 knockout mice, FcsFNDC4 supplementation in prediabetic mice, glucose uptake assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct ligand-receptor binding established, multiple orthogonal in vitro and in vivo methods, replicated in prediabetic mouse model","pmids":["34016966"],"is_preprint":false},{"year":2020,"finding":"Kidney-specific knockout of Gpr116 causes urinary acidification (reduced urine pH), increased blood pH, decreased pCO2, and greater accumulation of V-ATPase at the apical surface of acid-secreting A-intercalated cells; pretreatment with synthetic Gpr116 agonist peptide inhibits proton flux in intercalated cells; Gpr116 tonically inhibits V-ATPase trafficking and urinary acid secretion in the collecting duct.","method":"Kidney-specific Gpr116 knockout mice, immunogold electron microscopy of V-ATPase localization, split-open collecting duct proton flux assay with synthetic agonist peptide, blood gas analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — tissue-specific KO with defined molecular phenotype (V-ATPase trafficking), functional rescue with synthetic agonist, multiple orthogonal methods","pmids":["33004624"],"is_preprint":false},{"year":2019,"finding":"Loss of ADGRF5 in mice results in upregulation of CCL2, S100a8, and S100a9 in embryonic and neonatal lungs and in lung endothelial cells; RS504393 (CCR2 antagonist) treatment suppressed downstream inflammatory gene upregulation, placing ADGRF5-mediated CCL2 signaling upstream of airway inflammation including type 2 immune responses.","method":"Adgrf5 knockout mice, qPCR and western blotting of primary lung endothelial cells, pharmacological intervention with RS504393, histology, BAL cell counting, ELISA","journal":"Respiratory research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO model with pathway placement via pharmacological intervention, single lab, multiple readouts","pmids":["30654796"],"is_preprint":false},{"year":2022,"finding":"GPR116 maintains the muscle stem cell (MuSC) pool via nuclear functions of β-arrestin1; Stachel (tethered agonist) peptide stimulation of GPR116 leads to strong β-arrestin interaction and increased nuclear localization of β-arrestin1, where it interacts with CREB to regulate gene expression; GPR116-deficient MuSCs show progressive depletion and defective self-renewal.","method":"Gpr116 knockout mice, Stachel peptide stimulation, β-arrestin interaction assays, nuclear fractionation/localization studies, CREB co-immunoprecipitation, MuSC isolation and self-renewal assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with pathway placement, β-arrestin nuclear interaction identified by co-IP/fractionation, single lab with multiple orthogonal methods","pmids":["36384129"],"is_preprint":false},{"year":2022,"finding":"Autocatalytic cleavage upstream of the GPR116 tethered agonist (Stachel) sequence is required for N-terminal fragment (NTF) displacement and receptor activation; a non-cleavable GPR116 knock-in mouse phenocopies the pulmonary phenotype of GPR116 knockout mice; key conserved amino acids in the Stachel sequence and ECL2/3 are required for receptor activation, and residues in TM7 mediate stronger signaling in mouse vs. human GPR116.","method":"Non-cleavable knock-in mouse model, site-directed mutagenesis, species-swapping approaches, in vitro signaling assays, molecular modeling of tethered agonist:ECL2 interactions","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo knock-in phenocopy plus in vitro mutagenesis plus species-swapping, multiple orthogonal methods in one rigorous study","pmids":["36073784"],"is_preprint":false},{"year":2019,"finding":"ADGRF5/Gpr116 is highly expressed in CNS endothelium and regulates blood-brain barrier formation; Adgrf5 mutant retinae show increased perivenous vascular density and abnormal projections toward the inner plexus, with transient vascular protrusions into the inner retinal space, implicating ADGRF5 in vein-derived endothelial patterning of the deep retinal layer.","method":"Adgrf5 knockout mouse model, retinal vascular imaging, endothelial-specific analyses, comparison with Rac1 knockout retinae","journal":"Angiogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO model with defined vascular morphogenetic phenotype, single lab","pmids":["31256320"],"is_preprint":false},{"year":2023,"finding":"GPR116 promotes ferroptosis in sepsis-induced liver injury by inhibiting the system Xc-/GSH/GPX4 pathway, aggravating mitochondrial damage and lipid peroxidation; hepatocyte-specific GPR116 deletion prevents hepatic ferroptosis and alleviates sepsis-induced liver dysfunction.","method":"Hepatocyte-specific GPR116 knockout mice (in vivo sepsis model), GPR116 overexpression experiments, measurement of system Xc-/GSH/GPX4 pathway components, mitochondrial and lipid peroxidation assays","journal":"Cell biology and toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO with defined molecular pathway, overexpression confirmation, single lab","pmids":["37266730"],"is_preprint":false},{"year":2024,"finding":"In breast cancer cells, ADGRF5 inhibits ERK1/2 activity by enhancing RhoA activation, leading to decreased phosphorylation of C/EBPβ at Thr235, hindering its nuclear translocation and subsequent MMP8 transcriptional activation; ADGRF5 silencing increases MMP8 expression, CXCL8 secretion, and shifts tumor-associated neutrophils toward antitumor N1 phenotype.","method":"ADGRF5 knockdown in breast cancer cells, RhoA activation assays, ERK1/2 phosphorylation, C/EBPβ Thr235 phosphorylation and nuclear translocation, MMP8 promoter analysis, in vivo tumor models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined molecular pathway (RhoA→ERK→C/EBPβ→MMP8), multiple downstream readouts, single lab","pmids":["38937435"],"is_preprint":false},{"year":2024,"finding":"GPR116 is expressed in pancreatic delta cells and regulates somatostatin release; whole-body GPR116 deficiency also causes decreased beta-cell mass, lower number of small islets, and reduced pancreatic insulin content; glucose homeostasis in global knockout mice is maintained by counter-acting mechanisms modulating insulin degradation.","method":"Whole-body and cell-specific Gpr116 knockout mouse models, islet hormone secretion assays, histomorphometry of pancreatic islets, insulin content measurement","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO with defined secretory phenotype, single lab","pmids":["38228886"],"is_preprint":false},{"year":2024,"finding":"GPR116 protects against acetaminophen-induced liver injury by interacting with β-arrestin1, which in turn inhibits BiP (a critical ER stress regulator), thereby mitigating ER stress; activation of GPR116 by its ligand FNDC4 confers protection against early hepatotoxicity.","method":"Hepatocyte-specific GPR116 knockout mice, GPR116 overexpression, co-immunoprecipitation of GPR116 with β-arrestin1 and BiP, RNA-sequencing, APAP challenge model, FNDC4 treatment","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP establishing protein-protein interaction, KO and overexpression with mechanistic pathway, single lab","pmids":["39001944"],"is_preprint":false},{"year":2024,"finding":"ADGRF5 loss in glomerular endothelial cells alters expression of type IV collagens (COL4A3, COL4A4) and the mechanosensitive transcription factor KLF2, leading to glomerular filtration barrier dysfunction, albuminuria, and impaired kidney function; ADGRF5 knockdown in human primary glomerular endothelial cells reproduces these gene expression changes.","method":"Adgrf5 knockout mice (histology, kidney function tests), ADGRF5 siRNA knockdown in human primary glomerular endothelial cells, gene/protein expression analysis","journal":"Journal of the American Society of Nephrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model plus human cell knockdown with defined gene expression and functional outcomes, single lab","pmids":["38844335"],"is_preprint":false},{"year":2023,"finding":"GPR116 negatively regulates NK cell antitumor function via the Gαq/HIF1α/NF-κB signaling pathway; GPR116-deficient NK cells show higher cytotoxicity and produce more GzmB and IFNγ; downregulation of GPR116 in NKG2D-CAR-NK92 cells enhances their antitumor activity.","method":"GPR116 knockout mice, in vitro NK cell cytotoxicity assays, in vivo tumor models