{"gene":"ADGRL4","run_date":"2026-06-09T22:02:42","timeline":{"discoveries":[{"year":2000,"finding":"ETL (ADGRL4) encodes a 738-aa seven-transmembrane receptor with a large extracellular domain containing EGF-like repeats. In COS-7 cells transfected with Myc-tagged rat ETL, the protein exists as a stable dimer and undergoes endoproteolytic cleavage of the extracellular domain. The proteolytic activity is abolished by the specific mutation T455A. In transfected mammalian cells, ETL is associated with cell membranes and is also observed in cytoplasmic vesicles.","method":"Myc-tagged receptor transfection in COS-7 cells, site-directed mutagenesis (T455A), immunofluorescence/subcellular fractionation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-directed mutagenesis identifying cleavage site plus subcellular localization, single lab","pmids":["11050079"],"is_preprint":false},{"year":2013,"finding":"ELTD1 expression in tumor-associated endothelial cells is induced by VEGF/bFGF signaling and repressed by DLL4/Notch signaling. ELTD1 silencing impairs endothelial sprouting and vessel formation in vitro and in vivo, drastically reducing tumor growth.","method":"siRNA silencing, in vitro sprouting assays, in vivo tumor models, transcriptional pathway analysis","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (siRNA KD, in vitro angiogenesis assays, in vivo tumor models), replicated across multiple cancer types in one rigorous study","pmids":["23871637"],"is_preprint":false},{"year":2012,"finding":"ELTD1 deficiency in mice exacerbates pressure overload-induced cardiac hypertrophy and fibrosis, associated with enhanced ERK and JNK phosphorylation, indicating ELTD1 normally suppresses these MAPK pathways in the context of cardiac stress.","method":"ELTD1-knockout mice subjected to aortic banding (pressure overload), Western blot for phospho-ERK and phospho-JNK, histological analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined phenotype and pathway readout (ERK/JNK phosphorylation), single lab","pmids":["22606234"],"is_preprint":false},{"year":2017,"finding":"Loss of both GPR116 (ADGRF5) and ELTD1 (ADGRL4) in mice causes aortic arch malformations, cardiac outflow tract defects, and postnatal renal thrombotic microangiopathy. Loss of either receptor alone had no obvious cardiovascular or kidney phenotype, indicating functional redundancy. Endothelial-specific or neural crest-specific deletion of both receptors did not recapitulate the phenotype, indicating the relevant expression is in non-endothelial, non-neural-crest cells.","method":"ELTD1 and GPR116 single and double knockout mice, conditional cell-type-specific knockouts, histological and cardiovascular phenotyping","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with double KO and conditional KO in multiple cell types, single lab","pmids":["28806758"],"is_preprint":false},{"year":2019,"finding":"ELTD1 silencing in endothelial cells induces expression of ACLY (cytoplasmic metabolic regulator) and SLC25A1 (mitochondria-to-cytoplasm citrate transporter), upregulates DLL4, and suppresses JAG1 and HES2, indicating ELTD1 regulates Notch ligand balance in endothelial cells. Metabolomics showed altered pyrimidine, amino acid, and sugar metabolism upon ELTD1 silencing.","method":"Two independent siRNAs for ELTD1 knockdown in HUVECs, transcriptional profiling, target gene validation (qPCR/Western blot), liquid chromatography–mass spectrometry metabolomics","journal":"Metabolites","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent siRNAs plus orthogonal transcriptomic and metabolomic readouts, single lab","pmids":["31775252"],"is_preprint":false},{"year":2019,"finding":"ELTD1 activates the JAK/STAT3/HIF-1α signaling axis in glioma cells; p-STAT3 binds with HIF-1α. ELTD1 high expression promotes proliferation, migration, invasion, and orthotopic xenograft tumor growth.","method":"qRT-PCR, Western blotting, cell proliferation assays, Matrigel migration/invasion assays, brain orthotopic xenografts, co-immunoprecipitation/interaction assays for p-STAT3 and HIF-1α","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays plus pathway analysis and in vivo model, single lab","pmids":["31554859"],"is_preprint":false},{"year":2021,"finding":"ELTD1 overexpression in endothelial cells promotes sprouting angiogenesis and decreases in vitro anastomoses without activating canonical GPCR signaling (Gq, Gs, G12, Go, β-arrestin) or MAPK/ERK, PI3K/AKT, JNK, JAK/HIF-1α, beta-catenin, or STAT3 pathways. Full-length and C-terminal fragment constructs, as well as Stachel peptides, failed to activate canonical GPCR signaling in HEK293T cells. Overexpression upregulated JAG1 and downregulated DLL4, modulating the endothelial tip-cell phenotype.","method":"Stable ADGRL4/ELTD1-overexpressing HUVEC line, HEK293T transfection, HTRF FRET/luciferase reporter/Alphascreen GPCR signalling assays, angiogenesis assays, transcriptional profiling","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal GPCR signalling assays definitively showing no canonical coupling, plus functional angiogenesis readout with transcriptional profiling; negative canonical signalling result is itself mechanistically informative","pmids":["33893326"],"is_preprint":false},{"year":2021,"finding":"ELTD1 overexpression in endothelial cells results in endothelial-to-mesenchymal transition (EndMT) to a myofibroblast-like phenotype: loss of cell-cell contact, formation of stress fibers and mature focal adhesions, and increased smooth muscle actin expression. This transition is pro-angiogenic and associated with large increases in chemokines and cytokines regulating immune response. RNA-Seq identified pathways involved in myofibroblast biology (type II EMT).","method":"ELTD1 overexpression in endothelial cells, immunofluorescence for cytoskeletal markers, Matrigel network formation and sprouting assays, RNA-Seq with gene set enrichment analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression with multiple morphological/functional readouts plus transcriptomics, single lab","pmids":["34681953"],"is_preprint":false},{"year":2021,"finding":"ELTD1 promotes invasion and metastasis of colorectal cancer cells by accelerating the transcriptional activity of MMP2; MMP2 re-expression can rescue the impaired invasiveness caused by ELTD1 downregulation.","method":"siRNA knockdown and overexpression of ELTD1 in CRC cells, Matrigel invasion assays, in vivo metastasis models, MMP2 promoter activity assays, rescue experiments","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue experiment placing ELTD1 upstream of MMP2 transcriptional activity, in vitro and in vivo, single lab","pmids":["34421349"],"is_preprint":false},{"year":2021,"finding":"ELTD1 promotes gastric cancer proliferation, invasion, and EMT through MAPK/ERK signaling by interacting with and inhibiting C-terminal Src kinase (CSK). ELTD1 knockdown inhibits GC cell proliferation, migration, and invasion in vitro and in vivo, while overexpression has the opposite effect.","method":"siRNA knockdown, ELTD1 overexpression, Western blot for MAPK/ERK pathway, co-immunoprecipitation for ELTD1-CSK interaction, in vitro/in vivo functional assays","journal":"International journal of general medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP establishing ELTD1-CSK interaction plus downstream pathway activation with in vivo validation, single lab","pmids":["34475781"],"is_preprint":false},{"year":2021,"finding":"ELTD1 expression in murine breast cancer cells increases tumor growth and metastasis, enlarges vessel size and perfusion, and creates an immunosuppressive microenvironment with increased M2-like macrophages and PD-L1 expression via tumor-endothelial cell crosstalk releasing proangiogenic and immune-modulating factors.","method":"Syngeneic immunocompetent mouse breast cancer models with recombinant murine Eltd1 expression, histological analysis, flow cytometry, in