{"gene":"GPR180","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2021,"finding":"GPR180 is not a canonical GPCR but functions as a component of the TGFβ signalling pathway, regulating the activity of the TGFβ receptor complex through SMAD3 phosphorylation. GPR180 is required for CTHRC1 (Collagen triple helix repeat containing 1) to exert its effects on brown/beige adipocyte activity and glucose homeostasis, defining a CTHRC1/GPR180 axis as an alternative branch of TGFβ signalling.","method":"Genetic (knockout/knockdown) and pharmacological tools in adipocyte cell models and mice; SMAD3 phosphorylation assays; epistasis experiments placing GPR180 downstream of CTHRC1 and upstream of TGFβ receptor signalling","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotype plus pharmacological validation and pathway placement via SMAD3 phosphorylation; single lab, multiple orthogonal approaches but no in vitro reconstitution or structural validation","pmids":["34880217"],"is_preprint":false},{"year":2024,"finding":"GPR180 belongs to the GOST (Golgi-dynamics domain seven-transmembrane helix) protein family. X-ray crystallography of the N-terminal domain (1.9 Å resolution) confirmed structural homology to GOLD domains. Cellular imaging localised GPR180 to intracellular vesicular structures, implying exposure to acidic pH environments. HDX-MS identified pH-dependent conformational changes mapping to a putative ligand-binding site in the transmembrane region, revealing a role for GPR180 in intracellular vesicles.","method":"X-ray crystallography (1.9 Å); cellular imaging (localization to vesicular structures); Hydrogen/Deuterium Exchange Mass Spectrometry (HDX-MS) for conformational analysis","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — X-ray crystal structure combined with HDX-MS conformational mapping and direct cellular localization imaging; single lab but three orthogonal methods providing mechanistic insight","pmids":["39609618"],"is_preprint":false},{"year":2023,"finding":"Ablation of GPR180 in mice ameliorated hepatic and plasma lipid levels after high-fat diet, mediated by downregulation of mTORC1 signalling; specifically, GPR180 KO showed weakened phosphorylation of mTOR and decreased activated SREBP1 in both Gpr180 KO mice and a human hepatoma cell line (Huh7). Hepatic rescue of GPR180 expression via AAV8 in KO mice restored plasma and hepatic lipid levels, confirming GPR180 acts upstream of mTORC1/SREBP1 in hepatic lipid metabolism.","method":"Gpr180 knockout mice; shRNA knockdown via AAV8; transcriptome analysis; Western blot for p-mTOR and activated SREBP1; AAV8-mediated hepatic rescue experiment","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined lipid phenotype, rescue experiment confirming pathway, Western blot pathway validation; single lab, multiple orthogonal methods","pmids":["36726016"],"is_preprint":false},{"year":2025,"finding":"GPR180 reduces adiposity by inhibiting lipogenesis and fatty acid uptake in adipocytes. Adeno-associated virus-mediated overexpression of Gpr180 in subcutaneous white adipose tissue improved lipid metabolism and protected mice from HFD-induced obesity, while adipocyte-specific knockout of Gpr180 exacerbated lipid metabolism disorders. In cultured adipocytes differentiated from stromal vascular fraction cells, GPR180 directly inhibited lipogenesis and fatty acid uptake.","method":"AAV-mediated overexpression in subcutaneous adipose tissue; adipocyte-specific Gpr180 knockout mice; stromal vascular fraction (SVF) cell culture lipogenesis and fatty acid uptake assays","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain- and loss-of-function with defined metabolic phenotype plus in vitro cellular mechanistic assays; single lab, multiple orthogonal methods","pmids":["39925142"],"is_preprint":false},{"year":2003,"finding":"The human ITR (GPR180) gene was mapped to chromosome 13q31, spans 27,452 bp with nine exons, and encodes a rhodopsin-like G protein-coupled receptor described as associated with vascular remodeling. A high-density SNP map was constructed from 48 individuals, identifying 22 SNPs across the locus.","method":"Genomic sequencing; SNP mapping from 48 healthy Japanese individuals; genomic structure determination","journal":"Journal of human genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genomic characterization and SNP mapping only; no functional mechanistic experiment performed on the protein itself","pmids":["12730718"],"is_preprint":false}],"current_model":"GPR180 (also known as ITR) is a GOST-family protein with a GOLD domain N-terminus and seven-transmembrane region that localises to intracellular vesicular structures and undergoes pH-dependent conformational changes; it functions as a component of TGFβ signalling by promoting SMAD3 phosphorylation and mediating CTHRC1 action in thermogenic adipocytes, while in hepatocytes it acts upstream of mTORC1/SREBP1 to regulate lipid metabolism, and in adipocytes it suppresses lipogenesis and fatty acid uptake."