with GPR116-/- NK cells, pathway analysis (Gαq/HIF1α/NF-κB)","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO model with defined cellular phenotype and pathway placement, single lab, in vitro and in vivo validation","pmids":["36895027"],"is_preprint":false},{"year":2025,"finding":"GPR116 was identified as the key hydrostatic pressure mechanosensor in liver sinusoidal endothelial cells (LSECs); genetic silencing of GPR116 protected endothelial cells from hydrostatic pressure-induced damage in vitro and in cirrhotic murine models, and its downstream mechanotransduction pathway was delineated.","method":"Hepatic hypertension-on-a-chip system (2D static and 3D dynamic), genetic silencing of GPR116 in LSECs, cirrhotic murine models, cell- and gene-based therapies","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel in vitro mechanosensing model plus in vivo validation with genetic silencing, single lab","pmids":["41237250"],"is_preprint":false},{"year":2026,"finding":"ADGRF5 mediates shear stress mechanotransduction in glomerular endothelial cells via the Gαq/11-PKC-RAF1-MEK1/2-ERK1/2 cascade; activation requires the tethered agonist (Stachel) sequence and C-terminal helix 8; ADGRF5 knockdown attenuates shear flow-induced immediate early response genes and COL4A3/COL4A4 expression in human primary renal glomerular endothelial cells.","method":"ADGRF5 overexpression in PEAKrapid cells under laminar flow, inhibitor and knockdown experiments, mutagenesis of Stachel sequence and helix 8, endogenous validation in human primary renal glomerular endothelial cells","journal":"Journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mechanistic pathway established by mutagenesis, inhibitor dissection, and endogenous validation with multiple orthogonal methods in one study","pmids":["42233720"],"is_preprint":false},{"year":2018,"finding":"Organic barn dust increases GPR116 mRNA expression via protein kinase C alpha (PKCα) signaling, which in turn inhibits SP-D (surfactant protein D) production in alveolar epithelial cells; PKCα inhibition reverses both GPR116 upregulation and SP-D suppression.","method":"PKCα inhibitor experiments in human alveolar epithelial cell line and in vivo mouse model, mRNA and protein expression analysis of SP-D and GPR116","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological inhibition with single-method expression readouts, single lab","pmids":["30543664"],"is_preprint":false}],"current_model":"ADGRF5/GPR116 is an adhesion GPCR that is activated via a tethered agonist (Stachel) mechanism requiring autocatalytic cleavage; it couples primarily to Gαq/11 signaling to regulate diverse physiological processes including pulmonary surfactant homeostasis in alveolar type II cells (inhibiting secretion and promoting recycling), renal acid secretion via tonic inhibition of V-ATPase trafficking in intercalated cells, insulin sensitization in white adipocytes through direct high-affinity binding of the hepatokine FNDC4, NK cell and muscle stem cell function via β-arrestin1 nuclear signaling, and endothelial mechanotransduction (including shear stress and hydrostatic pressure sensing) through Gαq/11-PKC-ERK cascades; it also promotes breast cancer metastasis via Gαq-p63RhoGEF-RhoA/Rac1-dependent actin remodeling."},"narrative":{"mechanistic_narrative":"ADGRF5 (GPR116/Ig-Hepta) is an adhesion G-protein-coupled receptor that acts as a cell-surface sensor coupling extracellular cues to Gαq/11 signaling across epithelial, endothelial, immune, and stem cell compartments [PMID:23684610, PMID:28570277, PMID:36073784]. Like other adhesion GPCRs, it requires autocatalytic cleavage upstream of its tethered agonist (Stachel) sequence so that N-terminal fragment displacement exposes the agonist and activates the receptor; a non-cleavable knock-in mouse phenocopies the knockout pulmonary defect, establishing that this self-cleavage is obligatory for function in vivo, and the C-terminal helix 8 together with conserved Stachel and ECL2/3 residues are required for downstream signaling [PMID:36073784, PMID:42233720]. Its best-defined role is in alveolar type II cells, where it senses surfactant levels — monitoring the ligand SP-D — and drives Gαq/11-dependent inositol phosphate turnover, calcium mobilization, and cortical F-actin stabilization to restrain surfactant secretion and promote recycling; loss of GPR116 or of AT2 Gnaq/Gna11 causes massive surfactant accumulation and respiratory disease [PMID:23684610, PMID:23922714, PMID:23590306, PMID:28570277]. The receptor sustains epithelial transport homeostasis in the kidney, where it tonically inhibits V-ATPase trafficking and urinary acid secretion in intercalated cells [PMID:33004624], and functions as an endothelial mechanosensor, transducing shear stress through a Gαq/11-PKC-RAF1-MEK-ERK cascade that controls type IV collagen and KLF2 expression at the glomerular filtration barrier [PMID:38844335, PMID:42233720] and serving as a hydrostatic-pressure sensor in liver sinusoidal endothelium [PMID:41237250]. Beyond Gαq, GPR116 engages β-arrestin1 signaling: Stachel stimulation drives nuclear β-arrestin1 that interacts with CREB to maintain the muscle stem cell pool [PMID:36384129], and β-arrestin1 mediates hepatoprotection against ER stress [PMID:39001944]. The hepatokine FNDC4 binds GPR116 with high affinity to sensitize white adipocytes to insulin, linking the receptor to systemic glucose and energy homeostasis [PMID:22971422, PMID:34016966]. In cancer, GPR116 promotes breast cancer migration and metastasis via Gαq-p63RhoGEF-RhoA/Rac1-driven actin remodeling and suppresses an antitumor neutrophil program through a RhoA-ERK-C/EBPβ-MMP8 axis [PMID:24008316, PMID:38937435].","teleology":[{"year":2006,"claim":"Established that GPR116 is a multiply processed adhesion-type receptor, defining the proteolytic architecture that would later prove essential for activation.","evidence":"biochemical fragment characterization and furin-inhibitor experiments","pmids":["16882675"],"confidence":"Medium","gaps":["did not link cleavage to signaling or a physiological output","Stachel-mediated activation not yet recognized"]},{"year":2012,"claim":"First physiological role assigned to GPR116, showing adipose-specific deletion disrupts systemic glucose and energy homeostasis.","evidence":"adipose-specific conditional knockout mice with metabolic phenotyping","pmids":["22971422"],"confidence":"Medium","gaps":["no ligand or signaling pathway identified","molecular mechanism in adipocytes unresolved"]},{"year":2013,"claim":"Defined the receptor's flagship role as an alveolar surfactant sensor and identified SP-D as a candidate ligand, answering what GPR116 detects and what it controls in the lung.","evidence":"global and conditional knockout mice, surfactant lipid/protein metabolic tracing, and co-IP of SP-D with the ectodomain","pmids":["23684610","23922714","23590306"],"confidence":"High","gaps":["G protein coupling not yet demonstrated","whether SP-D is the activating agonist versus a co-factor unresolved"]},{"year":2013,"claim":"Placed GPR116 in a cancer-promoting signaling pathway, linking it to Gαq-p63RhoGEF-RhoA/Rac1-driven actin dynamics and metastasis.","evidence":"knockdown/ectopic expression in breast cancer lines plus in vivo metastasis models with pathway dissection","pmids":["24008316"],"confidence":"Medium","gaps":["receptor activation mechanism in tumor cells not defined","endogenous activating ligand unknown"]},{"year":2015,"claim":"Extended GPR116 function to vascular barrier maintenance and immune regulation, showing endothelial deletion causes vascular leakage and loss provokes alveolar macrophage inflammation.","evidence":"endothelial-specific conditional knockout, oxygen-induced retinopathy model, and BAL/ROS/NF-κB/MMP analyses in knockout mice","pmids":["26394398","25778400"],"confidence":"Medium","gaps":["mechanotransduction mechanism not yet delineated","macrophage effects could be secondary to surfactant pathology"]},{"year":2017,"claim":"Established the core signaling logic: tethered-agonist peptides activate Gαq/11 to inhibit surfactant secretion, and AT2 Gnaq/Gna11 deletion phenocopies the knockout, proving the effector pathway.","evidence":"synthetic Stachel peptides, IP/calcium/F-actin assays, and AT2-specific Gnaq/Gna11 double