vivo tumor growth/metastasis assays","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — syngeneic in vivo model with multiple phenotypic readouts and mechanistic characterization, single lab","pmids":["34348993"],"is_preprint":false},{"year":2022,"finding":"ELTD1 deletion in mice improves tumor vascular function in orthotopic glioma, with transcriptional profiling of isolated tumor endothelial cells showing increased inflammatory response and decreased proliferation pathways. ELTD1 deletion also improves T-cell infiltration after PD-1 checkpoint blockade.","method":"ELTD1-/- mice with orthotopic glioma models, endothelial cell isolation and transcriptional profiling, tumor vascular function assays, PD-1 antibody treatment, immune infiltrate analysis","journal":"Neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with mechanistic transcriptional profiling plus functional immune readout, single lab","pmids":["34347079"],"is_preprint":false},{"year":2022,"finding":"STAT5A directly regulates ELTD1 transcription (demonstrated by ChIP and luciferase assay). High glucose-induced STAT5A nuclear translocation leads to increased ELTD1 expression, which in turn promotes endothelial-to-mesenchymal transition (EndMT) in diabetic nephropathy. ELTD1 silencing reverses high glucose-mediated EndMT, and STAT5A overexpression-induced EndMT is inhibited by si-ELTD1.","method":"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, siRNA silencing of ELTD1 and STAT5A, STAT5A overexpression in human glomerular endothelial cells, DN rat model","journal":"Clinical and experimental pharmacology & physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus luciferase assay establishing direct transcriptional regulation, with functional epistasis via rescue, single lab","pmids":["35320597"],"is_preprint":false},{"year":2022,"finding":"A highly glycosylated form of the ELTD1 extracellular domain (ECD) is present in extracellular vesicles (EVs) derived from endothelial cells. ELTD1-enriched EVs are pro-angiogenic in vivo and in vitro, and the ECD alone is sufficient to induce endothelial sprouting. Under laminar flow (quiescent endothelium), ELTD1 levels in EVs are reduced. Elevated vesicular ELTD1 is detected in plasma of patients with preeclampsia.","method":"EV isolation and characterization, mass spectrometry-based proteomics, in vitro sprouting assay with purified ECD, in vivo angiogenesis assay, FACS for vesicular ELTD1 in patient plasma, laminar flow experiments","journal":"Journal of extracellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (proteomics, functional ECD assay, in vivo angiogenesis, patient samples), single lab","pmids":["38939053"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structure of ADGRL4 coupled to heterotrimeric Gq determined at 3.1 Å resolution. ADGRL4 couples weakly to Gq (demonstrated by bioluminescent assay) but shows no robust coupling to Gs, G12, Go, or β-arrestin 1 or 2. The coupling to Gq involves fewer interactions between receptor and G protein compared to other aGPCRs. The structure is consistent with activation by a tethered agonist (Stachel mechanism).","method":"Cryo-EM structure determination (3.1 Å), bioluminescent GPCR signalling assay, heterotrimeric Gq complex reconstitution","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure combined with functional signalling assay establishing weak Gq coupling and ruling out other G proteins; rigorous single study with structural and biochemical validation","pmids":["41469374"],"is_preprint":false},{"year":2025,"finding":"Ku80 (a DNA repair factor) and erythrocyte beta spectrin (SPTB) were identified as ligands for ELTD1 by affinity capture and mass spectrometry. Ku80 demonstrated higher potency in activating ELTD1 than SPTB. When recombinantly expressed in U87 cells, ELTD1 activates canonical GPCR pathways, particularly the Gq pathway. Conditioned medium from U87 cells activates ELTD1 in HEK293 cells, supporting an autocrine ELTD1-activating factor. INCA-X (antibody targeting ku80/ku70 complex) and ELTD1 siRNA impaired endothelial tube formation similarly, suggesting a common pathway.","method":"Affinity capture and mass spectrometry for ligand identification, xCelligence label-free functional assay, conditioned medium transfer assay, siRNA knockdown, endothelial tube formation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity capture MS for ligand identification plus functional activation assay and epistasis via siRNA/antibody, single lab; note this contrasts with Favara 2021 finding of no canonical GPCR signalling in a different cell system","pmids":["40245572"],"is_preprint":false},{"year":2025,"finding":"ELTD1 inhibits differentiation of hemogenic endothelium progenitors (HEPs) from hESCs through the HPIP-Wnt pathway. ELTD1 interacts physically with HPIP (protein-protein interaction), and HPIP modulates Wnt signaling through LEF1. Knockdown or deletion of ELTD1 facilitates HEP generation and promotes endothelial-to-hematopoietic transition; ELTD1 overexpression suppresses this. The ELTD1-HPIP-LEF1-Wnt regulatory axis governs HEP generation during early hematopoietic differentiation.","method":"ELTD1 gain- and loss-of-function experiments in hESCs, iCRISPR/Cas9 knockout, dynamic gene expression profiling, co-immunoprecipitation for ELTD1-HPIP interaction, luciferase/functional Wnt pathway assays, hematopoietic differentiation readouts","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP establishing ELTD1-HPIP interaction plus gain/loss-of-function with pathway epistasis, single lab","pmids":["40456828"],"is_preprint":false},{"year":2026,"finding":"Cellular stress induces ADGRL4 expression via the canonical JNK-ATF2/c-Jun pathway. Stress-induced shedding of the ADGRL4 N-terminal fragment activates the C-terminal fragment, which couples with Gαs to stimulate cAMP-PKA signaling and consequently suppress YAP1 activity. In the absence of ADGRL4, hyperactivated YAP1 forms a transcriptional complex with β-catenin to drive tumor growth. ADGRL4 simultaneously promotes angiogenesis extracellularly, creating dual tumor-suppressive and relapse-promoting effects.","method":"Loss-of-function and overexpression experiments, JNK pathway inhibition, cAMP/PKA signalling assays, YAP1 activity assays, co-immunoprecipitation for YAP1-β-catenin complex, in vivo tumor models","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway assays establishing Gαs/cAMP/PKA/YAP1 mechanism with in vivo validation, single lab, single study","pmids":["41734371"],"is_preprint":false},{"year":2026,"finding":"ADGRL4 activation promotes beige adipocyte differentiation, upregulates UCP1 expression, and reduces lipid droplet accumulation in vitro. In vivo, ADGRL4 activation induces beige fat development and reduces fat deposition and body weight in mice on high-fat diet. Mechanistically, ADGRL4 enhances AKT phosphorylation without altering total AKT levels, activating a downstream p-AKT/UCP1 signaling cascade driving adipose browning.","method":"In vitro beige adipocyte differentiation assays, ADGRL4 activation in cell lines, Western blot for p-AKT and UCP1, in vivo mouse models (normal chow and high-fat diet), metabolic phenotyping","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo functional assays with mechanistic p-AKT/UCP1 pathway readout, single lab, single study","pmids":["41740879"],"is_preprint":false},{"year":2025,"finding":"ADGRL4 cryo-EM structure determination (same finding as PMID 41469374, preprint version). ADGRL4 couples weakly to Gq; no coupling to Gs, G12, Go, or β-arrestins. Cryo-EM structure at 3.1 Å shows distinct Gq coupling with fewer receptor-G protein interactions versus other aGPCRs. Consistent with tethered agonist (Stachel) activation.","method":"Cryo-EM structure determination (3.1 Å), bioluminescent signalling assay, heterotrimeric Gq complex reconstitution","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Strong — same data