},"narrative":{"mechanistic_narrative":"GPR180 is a multi-pass membrane protein that acts as a regulator of TGFβ signalling and lipid metabolism rather than as a canonical G protein-coupled receptor [PMID:34880217, PMID:39609618]. Structurally it belongs to the GOST family, with a crystallographically resolved N-terminal GOLD-like domain and a seven-transmembrane region; it localises to intracellular vesicular structures and undergoes pH-dependent conformational changes that map to a putative ligand-binding site in the transmembrane region, consistent with sensing the acidic vesicular environment [PMID:39609618]. Functionally, GPR180 operates downstream of CTHRC1 and upstream of the TGFβ receptor complex, promoting SMAD3 phosphorylation, and this CTHRC1/GPR180 axis is required for control of brown/beige adipocyte activity and glucose homeostasis [PMID:34880217]. In the liver, GPR180 acts upstream of mTORC1/SREBP1: its loss reduces mTOR phosphorylation and SREBP1 activation and ameliorates hepatic and plasma lipids after high-fat diet, with hepatic re-expression restoring the lipid phenotype [PMID:36726016]. In white adipocytes, GPR180 directly inhibits lipogenesis and fatty acid uptake, and its overexpression protects mice from diet-induced obesity while adipocyte-specific deletion worsens lipid handling [PMID:39925142].","teleology":[{"year":2003,"claim":"Before any functional study, the genomic identity of human ITR/GPR180 had to be established, defining the locus as a candidate seven-transmembrane receptor gene associated with vascular remodeling.","evidence":"Genomic sequencing, structure determination, and SNP mapping across the 13q31 locus in 48 individuals","pmids":["12730718"],"confidence":"Low","gaps":["No functional experiment was performed on the protein itself","The annotation as a rhodopsin-like GPCR was inferred from sequence, not activity","No link to any signalling pathway or ligand was established"]},{"year":2021,"claim":"The key question of what pathway GPR180 belongs to was answered by placing it not as a classical GPCR but as a component of TGFβ signalling acting in a CTHRC1-dependent branch.","evidence":"Knockout/knockdown and pharmacological tools in adipocyte models and mice; SMAD3 phosphorylation assays and epistasis positioning GPR180 downstream of CTHRC1 and upstream of the TGFβ receptor","pmids":["34880217"],"confidence":"Medium","gaps":["No in vitro reconstitution of the GPR180–TGFβ receptor interaction","Direct physical binding to CTHRC1 or the receptor complex not demonstrated","Mechanism by which GPR180 modulates SMAD3 phosphorylation unresolved"]},{"year":2023,"claim":"Whether GPR180 has metabolic functions beyond adipocyte thermogenesis was addressed by showing it regulates hepatic lipid metabolism upstream of mTORC1/SREBP1.","evidence":"Gpr180 knockout mice on high-fat diet, AAV8 hepatic rescue, transcriptomics, and Western blots for p-mTOR and activated SREBP1 in mouse liver and Huh7 cells","pmids":["36726016"],"confidence":"Medium","gaps":["Molecular link between GPR180 and mTOR activation not defined","Whether the hepatic effect depends on the CTHRC1/TGFβ axis is unknown","No identified upstream ligand driving hepatic signalling"]},{"year":2025,"claim":"The cell-autonomous metabolic role in white adipocytes was clarified by demonstrating GPR180 directly suppresses lipogenesis and fatty acid uptake to limit adiposity.","evidence":"AAV overexpression in subcutaneous adipose tissue, adipocyte-specific knockout mice, and lipogenesis/fatty acid uptake assays in SVF-derived adipocytes","pmids":["39925142"],"confidence":"Medium","gaps":["Direct molecular effectors of lipogenesis/uptake suppression not identified","Relationship to the hepatic mTORC1/SREBP1 mechanism unclear","Whether SMAD3 signalling mediates the adipocyte phenotype not tested"]},{"year":2024,"claim":"The structural and subcellular basis of GPR180 function was established by assigning it to the GOST family with a GOLD-like N-terminal domain and showing it acts within intracellular acidic vesicles.","evidence":"X-ray