knockout mice","pmids":["28570277"],"confidence":"High","gaps":["did not prove cleavage requirement in vivo","endogenous trigger for Stachel exposure unresolved"]},{"year":2017,"claim":"Revealed functional overlap with ELTD1 in non-endothelial cells controlling cardiovascular and renal development through genetic epistasis.","evidence":"single and double knockout plus cell-type-specific conditional double knockout mice","pmids":["28806758"],"confidence":"Medium","gaps":["responsible cell type not identified","molecular basis of ADGRF5/ELTD1 redundancy unknown"]},{"year":2019,"claim":"Connected GPR116 loss to specific inflammatory and vascular-patterning programs, positioning CCL2/CCR2 signaling downstream and implicating the receptor in CNS endothelial and retinal vascular morphogenesis.","evidence":"knockout mice with CCR2-antagonist intervention; retinal vascular imaging compared with Rac1 knockout","pmids":["30654796","31256320"],"confidence":"Medium","gaps":["whether inflammatory changes are cell-autonomous unresolved","link between receptor signaling and CCL2 induction not mechanistically traced"]},{"year":2020,"claim":"Defined a renal epithelial role, showing GPR116 tonically inhibits V-ATPase trafficking to restrain urinary acid secretion, with synthetic agonist functionally rescuing proton flux.","evidence":"kidney-specific knockout mice, immunogold EM of V-ATPase, split-open duct proton flux with agonist peptide, and blood gas analysis","pmids":["33004624"],"confidence":"High","gaps":["physiological ligand in the collecting duct unknown","G protein/effector linking receptor to V-ATPase trafficking not identified"]},{"year":2021,"claim":"Identified FNDC4 as a direct high-affinity ligand mediating the receptor's white-adipocyte insulin-sensitizing function, providing a molecular ligand for the 2012 metabolic phenotype.","evidence":"direct binding assay, knockout mice, FcsFNDC4 supplementation in prediabetic mice, and glucose uptake assays","pmids":["34016966"],"confidence":"High","gaps":["whether FNDC4 acts as a Stachel-exposing agonist or allosteric modulator unresolved","G protein/arrestin branch driving insulin sensitization not defined"]},{"year":2022,"claim":"Demonstrated obligatory autocatalytic cleavage for activation and a β-arrestin1 branch, showing a non-cleavable knock-in phenocopies the lung defect and that nuclear β-arrestin1-CREB signaling maintains muscle stem cells.","evidence":"non-cleavable knock-in mice, mutagenesis/species-swapping, Stachel stimulation, β-arrestin nuclear fractionation, and CREB co-IP","pmids":["36073784","36384129"],"confidence":"High","gaps":["structural basis of Stachel:ECL engagement modeled but not solved","balance between Gαq and β-arrestin branches across tissues unclear"]},{"year":2023,"claim":"Expanded GPR116 into immune and hepatic injury contexts, showing it negatively regulates NK antitumor function via Gαq/HIF1α/NF-κB and promotes hepatocyte ferroptosis by suppressing the system Xc-/GSH/GPX4 axis.","evidence":"knockout mice and NK cytotoxicity/tumor models; hepatocyte-specific knockout and overexpression with ferroptosis pathway readouts","pmids":["36895027","37266730"],"confidence":"Medium","gaps":["activating ligands in NK cells and hepatocytes unidentified","direct receptor-to-pathway coupling steps incompletely defined"]},{"year":2024,"claim":"Resolved the receptor as an endothelial mechanosensor and refined its β-arrestin1 and RhoA-ERK signaling roles in kidney filtration, hepatoprotection, breast cancer neutrophil polarization, and pancreatic islet biology.","evidence":"glomerular endothelial knockout/human-cell knockdown, β-arrestin1/BiP co-IP with APAP/FNDC4 models, RhoA-ERK-C/EBPβ-MMP8 dissection, and islet-specific knockout secretion assays","pmids":["38844335","39001944","38937435","38228886"],"confidence":"Medium","gaps":["how a single receptor selects Gαq versus β-arrestin outputs by tissue unresolved","force-to-Stachel coupling mechanism not directly shown"]},{"year":2025,"claim":"Confirmed GPR116 as a pressure/shear mechanosensor in vascular endothelium and delineated its shear cascade, establishing the full Gαq/11-PKC-RAF1-MEK-ERK pathway with Stachel and helix 8 requirements.","evidence":"hepatic hypertension-on-a-chip with LSEC silencing and cirrhotic models; flow assays with inhibitor/knockdown/mutagenesis and human primary glomerular endothelial validation","pmids":["41237250","42233720"],"confidence":"Medium","gaps":["physical mechanism converting force into NTF displacement not directly demonstrated","in vivo relevance of helix 8 requirement untested"]},{"year":null,"claim":"It remains unresolved how GPR116 physically converts diverse stimuli (SP-D, FNDC4, shear, hydrostatic pressure) into tethered-agonist exposure, and what governs the tissue-specific choice between Gαq/11 and β-arrestin1 signaling outputs.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no atomic structure of the activated receptor","no unified model linking ligand binding, force, and cleavage-dependent activation","determinants of Gαq-versus-arrestin bias unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[5,14,23]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[2,3,22,23]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[2,10]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,11,14,23]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,14,23]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[9,10]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[3,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[21,7]}],"complexes":[],"partners":["FNDC4","SP-D (SFTPD)","ARRB1","GNAQ","GNA11","CREB","BIP (HSPA5)","ELTD1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IZF2","full_name":"Adhesion G protein-coupled receptor F5","aliases":["G-protein coupled receptor 116"],"length_aa":1346,"mass_kda":149.5,"function":"Adhesion G protein-coupled receptor (PubMed:28570277). In alveolar type II (ATII or AT2) cells, required for normal lung surfactant homeostasis (PubMed:28570277). Modulation of both surfactant secretion and uptake by ATII cells is mediated by the downstream activation of GNAQ/GNA11 proteins and may be a consequence of increased cortical F-actin assembly induced by ADGRF5 activation (PubMed:28570277). In the kidney, may play a role in the regulation of acid excretion into the primary urine, possibly by regulating the surface expression of V-ATPase proton pump (By similarity). As a receptor for soluble FNDC4 (sFNDC4), required for proper systemic glucose tolerance, specifically sensitizing white adipose tissue to insulin. Also plays a role in sFNDC4-induced decrease of local inflammation in white adipose tissue (PubMed:34016966)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8IZF2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADGRF5","classification":"Not Classified","n_dependent_lines":17,"n_total_lines":1208,"dependency_fraction":0.014072847682119206},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ADGRF5","total_profiled":1310},"omim":[{"mim_id":"620874","title":"ADHESION G PROTEIN-COUPLED RECEPTOR F5; ADGRF5","url":"https://www.omim.org/entry/620874"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lung","ntpm":99.9}],"url":"https://www.proteinatlas.org/search/ADGRF5"},"hgnc":{"alias_symbol":["DKFZp564O1923","KIAA0758"],"prev_symbol":["GPR116"]},"alphafold":{"accession":"Q8IZF2","domains":[{"cath_id":"-","chopping":"75-94_102-167","consensus_level":"high","plddt":68.6091,"start":75,"end":167},{"cath_id":"3.30.70.960","chopping":"171-270","consensus_level":"high","plddt":83.1415,"start":171,"end":270},{"cath_id":"2.60.40.10","chopping":"275-366","consensus_level":"high","plddt":80.1861,"start":275,"end":366},{"cath_id":"2.60.40.10","chopping":"373-469","consensus_level":"high","plddt":75.4499,"start":373,"end":469},{"cath_id":"2.60.40.10","chopping":"475-564","consensus_level":"high","plddt":83.5383,"start":475,"end":564},{"cath_id":"2.60.40.10","chopping":"573-724","consensus_level":"medium","plddt":79.4577,"start":573,"end":724},{"cath_id":"1.25.40,1.25.40","chopping":"725-837","consensus_level":"medium","plddt":86.2681,"start":725,"end":837},{"cath_id":"2.60.220.50","chopping":"844-1002","consensus_level":"medium","plddt":75.4353,"start":844,"end":1002},{"cath_id":"1.20.1070.10","chopping":"1035-1221_1247-1278","consensus_level":"medium","plddt":78.8018,"start":1035,"end":1278}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IZF2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IZF2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IZF2-F1-predicted_aligned_error_v6.png","plddt_mean":74.