as peer-reviewed PMID 41469374; preprint entry included for completeness but not independent replication","pmids":[],"is_preprint":true},{"year":2015,"finding":"miR-139-5p suppresses glioma cell proliferation by directly targeting ELTD1; luciferase and Western blot assays confirmed ELTD1 as a direct target of miR-139-5p, and miR-139-5p overexpression reduces ELTD1 protein levels and regulates cell cycle in GBM cells.","method":"miR-139-5p mimic transfection in GBM cell lines, luciferase reporter assay, Western blot, MTT/colony formation assays","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single luciferase/Western blot validation of miRNA-target relationship, single lab","pmids":["26449464"],"is_preprint":false},{"year":2021,"finding":"ELTD1 inhibition by siRNA decreases Y79 retinoblastoma cell migration in vitro and invasion in vivo in an orthotopic xenograft model. ELTD1 displays punctate clusters at cell-to-cell adhesion sites in Weri-Rb-1 cells (non-metastatic), while its subcellular localization at these sites is distinct from the polarized distribution of GPR125.","method":"siRNA knockdown of ELTD1 in Rb cell lines, migration assay (in vitro), orthotopic xenograft murine model for invasion (in vivo), immunofluorescence subcellular localization","journal":"BMC cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — siRNA with migration/invasion readout and localization imaging, single lab, single study","pmids":["33430814"],"is_preprint":false}],"current_model":"ADGRL4/ELTD1 is an orphan adhesion GPCR expressed predominantly in endothelial cells whose 3.1 Å cryo-EM structure reveals weak coupling to heterotrimeric Gq (with no robust coupling to other G proteins or β-arrestins) and activation consistent with a tethered Stachel agonist mechanism; it undergoes GPS-mediated endoproteolytic cleavage (abolished by T455A mutation), forms stable dimers, localizes to the plasma membrane and cytoplasmic vesicles, sheds its extracellular domain into pro-angiogenic extracellular vesicles, and regulates endothelial sprouting angiogenesis and endothelial-to-mesenchymal transition through pathways including Notch (DLL4/JAG1 balance), JAK/STAT3/HIF-1α, MAPK/ERK, and cAMP-PKA/YAP1 suppression, while its expression is transcriptionally induced by VEGF/bFGF, repressed by DLL4/Notch, and directly driven by STAT5A; newly identified ligands include Ku80 and beta spectrin, and ELTD1-HPIP-LEF1-Wnt signaling governs hemogenic endothelium progenitor differentiation from hESCs."},"narrative":{"mechanistic_narrative":"ADGRL4/ELTD1 is an orphan adhesion G-protein-coupled receptor expressed predominantly in endothelial cells that governs sprouting angiogenesis, endothelial plasticity, and vascular remodeling [PMID:23871637, PMID:33893326]. It is a seven-transmembrane receptor with a large extracellular domain bearing EGF-like repeats; it forms stable dimers and undergoes GPS-mediated endoproteolytic cleavage of its ectodomain, an activity abolished by the T455A mutation, and localizes to the plasma membrane and cytoplasmic vesicles [PMID:11050079]. Its 3.1 Å cryo-EM structure reveals coupling to heterotrimeric Gq through an unusually small receptor–G-protein interface, with no robust coupling to Gs, G12, Go, or β-arrestins, and an architecture consistent with tethered Stachel agonist activation [PMID:41469374]. The receptor sheds a glycosylated extracellular domain into pro-angiogenic extracellular vesicles, and the ECD alone is sufficient to drive endothelial sprouting [PMID:38939053]. In the vasculature, ADGRL4 expression is induced by VEGF/bFGF and repressed by DLL4/Notch signaling, and the receptor in turn balances Notch ligand expression (suppressing DLL4, promoting JAG1) to shape the endothelial tip-cell phenotype [PMID:23871637, PMID:33893326], while also driving endothelial-to-mesenchymal transition toward a myofibroblast-like state [PMID:34681953]. In disease contexts it is transcriptionally activated by STAT5A to promote EndMT in diabetic nephropathy [PMID:35320597] and acts in tumors through Notch ligand rebalancing, JAK/STAT3/HIF-1α signaling, MMP2 transcription, and creation of an immunosuppressive vascular microenvironment [PMID:31554859, PMID:34421349, PMID:34347079]. ADGRL4 also functions in non-angiogenic settings, restraining hemogenic endothelium progenitor differentiation via an HPIP–LEF1–Wnt axis [PMID:40456828] and a Gαs–cAMP–PKA cascade that suppresses YAP1 [PMID:41734371].","teleology":[{"year":2000,"claim":"Established the basic architecture of the receptor — a dimeric seven-transmembrane protein with an EGF-repeat ectodomain that is autoproteolytically cleaved — placing ADGRL4 within the adhesion GPCR paradigm of GPS cleavage.","evidence":"Myc-tagged rat ETL transfection in COS-7 cells with T455A site-directed mutagenesis and subcellular localization","pmids":["11050079"],"confidence":"Medium","gaps":["No ligand or downstream signaling identified","Functional consequence of cleavage and dimerization not addressed","Done in heterologous overexpression only"]},{"year":2012,"claim":"First in vivo loss-of-function evidence that ELTD1 restrains MAPK signaling in a physiological stress context, linking the receptor to cardiac remodeling.","evidence":"ELTD1-knockout mice with aortic banding, phospho-ERK/JNK Western blot and histology","pmids":["22606234"],"confidence":"Medium","gaps":["Mechanism connecting receptor to ERK/JNK not defined","Cell type responsible not resolved","No ligand identified"]},{"year":2013,"claim":"Positioned ELTD1 as a VEGF/Notch-regulated driver of tumor angiogenesis, defining its core endothelial function and therapeutic relevance.","evidence":"siRNA silencing, in vitro sprouting assays, and in vivo tumor models across cancer types","pmids":["23871637"],"confidence":"High","gaps":["Signaling output downstream of the receptor not defined","No ligand identified","G-protein coupling unknown"]},{"year":2017,"claim":"Genetic epistasis revealed functional redundancy with GPR116/ADGRF5 in cardiovascular and renal development, and that the relevant cells are neither endothelial nor neural crest.","evidence":"Single and double ELTD1/GPR116 knockout plus cell-type-specific conditional knockouts with cardiovascular phenotyping","pmids":["28806758"],"confidence":"Medium","gaps":["Identity of the relevant non-endothelial cell type unresolved","Molecular basis of redundancy unknown","No shared ligand/pathway defined"]},{"year":2019,"claim":"Connected ELTD1 to Notch ligand balance and endothelial metabolism, showing it suppresses DLL4 while supporting JAG1/HES2 and shapes citrate-related metabolic programs.","evidence":"Two independent siRNAs in HUVECs with transcriptional profiling and LC-MS metabolomics","pmids":["31775252"],"confidence":"Medium","gaps":["Direct vs indirect regulation of Notch ligands unclear","Receptor-proximal signaling not defined","Metabolic changes correlative"]},{"year":2019,"claim":"Defined a tumor-cell-intrinsic JAK/STAT3/HIF-1α axis activated by ELTD1 in glioma, extending its role beyond endothelium.","evidence":"qRT-PCR, Western blot, proliferation/invasion assays, orthotopic xenografts, and p-STAT3/HIF-1α co-IP","pmids":["31554859"],"confidence":"Medium","gaps":["How the receptor engages JAK/STAT3 mechanistically unknown","No ligand identified","Conflicts with later reports of no STAT3 activation in endothelium"]},{"year":2021,"claim":"A rigorous panel of GPCR signaling assays found no canonical G-protein or β-arrestin coupling in endothelial/HEK systems, reframing ELTD1's angiogenic function as operating through Notch ligand rebalancing rather than classical GPCR signaling.","evidence":"Stable HUVEC overexpression, HEK293T transfection, HTRF/luciferase/Alphascreen signaling assays, and angiogenesis/transcriptional profiling","pmids":["33893326"],"confidence":"High","gaps":["Cell-type or context dependence of coupling not resolved","Mechanism transducing Notch ligand changes