crystallography of the N-terminal domain (1.9 Å), cellular imaging of vesicular localization, and HDX-MS mapping of pH-dependent conformational changes","pmids":["39609618"],"confidence":"High","gaps":["No endogenous ligand identified for the putative transmembrane binding site","How vesicular localization reconciles with plasma-membrane TGFβ receptor signalling is unresolved","Full-length structure including the transmembrane region not determined"]},{"year":null,"claim":"It remains unknown how GPR180's structural and vesicular biology mechanistically connects its disparate roles in TGFβ/SMAD3 signalling, hepatic mTORC1/SREBP1 regulation, and adipocyte lipid handling.","evidence":"No discovery in the corpus unifies the structural, signalling, and metabolic findings or identifies a direct ligand and binding partners","pmids":[],"confidence":"Low","gaps":["No identified physiological ligand engaging the transmembrane pocket","Direct physical partners in the TGFβ receptor complex unconfirmed","Causal chain linking vesicular conformational changes to downstream signalling not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,3]}],"complexes":[],"partners":["CTHRC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86V85","full_name":"Integral membrane protein GPR180","aliases":["Intimal thickness-related receptor"],"length_aa":440,"mass_kda":49.4,"function":"","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q86V85/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GPR180","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GPR180","total_profiled":1310},"omim":[{"mim_id":"607787","title":"G PROTEIN-COUPLED RECEPTOR 180; GPR180","url":"https://www.omim.org/entry/607787"},{"mim_id":"156600","title":"MICROCORIA, CONGENITAL","url":"https://www.omim.org/entry/156600"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GPR180"},"hgnc":{"alias_symbol":["ITR"],"prev_symbol":[]},"alphafold":{"accession":"Q86V85","domains":[{"cath_id":"2.60.120","chopping":"23-150","consensus_level":"high","plddt":87.8852,"start":23,"end":150},{"cath_id":"1.20.1070","chopping":"169-273_282-420","consensus_level":"high","plddt":84.0658,"start":169,"end":420}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86V85","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86V85-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86V85-F1-predicted_aligned_error_v6.png","plddt_mean":81.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GPR180","jax_strain_url":"https://www.jax.org/strain/search?query=GPR180"},"sequence":{"accession":"Q86V85","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86V85.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86V85/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86V85"}},"corpus_meta":[{"pmid":"10610772","id":"PMC_10610772","title":"Inositol 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canonical GPCR but functions as a component of the TGFβ signalling pathway, regulating the activity of the TGFβ receptor complex through SMAD3 phosphorylation. GPR180 is required for CTHRC1 (Collagen triple helix repeat containing 1) to exert its effects on brown/beige adipocyte activity and glucose homeostasis, defining a CTHRC1/GPR180 axis as an alternative branch of TGFβ signalling.\",\n      \"method\": \"Genetic (knockout/knockdown) and pharmacological tools in adipocyte cell models and mice; SMAD3 phosphorylation assays; epistasis experiments placing GPR180 downstream of CTHRC1 and upstream of TGFβ receptor signalling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotype plus pharmacological validation and pathway placement via SMAD3 phosphorylation; single lab, multiple orthogonal approaches but no in vitro reconstitution or structural validation\",\n      \"pmids\": [\"34880217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GPR180 belongs to the GOST (Golgi-dynamics domain seven-transmembrane helix) protein family. X-ray crystallography of the N-terminal domain (1.9 Å resolution) confirmed structural homology to GOLD domains. Cellular imaging localised GPR180 to intracellular vesicular structures, implying exposure to acidic pH environments. HDX-MS identified pH-dependent conformational changes mapping to a putative ligand-binding site in the transmembrane region, revealing a role for GPR180 in intracellular vesicles.