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADGRF5","jax_strain_url":"https://www.jax.org/strain/search?query=ADGRF5"},"sequence":{"accession":"Q8IZF2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IZF2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IZF2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IZF2"}},"corpus_meta":[{"pmid":"24008316","id":"PMC_24008316","title":"GPR116, an adhesion G-protein-coupled receptor, promotes breast cancer metastasis via the Gαq-p63RhoGEF-Rho GTPase pathway.","date":"2013","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/24008316","citation_count":95,"is_preprint":false},{"pmid":"23684610","id":"PMC_23684610","title":"Essential regulation of lung surfactant homeostasis by the orphan G protein-coupled receptor GPR116.","date":"2013","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/23684610","citation_count":67,"is_preprint":false},{"pmid":"23922714","id":"PMC_23922714","title":"Lung surfactant levels are regulated by Ig-Hepta/GPR116 by monitoring surfactant protein D.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23922714","citation_count":62,"is_preprint":false},{"pmid":"23590306","id":"PMC_23590306","title":"Orphan G protein-coupled receptor GPR116 regulates pulmonary surfactant pool size.","date":"2013","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23590306","citation_count":61,"is_preprint":false},{"pmid":"28570277","id":"PMC_28570277","title":"Epithelial Gpr116 regulates pulmonary alveolar homeostasis via Gq/11 signaling.","date":"2017","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/28570277","citation_count":56,"is_preprint":false},{"pmid":"34016966","id":"PMC_34016966","title":"Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34016966","citation_count":51,"is_preprint":false},{"pmid":"26394398","id":"PMC_26394398","title":"Gpr116 Receptor Regulates Distinctive Functions in Pneumocytes and Vascular Endothelium.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26394398","citation_count":51,"is_preprint":false},{"pmid":"22971422","id":"PMC_22971422","title":"Adipose tissue deletion of Gpr116 impairs insulin sensitivity through modulation of adipose function.","date":"2012","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/22971422","citation_count":47,"is_preprint":false},{"pmid":"28806758","id":"PMC_28806758","title":"Developmental vascular remodeling defects and postnatal kidney failure in mice lacking Gpr116 (Adgrf5) and Eltd1 (Adgrl4).","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28806758","citation_count":37,"is_preprint":false},{"pmid":"30654796","id":"PMC_30654796","title":"Loss of the adhesion G-protein coupled receptor ADGRF5 in mice induces airway inflammation and the expression of CCL2 in lung endothelial cells.","date":"2019","source":"Respiratory research","url":"https://pubmed.ncbi.nlm.nih.gov/30654796","citation_count":36,"is_preprint":false},{"pmid":"33004624","id":"PMC_33004624","title":"Adhesion-GPCR Gpr116 (ADGRF5) expression inhibits renal acid secretion.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33004624","citation_count":33,"is_preprint":false},{"pmid":"32047233","id":"PMC_32047233","title":"Recurrent novel THBS1-ADGRF5 gene fusion in a new tumor subtype \"Acral FibroChondroMyxoid Tumors\".","date":"2020","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/32047233","citation_count":24,"is_preprint":false},{"pmid":"25778400","id":"PMC_25778400","title":"Targeted Disruption of Ig-Hepta/Gpr116 Causes Emphysema-like Symptoms That Are Associated with Alveolar Macrophage Activation.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25778400","citation_count":24,"is_preprint":false},{"pmid":"37266730","id":"PMC_37266730","title":"GPR116 promotes ferroptosis in sepsis-induced liver injury by suppressing system Xc-/GSH/GPX4.","date":"2023","source":"Cell biology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/37266730","citation_count":22,"is_preprint":false},{"pmid":"16882675","id":"PMC_16882675","title":"Multiple processing of Ig-Hepta/GPR116, a G protein-coupled receptor with immunoglobulin (Ig)-like repeats, and generation of EGF2-like fragment.","date":"2006","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16882675","citation_count":22,"is_preprint":false},{"pmid":"36384129","id":"PMC_36384129","title":"The adhesion G-protein-coupled receptor Gpr116 is essential to maintain the skeletal muscle stem cell pool.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36384129","citation_count":21,"is_preprint":false},{"pmid":"31256320","id":"PMC_31256320","title":"Adgrf5 contributes to patterning of the endothelial deep layer in retina.","date":"2019","source":"Angiogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/31256320","citation_count":17,"is_preprint":false},{"pmid":"33106912","id":"PMC_33106912","title":"In silico molecular docking and physicochemical property studies on effective phytochemicals targeting GPR116 for breast cancer treatment.","date":"2020","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33106912","citation_count":16,"is_preprint":false},{"pmid":"36073784","id":"PMC_36073784","title":"Regulation of pulmonary surfactant by the adhesion GPCR GPR116/ADGRF5 requires a tethered agonist-mediated activation mechanism.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/36073784","citation_count":15,"is_preprint":false},{"pmid":"38937435","id":"PMC_38937435","title":"The adhesion-GPCR ADGRF5 fuels breast cancer progression by suppressing the MMP8-mediated antitumorigenic effects.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38937435","citation_count":13,"is_preprint":false},{"pmid":"36603001","id":"PMC_36603001","title":"The transcription factor Foxi1 promotes expression of V-ATPase and Gpr116 in M-1 cells.","date":"2023","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/36603001","citation_count":9,"is_preprint":false},{"pmid":"36895027","id":"PMC_36895027","title":"GPR116 receptor regulates the antitumor function of NK cells via Gαq/HIF1α/NF-κB signaling pathway as a potential immune checkpoint.","date":"2023","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/36895027","citation_count":9,"is_preprint":false},{"pmid":"41073785","id":"PMC_41073785","title":"Single-cell multi-omic and spatial profiling of esophageal squamous cell carcinoma reveals the immunosuppressive role of GPR116+ pericytes in cancer metastasis.","date":"2025","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41073785","citation_count":7,"is_preprint":false},{"pmid":"38228886","id":"PMC_38228886","title":"The adhesion GPCR GPR116/ADGRF5 has a dual function in pancreatic islets regulating somatostatin release and islet development.","date":"2024","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/38228886","citation_count":7,"is_preprint":false},{"pmid":"38844335","id":"PMC_38844335","title":"Glomerular Endothelial Cell Receptor Adhesion G-Protein-Coupled Receptor F5 (ADGRF5) and the Integrity of the Glomerular Filtration Barrier.","date":"2024","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/38844335","citation_count":7,"is_preprint":false},{"pmid":"30543664","id":"PMC_30543664","title":"Organic barn dust inhibits surfactant protein D production through protein kinase-c alpha dependent increase of GPR116.