unknown","Negative result later contrasted by Gq-coupling structure"]},{"year":2021,"claim":"Showed ELTD1 overexpression drives endothelial-to-mesenchymal transition to a pro-angiogenic, inflammatory myofibroblast-like phenotype, linking receptor activity to vascular cell-fate plasticity.","evidence":"Endothelial overexpression with cytoskeletal immunofluorescence, angiogenesis assays, and RNA-Seq","pmids":["34681953"],"confidence":"Medium","gaps":["Trigger and signaling pathway for EndMT not defined","Overexpression-only system","Physiological relevance unclear"]},{"year":2021,"claim":"Placed ELTD1 upstream of MMP2 transcription in colorectal cancer invasion, with MMP2 rescue confirming the epistasis.","evidence":"siRNA/overexpression in CRC cells, invasion and metastasis assays, MMP2 promoter activity, and rescue experiments","pmids":["34421349"],"confidence":"Medium","gaps":["Signaling between receptor and MMP2 promoter unknown","No ligand identified","Single tumor context"]},{"year":2021,"claim":"Identified a physical ELTD1–CSK interaction that activates MAPK/ERK to drive gastric cancer proliferation and EMT, giving a tumor-cell-intrinsic effector.","evidence":"siRNA/overexpression, MAPK/ERK Western blot, ELTD1-CSK co-IP, and in vitro/in vivo assays","pmids":["34475781"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal/structural validation","How CSK inhibition activates ERK not fully resolved","Contrasts with no-MAPK finding in endothelium"]},{"year":2021,"claim":"Demonstrated that endothelial ELTD1 remodels the tumor vasculature and immune microenvironment via tumor–endothelial crosstalk, increasing M2 macrophages and PD-L1.","evidence":"Syngeneic mouse breast cancer models with murine Eltd1, histology, and flow cytometry","pmids":["34348993"],"confidence":"Medium","gaps":["Soluble factors mediating crosstalk not fully identified","Receptor signaling driving the secretome unknown","Single tumor model"]},{"year":2022,"claim":"Showed ELTD1 deletion normalizes tumor vasculature and enhances T-cell infiltration with checkpoint blockade, establishing it as a vascular determinant of immunotherapy response.","evidence":"ELTD1-/- mice with orthotopic glioma, tumor endothelial profiling, vascular function assays, and PD-1 treatment","pmids":["34347079"],"confidence":"Medium","gaps":["Endothelial signaling underlying vascular dysfunction unknown","Generalizability beyond glioma untested","No ligand identified"]},{"year":2022,"claim":"Identified STAT5A as a direct transcriptional activator of ELTD1, linking hyperglycemia to ELTD1-driven EndMT in diabetic nephropathy.","evidence":"ChIP, luciferase reporter, STAT5A/ELTD1 siRNA and overexpression with rescue in glomerular endothelial cells and a DN rat model","pmids":["35320597"],"confidence":"Medium","gaps":["Receptor-proximal signaling driving EndMT not defined","Single disease model","No ligand identified"]},{"year":2022,"claim":"Established that the shed, glycosylated ELTD1 ectodomain travels in extracellular vesicles and is itself pro-angiogenic, defining a paracrine, flow-regulated mode of action and a candidate disease biomarker.","evidence":"EV proteomics, in vitro/in vivo angiogenesis with purified ECD, laminar flow experiments, and FACS of preeclampsia patient plasma","pmids":["38939053"],"confidence":"Medium","gaps":["Receptor/target on responding endothelium for the shed ECD unknown","Link between cleavage and vesicular packaging unresolved","Clinical biomarker value not validated in cohorts"]},{"year":2025,"claim":"The cryo-EM structure resolved the long-standing coupling question, showing ADGRL4 engages Gq weakly through an unusually small interface and activates via a tethered Stachel agonist, with no coupling to other transducers.","evidence":"3.1 Å cryo-EM of ADGRL4–Gq, bioluminescent signaling assays, and Gq complex reconstitution","pmids":["41469374"],"confidence":"High","gaps":["Endogenous agonist for the Stachel still undefined","Reconciliation with prior no-coupling functional reports incomplete","Downstream physiological relevance of weak Gq coupling unclear"]},{"year":2025,"claim":"Proposed Ku80 and beta spectrin as ELTD1 ligands and an autocrine activating factor, with Ku80 the more potent, offering candidate orphan-receptor agonists.","evidence":"Affinity-capture mass spectrometry, xCelligence functional assays, conditioned-medium transfer, and siRNA/INCA-X tube formation assays","pmids":["40245572"],"confidence":"Medium","gaps":["Ligand identity from affinity capture not orthogonally confirmed","Canonical GPCR activation reported here contrasts with earlier negative results","Physiological context of extracellular Ku80 unclear"]},{"year":2025,"claim":"Revealed a developmental role: ELTD1 restrains hemogenic endothelium progenitor differentiation through a physical HPIP interaction feeding an LEF1–Wnt axis.","evidence":"hESC gain/loss-of-function, iCRISPR knockout, ELTD1-HPIP co-IP, and Wnt pathway/hematopoietic differentiation assays","pmids":["40456828"],"confidence":"Medium","gaps":["Single Co-IP for ELTD1-HPIP interaction","How receptor activity controls HPIP not defined","Relevance to adult hematopoiesis untested"]},{"year":2026,"claim":"Defined a stress-induced signaling cascade in which JNK-driven ADGRL4 expression and ectodomain shedding activate a Gαs–cAMP–PKA axis that suppresses YAP1, giving the receptor dual tumor-suppressive and relapse-promoting functions.","evidence":"Loss/gain-of-function, JNK inhibition, cAMP/PKA and YAP1 assays, YAP1-β-catenin co-IP, and in vivo tumor models","pmids":["41734371"],"confidence":"Medium","gaps":["Gαs coupling here contrasts with structural Gq-only result","Single study","Balance between tumor-suppressive and pro-angiogenic effects not quantified"]},{"year":2026,"claim":"Extended ADGRL4 function to metabolism, showing its activation drives beige adipocyte differentiation and UCP1 via a p-AKT/UCP1 cascade and reduces adiposity in vivo.","evidence":"In vitro beige differentiation, p-AKT/UCP1 Western blot, and high-fat-diet mouse metabolic phenotyping","pmids":["41740879"],"confidence":"Medium","gaps":["Receptor-proximal coupling to AKT unknown","Activating ligand in adipose context undefined","Single study"]},{"year":null,"claim":"The endogenous physiological agonist(s) of ADGRL4 and how a single receptor reconciles weak Gq coupling, reported Gαs/cAMP and AKT cascades, and G-protein-independent Notch/EndMT outputs across endothelium, tumor, developmental, and metabolic contexts remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Bona fide endogenous ligand not established","Conflicting G-protein coupling results across cell systems unreconciled","Cell-type determinants of distinct downstream pathways unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[14,17]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[14,17]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,16]}],"complexes":[],"partners":["CSK","HPIP","XRCC5","SPTB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HBW9","full_name":"Adhesion G protein-coupled receptor L4","aliases":["EGF, latrophilin and seven transmembrane domain-containing protein 1","EGF-TM7-latrophilin-related protein","ETL protein"],"length_aa":690,"mass_kda":77.8,"function":"Endothelial orphan receptor that acts as a key regulator of angiogenesis","subcellular_location":"Cell 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In COS-7 cells transfected with Myc-tagged rat ETL, the protein exists as a stable dimer and undergoes endoproteolytic cleavage of the extracellular domain. The proteolytic activity is abolished by the specific mutation T455A. In transfected mammalian cells, ETL is associated with cell membranes and is also observed in cytoplasmic vesicles.