\",\n      \"method\": \"X-ray crystallography (1.9 Å); cellular imaging (localization to vesicular structures); Hydrogen/Deuterium Exchange Mass Spectrometry (HDX-MS) for conformational analysis\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — X-ray crystal structure combined with HDX-MS conformational mapping and direct cellular localization imaging; single lab but three orthogonal methods providing mechanistic insight\",\n      \"pmids\": [\"39609618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ablation of GPR180 in mice ameliorated hepatic and plasma lipid levels after high-fat diet, mediated by downregulation of mTORC1 signalling; specifically, GPR180 KO showed weakened phosphorylation of mTOR and decreased activated SREBP1 in both Gpr180 KO mice and a human hepatoma cell line (Huh7). Hepatic rescue of GPR180 expression via AAV8 in KO mice restored plasma and hepatic lipid levels, confirming GPR180 acts upstream of mTORC1/SREBP1 in hepatic lipid metabolism.\",\n      \"method\": \"Gpr180 knockout mice; shRNA knockdown via AAV8; transcriptome analysis; Western blot for p-mTOR and activated SREBP1; AAV8-mediated hepatic rescue experiment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined lipid phenotype, rescue experiment confirming pathway, Western blot pathway validation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36726016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GPR180 reduces adiposity by inhibiting lipogenesis and fatty acid uptake in adipocytes. Adeno-associated virus-mediated overexpression of Gpr180 in subcutaneous white adipose tissue improved lipid metabolism and protected mice from HFD-induced obesity, while adipocyte-specific knockout of Gpr180 exacerbated lipid metabolism disorders. In cultured adipocytes differentiated from stromal vascular fraction cells, GPR180 directly inhibited lipogenesis and fatty acid uptake.\",\n      \"method\": \"AAV-mediated overexpression in subcutaneous adipose tissue; adipocyte-specific Gpr180 knockout mice; stromal vascular fraction (SVF) cell culture lipogenesis and fatty acid uptake assays\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain- and loss-of-function with defined metabolic phenotype plus in vitro cellular mechanistic assays; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39925142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The human ITR (GPR180) gene was mapped to chromosome 13q31, spans 27,452 bp with nine exons, and encodes a rhodopsin-like G protein-coupled receptor described as associated with vascular remodeling. A high-density SNP map was constructed from 48 individuals, identifying 22 SNPs across the locus.\",\n      \"method\": \"Genomic sequencing; SNP mapping from 48 healthy Japanese individuals; genomic structure determination\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genomic characterization and SNP mapping only; no functional mechanistic experiment performed on the protein itself\",\n      \"pmids\": [\"12730718\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GPR180 (also known as ITR) is a GOST-family protein with a GOLD domain N-terminus and seven-transmembrane region that localises to intracellular vesicular structures and undergoes pH-dependent conformational changes; it functions as a component of TGFβ signalling by promoting SMAD3 phosphorylation and mediating CTHRC1 action in thermogenic adipocytes, while in hepatocytes it acts upstream of mTORC1/SREBP1 to regulate lipid metabolism, and in adipocytes it suppresses lipogenesis and fatty acid uptake.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GPR180 is a multi-pass membrane protein that acts as a regulator of TGFβ signalling and lipid metabolism rather than as a canonical G protein-coupled receptor [#0, #1]. Structurally it belongs to the GOST family, with a crystallographically resolved N-terminal GOLD-like domain and a seven-transmembrane region; it localises to intracellular vesicular structures and undergoes pH-dependent conformational changes that map to a putative ligand-binding site in the transmembrane region, consistent with sensing the acidic vesicular environment [#1]. Functionally, GPR180 operates downstream of CTHRC1 and upstream of the TGFβ receptor complex, promoting SMAD3 phosphorylation, and this CTHRC1/GPR180 axis is required for control of brown/beige adipocyte activity and glucose homeostasis [#0]. In the liver, GPR180 acts upstream of mTORC1/SREBP1: its loss reduces mTOR phosphorylation and SREBP1 activation and ameliorates hepatic and plasma lipids after high-fat diet, with hepatic re-expression restoring the lipid phenotype [#2]. In white adipocytes, GPR180 directly inhibits lipogenesis and fatty acid uptake, and its overexpression protects mice from diet-induced obesity while adipocyte-specific deletion worsens lipid handling [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Before any functional study, the genomic identity of human ITR/GPR180 had to be established, defining the locus as a candidate seven-transmembrane receptor gene associated with vascular remodeling.