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30543664","citation_count":5,"is_preprint":false},{"pmid":"39001944","id":"PMC_39001944","title":"GPR116 alleviates acetaminophen-induced liver injury in mice by inhibiting endoplasmic reticulum stress.","date":"2024","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/39001944","citation_count":4,"is_preprint":false},{"pmid":"41237250","id":"PMC_41237250","title":"Hepatic hypertension on-a-chip identifies GPR116 as a hydrostatic pressure mechanosensor to regulate vascular injury in cirrhosis.","date":"2025","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/41237250","citation_count":3,"is_preprint":false},{"pmid":"40158793","id":"PMC_40158793","title":"Transcriptome analysis and CRISPR-Cas9-mediated mutagenesis identify gpr116 as a candidate gene for growth promotion in grass carp (Ctenopharyngodon idella).","date":"2025","source":"Comparative biochemistry and physiology. Part A, Molecular & integrative physiology","url":"https://pubmed.ncbi.nlm.nih.gov/40158793","citation_count":2,"is_preprint":false},{"pmid":"41796902","id":"PMC_41796902","title":"Endothelial ADGRF5(GPR116) governs vascular adaptation required for sustained thermogenic remodeling of brown adipose tissue.","date":"2026","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/41796902","citation_count":0,"is_preprint":false},{"pmid":"42233720","id":"PMC_42233720","title":"Adhesion G protein-coupled receptor F5 (ADGRF5) mediates shear stress mechanotransduction in glomerular endothelial cells.","date":"2026","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/42233720","citation_count":0,"is_preprint":false},{"pmid":"42081321","id":"PMC_42081321","title":"Serum Exosomal ADGRF5: A Potential Diagnostic Biomarker for Metastasis in Triple-Negative Breast Cancer.","date":"2026","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/42081321","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.31.683372","title":"Endothelial deletion of ADGRF5 (GPR116) promotes fibro-inflammatory EndMT and impairs adaptive thermogenesis in brown adipose tissue","date":"2025-10-31","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.31.683372","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.20.24313547","title":"Artificial intelligence and omics-based autoantibody profiling highlights autoimmunity targeting ligand-receptor interaction in dementia","date":"2024-09-23","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.20.24313547","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.23.604746","title":"Contrastive Learning for Graph-Based Biological Interaction Discovery: Insights from Oncologic Pathways","date":"2024-07-24","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.23.604746","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19231,"output_tokens":6442,"usd":0.077161,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15490,"output_tokens":4892,"usd":0.099875,"stage2_stop_reason":"end_turn"},"total_usd":0.177036,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"GPR116 promotes breast cancer cell migration and invasion through the Gαq-p63RhoGEF-RhoA/Rac1 pathway, modulating lamellipodia formation and actin stress fibers in a RhoA- and Rac1-dependent manner.\",\n      \"method\": \"Knockdown in MDA-MB-231 cells, ectopic expression in MCF-7/Hs578T cells, in vivo mammary tumor metastasis mouse models, pathway dissection via Gαq-p63RhoGEF-RhoA/Rac1 signaling analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD/KO with defined cellular phenotype plus pathway placement, single lab but multiple orthogonal methods (in vitro and in vivo)\",\n      \"pmids\": [\"24008316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GPR116 expression in alveolar type II (ATII) cells is required for maintaining normal pulmonary surfactant homeostasis; global and conditional knockout mice show progressive surfactant lipid and protein accumulation, labored breathing, and reduced lifespan.\",\n      \"method\": \"Global Gpr116 gene disruption in mice, bone marrow transplantation studies, conditional knockout mice with cell-type-specific deletion, surfactant structure/function analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — independently replicated across multiple labs using genetic KO models with clear cellular and molecular phenotypic readout\",\n      \"pmids\": [\"23684610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Surfactant protein D (SP-D) was identified as a ligand of Ig-Hepta/GPR116; GPR116 on alveolar type II cells senses surfactant levels by monitoring SP-D concentration, and its signaling attenuates surfactant lipid/protein synthesis and secretion while stimulating surfactant recycling/uptake.\",\n      \"method\": \"Co-expression of SP-D and extracellular region of Ig-Hepta/GPR116 followed by immunoprecipitation; radioactive tracer studies of surfactant metabolism in wildtype vs knockout mice\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ligand identification by co-IP plus in vivo metabolic tracing, single lab with two orthogonal methods\",\n      \"pmids\": [\"23922714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GPR116 functions as a molecular sensor of alveolar surfactant lipid pool sizes by regulating surfactant secretion; knockout mice show 12–30-fold accumulation of alveolar surfactant phospholipids with increased saturated phosphatidylcholine synthesis; P2RY2 purinergic receptor is induced in knockout type II cells.\",\n      \"method\": \"Targeted mutation of Gpr116 locus (Gpr116Δexon17) in mice, mRNA microarray analyses, lipid quantification\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated genetic KO model with quantitative molecular phenotype across multiple labs\",\n      \"pmids\": [\"23590306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Ig-Hepta/GPR116 undergoes multiple proteolytic processing events yielding four fragments (presequence, proEGF2/alpha, Ig repeats/beta-chain, TM7/gamma-chain); the proEGF2 region is cleaved by furin to generate EGF2 and the alpha-fragment influences expression of some mRNA species.\",\n      \"method\": \"Biochemical characterization of processing fragments, furin inhibitor experiments, mRNA expression analysis\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro biochemical identification of cleavage sites and processing enzyme (furin), single lab\",\n      \"pmids\": [\"16882675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GPR116/ADGRF5 controls surfactant secretion and reuptake in alveolar type II cells via Gq/11 signaling; synthetic agonist peptides derived from the GPR116 ectodomain activated Gq/11-dependent inositol phosphate conversion, calcium mobilization, and cortical F-actin stabilization to inhibit surfactant secretion; AT2 cell-specific deletion of Gnaq and Gna11 phenocopied GPR116 knockout surfactant accumulation.\",\n      \"method\": \"Synthetic tethered agonist peptides, inositol phosphate conversion assay, calcium mobilization assay, F-actin imaging, AT2 cell-specific Gnaq/Gna11 double knockout mice\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal in vitro and in vivo methods (biochemical signaling assays + epistatic genetic rescue), mechanistic pathway established\",\n      \"pmids\": [\"28570277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss of Gpr116 in mice causes cerebral vascular leakage beginning at ~1.5 months; endothelial-specific deletion of Gpr116 results in significant increase of brain vascular leakage, and Gpr116 knockout mice show attenuated pathological retinal vascular response in oxygen-induced retinopathy, indicating Gpr116 modulates endothelial barrier properties.\",\n      \"method\": \"Constitutive Gpr116 knockout mouse model (exon 4–21 deletion), endothelial-specific conditional knockout, oxygen-induced retinopathy model, vascular permeability assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endothelial-specific KO with defined vascular permeability phenotype, single lab\",\n      \"pmids\": [\"26394398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Ig-Hepta/GPR116 deficiency leads to activation of alveolar macrophages producing reactive oxygen species, NF-κB activation and nuclear translocation in alveolar macrophages, and release of MMP-2 and MMP-9; monocyte chemotactic protein-1 (MCP-1) is elevated in embryonic lungs of knockout mice, suggesting GPR116 regulates macrophage immune responses.\",\n      \"method\": \"Analysis of bronchoalveolar lavage fluid from knockout mice, ROS detection, NF-κB immunofluorescence, MMP inhibitor experiments, MCP-1 ELISA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with multiple downstream molecular readouts, single lab\",\n      \"pmids\": [\"25778400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss of both GPR116 and ELTD1 (but not either alone) in mice causes aortic arch artery and cardiac outflow tract malformations, renal thrombotic microangiopathy, hemolysis, and splenomegaly; these phenotypes are not recapitulated by endothelial- or neural crest-specific double deletions, indicating expression in non-endothelial, non-neural crest cells accounts for these defects.