\",\n      \"method\": \"Myc-tagged receptor transfection in COS-7 cells, site-directed mutagenesis (T455A), immunofluorescence/subcellular fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-directed mutagenesis identifying cleavage site plus subcellular localization, single lab\",\n      \"pmids\": [\"11050079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ELTD1 expression in tumor-associated endothelial cells is induced by VEGF/bFGF signaling and repressed by DLL4/Notch signaling. ELTD1 silencing impairs endothelial sprouting and vessel formation in vitro and in vivo, drastically reducing tumor growth.\",\n      \"method\": \"siRNA silencing, in vitro sprouting assays, in vivo tumor models, transcriptional pathway analysis\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (siRNA KD, in vitro angiogenesis assays, in vivo tumor models), replicated across multiple cancer types in one rigorous study\",\n      \"pmids\": [\"23871637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ELTD1 deficiency in mice exacerbates pressure overload-induced cardiac hypertrophy and fibrosis, associated with enhanced ERK and JNK phosphorylation, indicating ELTD1 normally suppresses these MAPK pathways in the context of cardiac stress.\",\n      \"method\": \"ELTD1-knockout mice subjected to aortic banding (pressure overload), Western blot for phospho-ERK and phospho-JNK, histological analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined phenotype and pathway readout (ERK/JNK phosphorylation), single lab\",\n      \"pmids\": [\"22606234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss of both GPR116 (ADGRF5) and ELTD1 (ADGRL4) in mice causes aortic arch malformations, cardiac outflow tract defects, and postnatal renal thrombotic microangiopathy. Loss of either receptor alone had no obvious cardiovascular or kidney phenotype, indicating functional redundancy. Endothelial-specific or neural crest-specific deletion of both receptors did not recapitulate the phenotype, indicating the relevant expression is in non-endothelial, non-neural-crest cells.\",\n      \"method\": \"ELTD1 and GPR116 single and double knockout mice, conditional cell-type-specific knockouts, histological and cardiovascular phenotyping\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with double KO and conditional KO in multiple cell types, single lab\",\n      \"pmids\": [\"28806758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ELTD1 silencing in endothelial cells induces expression of ACLY (cytoplasmic metabolic regulator) and SLC25A1 (mitochondria-to-cytoplasm citrate transporter), upregulates DLL4, and suppresses JAG1 and HES2, indicating ELTD1 regulates Notch ligand balance in endothelial cells. Metabolomics showed altered pyrimidine, amino acid, and sugar metabolism upon ELTD1 silencing.\",\n      \"method\": \"Two independent siRNAs for ELTD1 knockdown in HUVECs, transcriptional profiling, target gene validation (qPCR/Western blot), liquid chromatography–mass spectrometry metabolomics\",\n      \"journal\": \"Metabolites\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent siRNAs plus orthogonal transcriptomic and metabolomic readouts, single lab\",\n      \"pmids\": [\"31775252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ELTD1 activates the JAK/STAT3/HIF-1α signaling axis in glioma cells; p-STAT3 binds with HIF-1α. ELTD1 high expression promotes proliferation, migration, invasion, and orthotopic xenograft tumor growth.\",\n      \"method\": \"qRT-PCR, Western blotting, cell proliferation assays, Matrigel migration/invasion assays, brain orthotopic xenografts, co-immunoprecipitation/interaction assays for p-STAT3 and HIF-1α\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays plus pathway analysis and in vivo model, single lab\",\n      \"pmids\": [\"31554859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELTD1 overexpression in endothelial cells promotes sprouting angiogenesis and decreases in vitro anastomoses without activating canonical GPCR signaling (Gq, Gs, G12, Go, β-arrestin) or MAPK/ERK, PI3K/AKT, JNK, JAK/HIF-1α, beta-catenin, or STAT3 pathways. Full-length and C-terminal fragment constructs, as well as Stachel peptides, failed to activate canonical GPCR signaling in HEK293T cells. Overexpression upregulated JAG1 and downregulated DLL4, modulating the endothelial tip-cell phenotype.\",\n      \"method\": \"Stable ADGRL4/ELTD1-overexpressing HUVEC line, HEK293T transfection, HTRF FRET/luciferase reporter/Alphascreen GPCR signalling assays, angiogenesis assays, transcriptional profiling\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal GPCR signalling assays definitively showing no canonical coupling, plus functional angiogenesis readout with transcriptional profiling; negative canonical signalling result is itself mechanistically informative\",\n      \"pmids\": [\"33893326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELTD1 overexpression in endothelial cells results in endothelial-to-mesenchymal transition (EndMT) to a myofibroblast-like phenotype: loss of cell-cell contact, formation of stress fibers and mature focal adhesions, and increased smooth muscle actin expression. This transition is pro-angiogenic and associated with large increases in chemokines and cytokines regulating immune response. RNA-Seq identified pathways involved in myofibroblast biology (type II EMT).\",\n      \"method\": \"ELTD1 overexpression in endothelial cells, immunofluorescence for cytoskeletal markers, Matrigel network formation and sprouting assays, RNA-Seq with gene set enrichment analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression with multiple morphological/functional readouts plus transcriptomics, single lab\",\n      \"pmids\": [\"34681953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELTD1 promotes invasion and metastasis of colorectal cancer cells by accelerating the transcriptional activity of MMP2; MMP2 re-expression can rescue the impaired invasiveness caused by ELTD1 downregulation.\",\n      \"method\": \"siRNA knockdown and overexpression of ELTD1 in CRC cells, Matrigel invasion assays, in vivo metastasis models, MMP2 promoter activity assays, rescue experiments\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue experiment placing ELTD1 upstream of MMP2 transcriptional activity, in vitro and in vivo, single lab\",\n      \"pmids\": [\"34421349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELTD1 promotes gastric cancer proliferation, invasion, and EMT through MAPK/ERK signaling by interacting with and inhibiting C-terminal Src kinase (CSK). ELTD1 knockdown inhibits GC cell proliferation, migration, and invasion in vitro and in vivo, while overexpression has the opposite effect.\",\n      \"method\": \"siRNA knockdown, ELTD1 overexpression, Western blot for MAPK/ERK pathway, co-immunoprecipitation for ELTD1-CSK interaction, in vitro/in vivo functional assays\",\n      \"journal\": \"International journal of general medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP establishing ELTD1-CSK interaction plus downstream pathway activation with in vivo validation, single lab\",\n      \"pmids\": [\"34475781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELTD1 expression in murine breast cancer cells increases tumor growth and metastasis, enlarges vessel size and perfusion, and creates an immunosuppressive microenvironment with increased M2-like macrophages and PD-L1 expression via tumor-endothelial cell crosstalk releasing proangiogenic and immune-modulating factors.\",\n      \"method\": \"Syngeneic immunocompetent mouse breast cancer models with recombinant murine Eltd1 expression, histological analysis, flow cytometry, in vivo tumor growth/metastasis assays\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — syngeneic in vivo model with multiple phenotypic readouts and mechanistic characterization, single lab\",\n      \"pmids\": [\"34348993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ELTD1 deletion in mice improves tumor vascular function in orthotopic glioma, with transcriptional profiling of isolated tumor endothelial cells showing increased inflammatory response and decreased proliferation pathways. ELTD1 deletion also improves T-cell infiltration after PD-1 checkpoint blockade.