\",\n      \"evidence\": \"Genomic sequencing, structure determination, and SNP mapping across the 13q31 locus in 48 individuals\",\n      \"pmids\": [\"12730718\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No functional experiment was performed on the protein itself\",\n        \"The annotation as a rhodopsin-like GPCR was inferred from sequence, not activity\",\n        \"No link to any signalling pathway or ligand was established\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The key question of what pathway GPR180 belongs to was answered by placing it not as a classical GPCR but as a component of TGFβ signalling acting in a CTHRC1-dependent branch.\",\n      \"evidence\": \"Knockout/knockdown and pharmacological tools in adipocyte models and mice; SMAD3 phosphorylation assays and epistasis positioning GPR180 downstream of CTHRC1 and upstream of the TGFβ receptor\",\n      \"pmids\": [\"34880217\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vitro reconstitution of the GPR180–TGFβ receptor interaction\",\n        \"Direct physical binding to CTHRC1 or the receptor complex not demonstrated\",\n        \"Mechanism by which GPR180 modulates SMAD3 phosphorylation unresolved\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Whether GPR180 has metabolic functions beyond adipocyte thermogenesis was addressed by showing it regulates hepatic lipid metabolism upstream of mTORC1/SREBP1.\",\n      \"evidence\": \"Gpr180 knockout mice on high-fat diet, AAV8 hepatic rescue, transcriptomics, and Western blots for p-mTOR and activated SREBP1 in mouse liver and Huh7 cells\",\n      \"pmids\": [\"36726016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular link between GPR180 and mTOR activation not defined\",\n        \"Whether the hepatic effect depends on the CTHRC1/TGFβ axis is unknown\",\n        \"No identified upstream ligand driving hepatic signalling\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The cell-autonomous metabolic role in white adipocytes was clarified by demonstrating GPR180 directly suppresses lipogenesis and fatty acid uptake to limit adiposity.\",\n      \"evidence\": \"AAV overexpression in subcutaneous adipose tissue, adipocyte-specific knockout mice, and lipogenesis/fatty acid uptake assays in SVF-derived adipocytes\",\n      \"pmids\": [\"39925142\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct molecular effectors of lipogenesis/uptake suppression not identified\",\n        \"Relationship to the hepatic mTORC1/SREBP1 mechanism unclear\",\n        \"Whether SMAD3 signalling mediates the adipocyte phenotype not tested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The structural and subcellular basis of GPR180 function was established by assigning it to the GOST family with a GOLD-like N-terminal domain and showing it acts within intracellular acidic vesicles.\",\n      \"evidence\": \"X-ray crystallography of the N-terminal domain (1.9 Å), cellular imaging of vesicular localization, and HDX-MS mapping of pH-dependent conformational changes\",\n      \"pmids\": [\"39609618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No endogenous ligand identified for the putative transmembrane binding site\",\n        \"How vesicular localization reconciles with plasma-membrane TGFβ receptor signalling is unresolved\",\n        \"Full-length structure including the transmembrane region not determined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how GPR180's structural and vesicular biology mechanistically connects its disparate roles in TGFβ/SMAD3 signalling, hepatic mTORC1/SREBP1 regulation, and adipocyte lipid handling.\",\n      \"evidence\": \"No discovery in the corpus unifies the structural, signalling, and metabolic findings or identifies a direct ligand and binding partners\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No identified physiological ligand engaging the transmembrane pocket\",\n        \"Direct physical partners in the TGFβ receptor complex unconfirmed\",\n        \"Causal chain linking vesicular conformational changes to downstream signalling not established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CTHRC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}