\",\n      \"method\": \"Double knockout mouse model, endothelial-specific and neural crest-specific conditional double knockouts, histological and cardiovascular analyses\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via double KO and cell-type-specific conditional KO, single lab\",\n      \"pmids\": [\"28806758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Adipose tissue-specific deletion of Gpr116 in mice causes glucose intolerance and insulin resistance, hepatosteatosis, reduced circulating adiponectin, and increased serum resistin, indicating GPR116 controls adipocyte biology and systemic energy homeostasis.\",\n      \"method\": \"Adipose tissue-specific conditional Gpr116 knockout mice on standard chow and high-fat diet, glucose tolerance tests, insulin tolerance tests, serum adipokine measurements\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with defined metabolic phenotype, single lab\",\n      \"pmids\": [\"22971422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FNDC4 (a hepatokine) directly binds GPR116 in white adipose tissue with high affinity; sFNDC4 binding to GPR116 promotes insulin signaling and insulin-mediated glucose uptake in white adipocytes; GPR116 mediates the insulin-sensitizing effects of FNDC4 in a white-adipocyte-selective manner.\",\n      \"method\": \"Direct binding assay (high-affinity binding of sFNDC4 to GPR116), GPR116 knockout mice, FcsFNDC4 supplementation in prediabetic mice, glucose uptake assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct ligand-receptor binding established, multiple orthogonal in vitro and in vivo methods, replicated in prediabetic mouse model\",\n      \"pmids\": [\"34016966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Kidney-specific knockout of Gpr116 causes urinary acidification (reduced urine pH), increased blood pH, decreased pCO2, and greater accumulation of V-ATPase at the apical surface of acid-secreting A-intercalated cells; pretreatment with synthetic Gpr116 agonist peptide inhibits proton flux in intercalated cells; Gpr116 tonically inhibits V-ATPase trafficking and urinary acid secretion in the collecting duct.\",\n      \"method\": \"Kidney-specific Gpr116 knockout mice, immunogold electron microscopy of V-ATPase localization, split-open collecting duct proton flux assay with synthetic agonist peptide, blood gas analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — tissue-specific KO with defined molecular phenotype (V-ATPase trafficking), functional rescue with synthetic agonist, multiple orthogonal methods\",\n      \"pmids\": [\"33004624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss of ADGRF5 in mice results in upregulation of CCL2, S100a8, and S100a9 in embryonic and neonatal lungs and in lung endothelial cells; RS504393 (CCR2 antagonist) treatment suppressed downstream inflammatory gene upregulation, placing ADGRF5-mediated CCL2 signaling upstream of airway inflammation including type 2 immune responses.\",\n      \"method\": \"Adgrf5 knockout mice, qPCR and western blotting of primary lung endothelial cells, pharmacological intervention with RS504393, histology, BAL cell counting, ELISA\",\n      \"journal\": \"Respiratory research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO model with pathway placement via pharmacological intervention, single lab, multiple readouts\",\n      \"pmids\": [\"30654796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GPR116 maintains the muscle stem cell (MuSC) pool via nuclear functions of β-arrestin1; Stachel (tethered agonist) peptide stimulation of GPR116 leads to strong β-arrestin interaction and increased nuclear localization of β-arrestin1, where it interacts with CREB to regulate gene expression; GPR116-deficient MuSCs show progressive depletion and defective self-renewal.\",\n      \"method\": \"Gpr116 knockout mice, Stachel peptide stimulation, β-arrestin interaction assays, nuclear fractionation/localization studies, CREB co-immunoprecipitation, MuSC isolation and self-renewal assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with pathway placement, β-arrestin nuclear interaction identified by co-IP/fractionation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36384129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Autocatalytic cleavage upstream of the GPR116 tethered agonist (Stachel) sequence is required for N-terminal fragment (NTF) displacement and receptor activation; a non-cleavable GPR116 knock-in mouse phenocopies the pulmonary phenotype of GPR116 knockout mice; key conserved amino acids in the Stachel sequence and ECL2/3 are required for receptor activation, and residues in TM7 mediate stronger signaling in mouse vs. human GPR116.\",\n      \"method\": \"Non-cleavable knock-in mouse model, site-directed mutagenesis, species-swapping approaches, in vitro signaling assays, molecular modeling of tethered agonist:ECL2 interactions\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo knock-in phenocopy plus in vitro mutagenesis plus species-swapping, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"36073784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ADGRF5/Gpr116 is highly expressed in CNS endothelium and regulates blood-brain barrier formation; Adgrf5 mutant retinae show increased perivenous vascular density and abnormal projections toward the inner plexus, with transient vascular protrusions into the inner retinal space, implicating ADGRF5 in vein-derived endothelial patterning of the deep retinal layer.\",\n      \"method\": \"Adgrf5 knockout mouse model, retinal vascular imaging, endothelial-specific analyses, comparison with Rac1 knockout retinae\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO model with defined vascular morphogenetic phenotype, single lab\",\n      \"pmids\": [\"31256320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GPR116 promotes ferroptosis in sepsis-induced liver injury by inhibiting the system Xc-/GSH/GPX4 pathway, aggravating mitochondrial damage and lipid peroxidation; hepatocyte-specific GPR116 deletion prevents hepatic ferroptosis and alleviates sepsis-induced liver dysfunction.\",\n      \"method\": \"Hepatocyte-specific GPR116 knockout mice (in vivo sepsis model), GPR116 overexpression experiments, measurement of system Xc-/GSH/GPX4 pathway components, mitochondrial and lipid peroxidation assays\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO with defined molecular pathway, overexpression confirmation, single lab\",\n      \"pmids\": [\"37266730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In breast cancer cells, ADGRF5 inhibits ERK1/2 activity by enhancing RhoA activation, leading to decreased phosphorylation of C/EBPβ at Thr235, hindering its nuclear translocation and subsequent MMP8 transcriptional activation; ADGRF5 silencing increases MMP8 expression, CXCL8 secretion, and shifts tumor-associated neutrophils toward antitumor N1 phenotype.\",\n      \"method\": \"ADGRF5 knockdown in breast cancer cells, RhoA activation assays, ERK1/2 phosphorylation, C/EBPβ Thr235 phosphorylation and nuclear translocation, MMP8 promoter analysis, in vivo tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined molecular pathway (RhoA→ERK→C/EBPβ→MMP8), multiple downstream readouts, single lab\",\n      \"pmids\": [\"38937435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GPR116 is expressed in pancreatic delta cells and regulates somatostatin release; whole-body GPR116 deficiency also causes decreased beta-cell mass, lower number of small islets, and reduced pancreatic insulin content; glucose homeostasis in global knockout mice is maintained by counter-acting mechanisms modulating insulin degradation.\",\n      \"method\": \"Whole-body and cell-specific Gpr116 knockout mouse models, islet hormone secretion assays, histomorphometry of pancreatic islets, insulin content measurement\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO with defined secretory phenotype, single lab\",\n      \"pmids\": [\"38228886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GPR116 protects against acetaminophen-induced liver injury by interacting with β-arrestin1, which in turn inhibits BiP (a critical ER stress regulator), thereby mitigating ER stress; activation of GPR116 by its ligand FNDC4 confers protection against early hepatotoxicity.