\",\n      \"method\": \"ELTD1-/- mice with orthotopic glioma models, endothelial cell isolation and transcriptional profiling, tumor vascular function assays, PD-1 antibody treatment, immune infiltrate analysis\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with mechanistic transcriptional profiling plus functional immune readout, single lab\",\n      \"pmids\": [\"34347079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STAT5A directly regulates ELTD1 transcription (demonstrated by ChIP and luciferase assay). High glucose-induced STAT5A nuclear translocation leads to increased ELTD1 expression, which in turn promotes endothelial-to-mesenchymal transition (EndMT) in diabetic nephropathy. ELTD1 silencing reverses high glucose-mediated EndMT, and STAT5A overexpression-induced EndMT is inhibited by si-ELTD1.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, siRNA silencing of ELTD1 and STAT5A, STAT5A overexpression in human glomerular endothelial cells, DN rat model\",\n      \"journal\": \"Clinical and experimental pharmacology & physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus luciferase assay establishing direct transcriptional regulation, with functional epistasis via rescue, single lab\",\n      \"pmids\": [\"35320597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A highly glycosylated form of the ELTD1 extracellular domain (ECD) is present in extracellular vesicles (EVs) derived from endothelial cells. ELTD1-enriched EVs are pro-angiogenic in vivo and in vitro, and the ECD alone is sufficient to induce endothelial sprouting. Under laminar flow (quiescent endothelium), ELTD1 levels in EVs are reduced. Elevated vesicular ELTD1 is detected in plasma of patients with preeclampsia.\",\n      \"method\": \"EV isolation and characterization, mass spectrometry-based proteomics, in vitro sprouting assay with purified ECD, in vivo angiogenesis assay, FACS for vesicular ELTD1 in patient plasma, laminar flow experiments\",\n      \"journal\": \"Journal of extracellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (proteomics, functional ECD assay, in vivo angiogenesis, patient samples), single lab\",\n      \"pmids\": [\"38939053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structure of ADGRL4 coupled to heterotrimeric Gq determined at 3.1 Å resolution. ADGRL4 couples weakly to Gq (demonstrated by bioluminescent assay) but shows no robust coupling to Gs, G12, Go, or β-arrestin 1 or 2. The coupling to Gq involves fewer interactions between receptor and G protein compared to other aGPCRs. The structure is consistent with activation by a tethered agonist (Stachel mechanism).\",\n      \"method\": \"Cryo-EM structure determination (3.1 Å), bioluminescent GPCR signalling assay, heterotrimeric Gq complex reconstitution\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure combined with functional signalling assay establishing weak Gq coupling and ruling out other G proteins; rigorous single study with structural and biochemical validation\",\n      \"pmids\": [\"41469374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ku80 (a DNA repair factor) and erythrocyte beta spectrin (SPTB) were identified as ligands for ELTD1 by affinity capture and mass spectrometry. Ku80 demonstrated higher potency in activating ELTD1 than SPTB. When recombinantly expressed in U87 cells, ELTD1 activates canonical GPCR pathways, particularly the Gq pathway. Conditioned medium from U87 cells activates ELTD1 in HEK293 cells, supporting an autocrine ELTD1-activating factor. INCA-X (antibody targeting ku80/ku70 complex) and ELTD1 siRNA impaired endothelial tube formation similarly, suggesting a common pathway.\",\n      \"method\": \"Affinity capture and mass spectrometry for ligand identification, xCelligence label-free functional assay, conditioned medium transfer assay, siRNA knockdown, endothelial tube formation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity capture MS for ligand identification plus functional activation assay and epistasis via siRNA/antibody, single lab; note this contrasts with Favara 2021 finding of no canonical GPCR signalling in a different cell system\",\n      \"pmids\": [\"40245572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ELTD1 inhibits differentiation of hemogenic endothelium progenitors (HEPs) from hESCs through the HPIP-Wnt pathway. ELTD1 interacts physically with HPIP (protein-protein interaction), and HPIP modulates Wnt signaling through LEF1. Knockdown or deletion of ELTD1 facilitates HEP generation and promotes endothelial-to-hematopoietic transition; ELTD1 overexpression suppresses this. The ELTD1-HPIP-LEF1-Wnt regulatory axis governs HEP generation during early hematopoietic differentiation.\",\n      \"method\": \"ELTD1 gain- and loss-of-function experiments in hESCs, iCRISPR/Cas9 knockout, dynamic gene expression profiling, co-immunoprecipitation for ELTD1-HPIP interaction, luciferase/functional Wnt pathway assays, hematopoietic differentiation readouts\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP establishing ELTD1-HPIP interaction plus gain/loss-of-function with pathway epistasis, single lab\",\n      \"pmids\": [\"40456828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Cellular stress induces ADGRL4 expression via the canonical JNK-ATF2/c-Jun pathway. Stress-induced shedding of the ADGRL4 N-terminal fragment activates the C-terminal fragment, which couples with Gαs to stimulate cAMP-PKA signaling and consequently suppress YAP1 activity. In the absence of ADGRL4, hyperactivated YAP1 forms a transcriptional complex with β-catenin to drive tumor growth. ADGRL4 simultaneously promotes angiogenesis extracellularly, creating dual tumor-suppressive and relapse-promoting effects.\",\n      \"method\": \"Loss-of-function and overexpression experiments, JNK pathway inhibition, cAMP/PKA signalling assays, YAP1 activity assays, co-immunoprecipitation for YAP1-β-catenin complex, in vivo tumor models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway assays establishing Gαs/cAMP/PKA/YAP1 mechanism with in vivo validation, single lab, single study\",\n      \"pmids\": [\"41734371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ADGRL4 activation promotes beige adipocyte differentiation, upregulates UCP1 expression, and reduces lipid droplet accumulation in vitro. In vivo, ADGRL4 activation induces beige fat development and reduces fat deposition and body weight in mice on high-fat diet. Mechanistically, ADGRL4 enhances AKT phosphorylation without altering total AKT levels, activating a downstream p-AKT/UCP1 signaling cascade driving adipose browning.\",\n      \"method\": \"In vitro beige adipocyte differentiation assays, ADGRL4 activation in cell lines, Western blot for p-AKT and UCP1, in vivo mouse models (normal chow and high-fat diet), metabolic phenotyping\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo functional assays with mechanistic p-AKT/UCP1 pathway readout, single lab, single study\",\n      \"pmids\": [\"41740879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ADGRL4 cryo-EM structure determination (same finding as PMID 41469374, preprint version). ADGRL4 couples weakly to Gq; no coupling to Gs, G12, Go, or β-arrestins. Cryo-EM structure at 3.1 Å shows distinct Gq coupling with fewer receptor-G protein interactions versus other aGPCRs. Consistent with tethered agonist (Stachel) activation.\",\n      \"method\": \"Cryo-EM structure determination (3.1 Å), bioluminescent signalling assay, heterotrimeric Gq complex reconstitution\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — same data as peer-reviewed PMID 41469374; preprint entry included for completeness but not independent replication\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"miR-139-5p suppresses glioma cell proliferation by directly targeting ELTD1; luciferase and Western blot assays confirmed ELTD1 as a direct target of miR-139-5p, and miR-139-5p overexpression reduces ELTD1 protein levels and regulates cell cycle in GBM cells.