\",\n      \"method\": \"Hepatocyte-specific GPR116 knockout mice, GPR116 overexpression, co-immunoprecipitation of GPR116 with β-arrestin1 and BiP, RNA-sequencing, APAP challenge model, FNDC4 treatment\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP establishing protein-protein interaction, KO and overexpression with mechanistic pathway, single lab\",\n      \"pmids\": [\"39001944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ADGRF5 loss in glomerular endothelial cells alters expression of type IV collagens (COL4A3, COL4A4) and the mechanosensitive transcription factor KLF2, leading to glomerular filtration barrier dysfunction, albuminuria, and impaired kidney function; ADGRF5 knockdown in human primary glomerular endothelial cells reproduces these gene expression changes.\",\n      \"method\": \"Adgrf5 knockout mice (histology, kidney function tests), ADGRF5 siRNA knockdown in human primary glomerular endothelial cells, gene/protein expression analysis\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model plus human cell knockdown with defined gene expression and functional outcomes, single lab\",\n      \"pmids\": [\"38844335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GPR116 negatively regulates NK cell antitumor function via the Gαq/HIF1α/NF-κB signaling pathway; GPR116-deficient NK cells show higher cytotoxicity and produce more GzmB and IFNγ; downregulation of GPR116 in NKG2D-CAR-NK92 cells enhances their antitumor activity.\",\n      \"method\": \"GPR116 knockout mice, in vitro NK cell cytotoxicity assays, in vivo tumor models with GPR116-/- NK cells, pathway analysis (Gαq/HIF1α/NF-κB)\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO model with defined cellular phenotype and pathway placement, single lab, in vitro and in vivo validation\",\n      \"pmids\": [\"36895027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GPR116 was identified as the key hydrostatic pressure mechanosensor in liver sinusoidal endothelial cells (LSECs); genetic silencing of GPR116 protected endothelial cells from hydrostatic pressure-induced damage in vitro and in cirrhotic murine models, and its downstream mechanotransduction pathway was delineated.\",\n      \"method\": \"Hepatic hypertension-on-a-chip system (2D static and 3D dynamic), genetic silencing of GPR116 in LSECs, cirrhotic murine models, cell- and gene-based therapies\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel in vitro mechanosensing model plus in vivo validation with genetic silencing, single lab\",\n      \"pmids\": [\"41237250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ADGRF5 mediates shear stress mechanotransduction in glomerular endothelial cells via the Gαq/11-PKC-RAF1-MEK1/2-ERK1/2 cascade; activation requires the tethered agonist (Stachel) sequence and C-terminal helix 8; ADGRF5 knockdown attenuates shear flow-induced immediate early response genes and COL4A3/COL4A4 expression in human primary renal glomerular endothelial cells.\",\n      \"method\": \"ADGRF5 overexpression in PEAKrapid cells under laminar flow, inhibitor and knockdown experiments, mutagenesis of Stachel sequence and helix 8, endogenous validation in human primary renal glomerular endothelial cells\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mechanistic pathway established by mutagenesis, inhibitor dissection, and endogenous validation with multiple orthogonal methods in one study\",\n      \"pmids\": [\"42233720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Organic barn dust increases GPR116 mRNA expression via protein kinase C alpha (PKCα) signaling, which in turn inhibits SP-D (surfactant protein D) production in alveolar epithelial cells; PKCα inhibition reverses both GPR116 upregulation and SP-D suppression.\",\n      \"method\": \"PKCα inhibitor experiments in human alveolar epithelial cell line and in vivo mouse model, mRNA and protein expression analysis of SP-D and GPR116\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological inhibition with single-method expression readouts, single lab\",\n      \"pmids\": [\"30543664\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADGRF5/GPR116 is an adhesion GPCR that is activated via a tethered agonist (Stachel) mechanism requiring autocatalytic cleavage; it couples primarily to Gαq/11 signaling to regulate diverse physiological processes including pulmonary surfactant homeostasis in alveolar type II cells (inhibiting secretion and promoting recycling), renal acid secretion via tonic inhibition of V-ATPase trafficking in intercalated cells, insulin sensitization in white adipocytes through direct high-affinity binding of the hepatokine FNDC4, NK cell and muscle stem cell function via β-arrestin1 nuclear signaling, and endothelial mechanotransduction (including shear stress and hydrostatic pressure sensing) through Gαq/11-PKC-ERK cascades; it also promotes breast cancer metastasis via Gαq-p63RhoGEF-RhoA/Rac1-dependent actin remodeling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADGRF5 (GPR116/Ig-Hepta) is an adhesion G-protein-coupled receptor that acts as a cell-surface sensor coupling extracellular cues to Gαq/11 signaling across epithelial, endothelial, immune, and stem cell compartments [#1, #5, #14]. Like other adhesion GPCRs, it requires autocatalytic cleavage upstream of its tethered agonist (Stachel) sequence so that N-terminal fragment displacement exposes the agonist and activates the receptor; a non-cleavable knock-in mouse phenocopies the knockout pulmonary defect, establishing that this self-cleavage is obligatory for function in vivo, and the C-terminal helix 8 together with conserved Stachel and ECL2/3 residues are required for downstream signaling [#14, #23]. Its best-defined role is in alveolar type II cells, where it senses surfactant levels — monitoring the ligand SP-D — and drives Gαq/11-dependent inositol phosphate turnover, calcium mobilization, and cortical F-actin stabilization to restrain surfactant secretion and promote recycling; loss of GPR116 or of AT2 Gnaq/Gna11 causes massive surfactant accumulation and respiratory disease [#1, #2, #3, #5]. The receptor sustains epithelial transport homeostasis in the kidney, where it tonically inhibits V-ATPase trafficking and urinary acid secretion in intercalated cells [#11], and functions as an endothelial mechanosensor, transducing shear stress through a Gαq/11-PKC-RAF1-MEK-ERK cascade that controls type IV collagen and KLF2 expression at the glomerular filtration barrier [#20, #23] and serving as a hydrostatic-pressure sensor in liver sinusoidal endothelium [#22]. Beyond Gαq, GPR116 engages β-arrestin1 signaling: Stachel stimulation drives nuclear β-arrestin1 that interacts with CREB to maintain the muscle stem cell pool [#13], and β-arrestin1 mediates hepatoprotection against ER stress [#19]. The hepatokine FNDC4 binds GPR116 with high affinity to sensitize white adipocytes to insulin, linking the receptor to systemic glucose and energy homeostasis [#9, #10]. In cancer, GPR116 promotes breast cancer migration and metastasis via Gαq-p63RhoGEF-RhoA/Rac1-driven actin remodeling and suppresses an antitumor neutrophil program through a RhoA-ERK-C/EBPβ-MMP8 axis [#0, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that GPR116 is a multiply processed adhesion-type receptor, defining the proteolytic architecture that would later prove essential for activation.\",\n      \"evidence\": \"biochemical fragment characterization and furin-inhibitor experiments\",\n      \"pmids\": [\"16882675\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"did not link cleavage to signaling or a physiological output\", \"Stachel-mediated activation not yet recognized\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"First physiological role assigned to GPR116, showing adipose-specific deletion disrupts systemic glucose and energy homeostasis.\",\n      \"evidence\": \"adipose-specific conditional knockout mice with metabolic phenotyping\",\n      \"pmids\": [\"22971422\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no ligand or signaling pathway identified\", \"molecular mechanism in adipocytes unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the receptor's flagship role as an alveolar surfactant sensor and identified SP-D as a candidate ligand, answering what GPR116 detects and what it controls in the lung.\",\n      \"evidence\": \"global and conditional knockout mice, surfactant lipid/protein metabolic tracing, and co-IP of SP-D with the ectodomain\",\n      \"pmids\": [\"23684610\", \"23922714\", \"23590306\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"G protein coupling not yet demonstrated\", \"whether SP-D is the activating agonist versus a co-factor unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed GPR116 in a cancer-promoting signaling pathway, linking it to Gαq-p63RhoGEF-RhoA/Rac1-driven actin dynamics and metastasis.\",\n      \"evidence\": \"knockdown/ectopic expression in breast cancer lines plus in vivo metastasis models with pathway dissection\",\n      \"pmids\": [\"24008316\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"receptor activation mechanism in tumor cells not defined\", \"endogenous activating ligand unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended GPR116 function to vascular barrier maintenance and immune regulation, showing endothelial deletion causes vascular leakage and loss provokes alveolar macrophage inflammation.\",\n      \"evidence\": \"endothelial-specific conditional knockout, oxygen-induced retinopathy model, and BAL/ROS/NF-κB/MMP analyses in knockout mice\",\n      \"pmids\": [\"26394398\", \"25778400\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanotransduction mechanism not yet delineated\", \"macrophage effects could be secondary to surfactant pathology\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established the core signaling logic: tethered-agonist peptides activate Gαq/11 to inhibit surfactant secretion, and AT2 Gnaq/Gna11 deletion phenocopies the knockout, proving the effector pathway.\",\n      \"evidence\": \"synthetic Stachel peptides, IP/calcium/F-actin assays, and AT2-specific Gnaq/Gna11 double knockout mice\",\n      \"pmids\": [\"28570277\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"did not prove cleavage requirement in vivo\", \"endogenous trigger for Stachel exposure unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed functional overlap with ELTD1 in non-endothelial cells controlling cardiovascular and renal development through genetic epistasis.\",\n      \"evidence\": \"single and double knockout plus cell-type-specific conditional double knockout mice\",\n      \"pmids\": [\"28806758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"responsible cell type not identified\", \"molecular basis of ADGRF5/ELTD1 redundancy unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected GPR116 loss to specific inflammatory and vascular-patterning programs, positioning CCL2/CCR2 signaling downstream and implicating the receptor in CNS endothelial and retinal vascular morphogenesis.\",\n      \"evidence\": \"knockout mice with CCR2-antagonist intervention; retinal vascular imaging compared with Rac1 knockout\",\n      \"pmids\": [\"30654796\", \"31256320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether inflammatory changes are cell-autonomous unresolved\", \"link between receptor signaling and CCL2 induction not mechanistically traced\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a renal epithelial role, showing GPR116 tonically inhibits V-ATPase trafficking to restrain urinary acid secretion, with synthetic agonist functionally rescuing proton flux.\",\n      \"evidence\": \"kidney-specific knockout mice, immunogold EM of V-ATPase, split-open duct proton flux with agonist peptide, and blood gas analysis\",\n      \"pmids\": [\"33004624\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"physiological ligand in the collecting duct unknown\", \"G protein/effector linking receptor to V-ATPase trafficking not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified FNDC4 as a direct high-affinity ligand mediating the receptor's white-adipocyte insulin-sensitizing function, providing a molecular ligand for the 2012 metabolic phenotype.\",\n      \"evidence\": \"direct binding assay, knockout mice, FcsFNDC4 supplementation in prediabetic mice, and glucose uptake assays\",\n      \"pmids\": [\"34016966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"whether FNDC4 acts as a Stachel-exposing agonist or allosteric modulator unresolved\", \"G protein/arrestin branch driving insulin sensitization not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated obligatory autocatalytic cleavage for activation and a β-arrestin1 branch, showing a non-cleavable knock-in phenocopies the lung defect and that nuclear β-arrestin1-CREB signaling maintains muscle stem cells.\",\n      \"evidence\": \"non-cleavable knock-in mice, mutagenesis/species-swapping, Stachel stimulation, β-arrestin nuclear fractionation, and CREB co-IP\",\n      \"pmids\": [\"36073784\", \"36384129\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"structural basis of Stachel:ECL engagement modeled but not solved\", \"balance between Gαq and β-arrestin branches across tissues unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Expanded GPR116 into immune and hepatic injury contexts, showing it negatively regulates NK antitumor function via Gαq/HIF1α/NF-κB and promotes hepatocyte ferroptosis by suppressing the system Xc-/GSH/GPX4 axis.\",\n      \"evidence\": \"knockout mice and NK cytotoxicity/tumor models; hepatocyte-specific knockout and overexpression with ferroptosis pathway readouts\",\n      \"pmids\": [\"36895027\", \"37266730\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"activating ligands in NK cells and hepatocytes unidentified\", \"direct receptor-to-pathway coupling steps incompletely defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the receptor as an endothelial mechanosensor and refined its β-arrestin1 and RhoA-ERK signaling roles in kidney filtration, hepatoprotection, breast cancer neutrophil polarization, and pancreatic islet biology.\",\n      \"evidence\": \"glomerular endothelial knockout/human-cell knockdown, β-arrestin1/BiP co-IP with APAP/FNDC4 models, RhoA-ERK-C/EBPβ-MMP8 dissection, and islet-specific knockout secretion assays\",\n      \"pmids\": [\"38844335\", \"39001944\", \"38937435\", \"38228886\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"how a single receptor selects Gαq versus β-arrestin outputs by tissue unresolved\", \"force-to-Stachel coupling mechanism not directly shown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Confirmed GPR116 as a pressure/shear mechanosensor in vascular endothelium and delineated its shear cascade, establishing the full Gαq/11-PKC-RAF1-MEK-ERK pathway with Stachel and helix 8 requirements.\",\n      \"evidence\": \"hepatic hypertension-on-a-chip with LSEC silencing and cirrhotic models; flow assays with inhibitor/knockdown/mutagenesis and human primary glomerular endothelial validation\",\n      \"pmids\": [\"41237250\", \"42233720\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"physical mechanism converting force into NTF displacement not directly demonstrated\", \"in vivo relevance of helix 8 requirement untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how GPR116 physically converts diverse stimuli (SP-D, FNDC4, shear, hydrostatic pressure) into tethered-agonist exposure, and what governs the tissue-specific choice between Gαq/11 and β-arrestin1 signaling outputs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no atomic structure of the activated receptor\", \"no unified model linking ligand binding, force, and cleavage-dependent activation\", \"determinants of Gαq-versus-arrestin bias unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [5, 14, 23]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [2, 3, 22, 23]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [2, 10]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 11, 14, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 14, 23]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [3, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [21, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FNDC4\", \"SP-D (SFTPD)\", \"ARRB1\", \"GNAQ\", \"GNA11\", \"CREB\", \"BiP (HSPA5)\", \"ELTD1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}