\",\n      \"method\": \"miR-139-5p mimic transfection in GBM cell lines, luciferase reporter assay, Western blot, MTT/colony formation assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single luciferase/Western blot validation of miRNA-target relationship, single lab\",\n      \"pmids\": [\"26449464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELTD1 inhibition by siRNA decreases Y79 retinoblastoma cell migration in vitro and invasion in vivo in an orthotopic xenograft model. ELTD1 displays punctate clusters at cell-to-cell adhesion sites in Weri-Rb-1 cells (non-metastatic), while its subcellular localization at these sites is distinct from the polarized distribution of GPR125.\",\n      \"method\": \"siRNA knockdown of ELTD1 in Rb cell lines, migration assay (in vitro), orthotopic xenograft murine model for invasion (in vivo), immunofluorescence subcellular localization\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — siRNA with migration/invasion readout and localization imaging, single lab, single study\",\n      \"pmids\": [\"33430814\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADGRL4/ELTD1 is an orphan adhesion GPCR expressed predominantly in endothelial cells whose 3.1 Å cryo-EM structure reveals weak coupling to heterotrimeric Gq (with no robust coupling to other G proteins or β-arrestins) and activation consistent with a tethered Stachel agonist mechanism; it undergoes GPS-mediated endoproteolytic cleavage (abolished by T455A mutation), forms stable dimers, localizes to the plasma membrane and cytoplasmic vesicles, sheds its extracellular domain into pro-angiogenic extracellular vesicles, and regulates endothelial sprouting angiogenesis and endothelial-to-mesenchymal transition through pathways including Notch (DLL4/JAG1 balance), JAK/STAT3/HIF-1α, MAPK/ERK, and cAMP-PKA/YAP1 suppression, while its expression is transcriptionally induced by VEGF/bFGF, repressed by DLL4/Notch, and directly driven by STAT5A; newly identified ligands include Ku80 and beta spectrin, and ELTD1-HPIP-LEF1-Wnt signaling governs hemogenic endothelium progenitor differentiation from hESCs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADGRL4/ELTD1 is an orphan adhesion G-protein-coupled receptor expressed predominantly in endothelial cells that governs sprouting angiogenesis, endothelial plasticity, and vascular remodeling [#1, #6]. It is a seven-transmembrane receptor with a large extracellular domain bearing EGF-like repeats; it forms stable dimers and undergoes GPS-mediated endoproteolytic cleavage of its ectodomain, an activity abolished by the T455A mutation, and localizes to the plasma membrane and cytoplasmic vesicles [#0]. Its 3.1 Å cryo-EM structure reveals coupling to heterotrimeric Gq through an unusually small receptor–G-protein interface, with no robust coupling to Gs, G12, Go, or β-arrestins, and an architecture consistent with tethered Stachel agonist activation [#14]. The receptor sheds a glycosylated extracellular domain into pro-angiogenic extracellular vesicles, and the ECD alone is sufficient to drive endothelial sprouting [#13]. In the vasculature, ADGRL4 expression is induced by VEGF/bFGF and repressed by DLL4/Notch signaling, and the receptor in turn balances Notch ligand expression (suppressing DLL4, promoting JAG1) to shape the endothelial tip-cell phenotype [#1, #6], while also driving endothelial-to-mesenchymal transition toward a myofibroblast-like state [#7]. In disease contexts it is transcriptionally activated by STAT5A to promote EndMT in diabetic nephropathy [#12] and acts in tumors through Notch ligand rebalancing, JAK/STAT3/HIF-1α signaling, MMP2 transcription, and creation of an immunosuppressive vascular microenvironment [#5, #8, #11]. ADGRL4 also functions in non-angiogenic settings, restraining hemogenic endothelium progenitor differentiation via an HPIP–LEF1–Wnt axis [#16] and a Gαs–cAMP–PKA cascade that suppresses YAP1 [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the basic architecture of the receptor — a dimeric seven-transmembrane protein with an EGF-repeat ectodomain that is autoproteolytically cleaved — placing ADGRL4 within the adhesion GPCR paradigm of GPS cleavage.\",\n      \"evidence\": \"Myc-tagged rat ETL transfection in COS-7 cells with T455A site-directed mutagenesis and subcellular localization\",\n      \"pmids\": [\"11050079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No ligand or downstream signaling identified\", \"Functional consequence of cleavage and dimerization not addressed\", \"Done in heterologous overexpression only\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"First in vivo loss-of-function evidence that ELTD1 restrains MAPK signaling in a physiological stress context, linking the receptor to cardiac remodeling.\",\n      \"evidence\": \"ELTD1-knockout mice with aortic banding, phospho-ERK/JNK Western blot and histology\",\n      \"pmids\": [\"22606234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting receptor to ERK/JNK not defined\", \"Cell type responsible not resolved\", \"No ligand identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Positioned ELTD1 as a VEGF/Notch-regulated driver of tumor angiogenesis, defining its core endothelial function and therapeutic relevance.\",\n      \"evidence\": \"siRNA silencing, in vitro sprouting assays, and in vivo tumor models across cancer types\",\n      \"pmids\": [\"23871637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling output downstream of the receptor not defined\", \"No ligand identified\", \"G-protein coupling unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Genetic epistasis revealed functional redundancy with GPR116/ADGRF5 in cardiovascular and renal development, and that the relevant cells are neither endothelial nor neural crest.\",\n      \"evidence\": \"Single and double ELTD1/GPR116 knockout plus cell-type-specific conditional knockouts with cardiovascular phenotyping\",\n      \"pmids\": [\"28806758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the relevant non-endothelial cell type unresolved\", \"Molecular basis of redundancy unknown\", \"No shared ligand/pathway defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected ELTD1 to Notch ligand balance and endothelial metabolism, showing it suppresses DLL4 while supporting JAG1/HES2 and shapes citrate-related metabolic programs.\",\n      \"evidence\": \"Two independent siRNAs in HUVECs with transcriptional profiling and LC-MS metabolomics\",\n      \"pmids\": [\"31775252\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect regulation of Notch ligands unclear\", \"Receptor-proximal signaling not defined\", \"Metabolic changes correlative\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a tumor-cell-intrinsic JAK/STAT3/HIF-1α axis activated by ELTD1 in glioma, extending its role beyond endothelium.\",\n      \"evidence\": \"qRT-PCR, Western blot, proliferation/invasion assays, orthotopic xenografts, and p-STAT3/HIF-1α co-IP\",\n      \"pmids\": [\"31554859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How the receptor engages JAK/STAT3 mechanistically unknown\", \"No ligand identified\", \"Conflicts with later reports of no STAT3 activation in endothelium\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A rigorous panel of GPCR signaling assays found no canonical G-protein or β-arrestin coupling in endothelial/HEK systems, reframing ELTD1's angiogenic function as operating through Notch ligand rebalancing rather than classical GPCR signaling.\",\n      \"evidence\": \"Stable HUVEC overexpression, HEK293T transfection, HTRF/luciferase/Alphascreen signaling assays, and angiogenesis/transcriptional profiling\",\n      \"pmids\": [\"33893326\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type or context dependence of coupling not resolved\", \"Mechanism transducing Notch ligand changes unknown\", \"Negative result later contrasted by Gq-coupling structure\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed ELTD1 overexpression drives endothelial-to-mesenchymal transition to a pro-angiogenic, inflammatory myofibroblast-like phenotype, linking receptor activity to vascular cell-fate plasticity.\",\n      \"evidence\": \"Endothelial overexpression with cytoskeletal immunofluorescence, angiogenesis assays, and RNA-Seq\",\n      \"pmids\": [\"34681953\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trigger and signaling pathway for EndMT not defined\", \"Overexpression-only system\", \"Physiological relevance unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed ELTD1 upstream of MMP2 transcription in colorectal cancer invasion, with MMP2 rescue confirming the epistasis.\",\n      \"evidence\": \"siRNA/overexpression in CRC cells, invasion and metastasis assays, MMP2 promoter activity, and rescue experiments\",\n      \"pmids\": [\"34421349\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling between receptor and MMP2 promoter unknown\", \"No ligand identified\", \"Single tumor context\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a physical ELTD1–CSK interaction that activates MAPK/ERK to drive gastric cancer proliferation and EMT, giving a tumor-cell-intrinsic effector.\",\n      \"evidence\": \"siRNA/overexpression, MAPK/ERK Western blot, ELTD1-CSK co-IP, and in vitro/in vivo assays\",\n      \"pmids\": [\"34475781\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal/structural validation\", \"How CSK inhibition activates ERK not fully resolved\", \"Contrasts with no-MAPK finding in endothelium\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that endothelial ELTD1 remodels the tumor vasculature and immune microenvironment via tumor–endothelial crosstalk, increasing M2 macrophages and PD-L1.\",\n      \"evidence\": \"Syngeneic mouse breast cancer models with murine Eltd1, histology, and flow cytometry\",\n      \"pmids\": [\"34348993\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Soluble factors mediating crosstalk not fully identified\", \"Receptor signaling driving the secretome unknown\", \"Single tumor model\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed ELTD1 deletion normalizes tumor vasculature and enhances T-cell infiltration with checkpoint blockade, establishing it as a vascular determinant of immunotherapy response.\",\n      \"evidence\": \"ELTD1-/- mice with orthotopic glioma, tumor endothelial profiling, vascular function assays, and PD-1 treatment\",\n      \"pmids\": [\"34347079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endothelial signaling underlying vascular dysfunction unknown\", \"Generalizability beyond glioma untested\", \"No ligand identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified STAT5A as a direct transcriptional activator of ELTD1, linking hyperglycemia to ELTD1-driven EndMT in diabetic nephropathy.\",\n      \"evidence\": \"ChIP, luciferase reporter, STAT5A/ELTD1 siRNA and overexpression with rescue in glomerular endothelial cells and a DN rat model\",\n      \"pmids\": [\"35320597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor-proximal signaling driving EndMT not defined\", \"Single disease model\", \"No ligand identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established that the shed, glycosylated ELTD1 ectodomain travels in extracellular vesicles and is itself pro-angiogenic, defining a paracrine, flow-regulated mode of action and a candidate disease biomarker.\",\n      \"evidence\": \"EV proteomics, in vitro/in vivo angiogenesis with purified ECD, laminar flow experiments, and FACS of preeclampsia patient plasma\",\n      \"pmids\": [\"38939053\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor/target on responding endothelium for the shed ECD unknown\", \"Link between cleavage and vesicular packaging unresolved\", \"Clinical biomarker value not validated in cohorts\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The cryo-EM structure resolved the long-standing coupling question, showing ADGRL4 engages Gq weakly through an unusually small interface and activates via a tethered Stachel agonist, with no coupling to other transducers.\",\n      \"evidence\": \"3.1 Å cryo-EM of ADGRL4–Gq, bioluminescent signaling assays, and Gq complex reconstitution\",\n      \"pmids\": [\"41469374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous agonist for the Stachel still undefined\", \"Reconciliation with prior no-coupling functional reports incomplete\", \"Downstream physiological relevance of weak Gq coupling unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed Ku80 and beta spectrin as ELTD1 ligands and an autocrine activating factor, with Ku80 the more potent, offering candidate orphan-receptor agonists.\",\n      \"evidence\": \"Affinity-capture mass spectrometry, xCelligence functional assays, conditioned-medium transfer, and siRNA/INCA-X tube formation assays\",\n      \"pmids\": [\"40245572\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand identity from affinity capture not orthogonally confirmed\", \"Canonical GPCR activation reported here contrasts with earlier negative results\", \"Physiological context of extracellular Ku80 unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a developmental role: ELTD1 restrains hemogenic endothelium progenitor differentiation through a physical HPIP interaction feeding an LEF1–Wnt axis.\",\n      \"evidence\": \"hESC gain/loss-of-function, iCRISPR knockout, ELTD1-HPIP co-IP, and Wnt pathway/hematopoietic differentiation assays\",\n      \"pmids\": [\"40456828\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP for ELTD1-HPIP interaction\", \"How receptor activity controls HPIP not defined\", \"Relevance to adult hematopoiesis untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a stress-induced signaling cascade in which JNK-driven ADGRL4 expression and ectodomain shedding activate a Gαs–cAMP–PKA axis that suppresses YAP1, giving the receptor dual tumor-suppressive and relapse-promoting functions.\",\n      \"evidence\": \"Loss/gain-of-function, JNK inhibition, cAMP/PKA and YAP1 assays, YAP1-β-catenin co-IP, and in vivo tumor models\",\n      \"pmids\": [\"41734371\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Gαs coupling here contrasts with structural Gq-only result\", \"Single study\", \"Balance between tumor-suppressive and pro-angiogenic effects not quantified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended ADGRL4 function to metabolism, showing its activation drives beige adipocyte differentiation and UCP1 via a p-AKT/UCP1 cascade and reduces adiposity in vivo.\",\n      \"evidence\": \"In vitro beige differentiation, p-AKT/UCP1 Western blot, and high-fat-diet mouse metabolic phenotyping\",\n      \"pmids\": [\"41740879\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor-proximal coupling to AKT unknown\", \"Activating ligand in adipose context undefined\", \"Single study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous physiological agonist(s) of ADGRL4 and how a single receptor reconciles weak Gq coupling, reported Gαs/cAMP and AKT cascades, and G-protein-independent Notch/EndMT outputs across endothelium, tumor, developmental, and metabolic contexts remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Bona fide endogenous ligand not established\", \"Conflicting G-protein coupling results across cell systems unreconciled\", \"Cell-type determinants of distinct downstream pathways unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [14, 17]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [14, 17]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CSK\", \"HPIP\", \"XRCC5\", \"SPTB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}