{"gene":"FAM237A","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2020,"finding":"FAM237A was identified as a specific activator of GPR83 (a GPCR implicated in CNS and regulatory T-cell function); the active form of FAM237A is a C-terminally cleaved, amidated 9 kDa secreted protein produced via posttranslational processing in the regulated secretory pathway.","method":"Functional GPCR screen using endocrine host cells expressing preprohormones; posttranslational processing characterization","journal":"SLAS discovery : advancing life sciences R & D","confidence":"Medium","confidence_rationale":"Tier 2 — functional cell-based screen with biochemical characterization of processed form, single lab","pmids":["32713278"],"is_preprint":false},{"year":2023,"finding":"Mature human FAM237A binds to GPR83 with nanomolar affinity, activates this receptor, and induces its internalization in transfected HEK293T cells; PEN and proCCK56-63 do not interact with GPR83 under the same assay conditions, establishing FAM237A as the primary endogenous agonist of GPR83.","method":"NanoLuc Binary Technology (NanoBiT)-based ligand-binding assay, fluorescent ligand-based visualization, and NanoBiT-based β-arrestin recruitment assay in HEK293T cells","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal cell-based assays (binding, activation, internalization) in a single study, with rigorous negative controls","pmids":["36853120"],"is_preprint":false}],"current_model":"FAM237A (also known as neurosecretory protein GL/NPGL) is processed from a preprohormone into a C-terminally cleaved and amidated ~9 kDa mature neuropeptide that binds to and activates the brain-enriched orphan GPCR GPR83 with nanomolar affinity, inducing β-arrestin recruitment and receptor internalization."},"narrative":{"teleology":[{"year":2020,"claim":"Establishing that the FAM237A gene product is not merely a precursor but undergoes regulated secretory pathway processing to yield a C-terminally amidated ~9 kDa neuropeptide that specifically activates the orphan receptor GPR83 resolved the ligand identity question for this brain-enriched GPCR.","evidence":"Functional GPCR screen using endocrine host cells co-expressing preprohormones with biochemical characterization of the processed form","pmids":["32713278"],"confidence":"Medium","gaps":["Single-lab discovery without independent replication at the time","Downstream signaling cascades beyond GPCR activation not characterized","In vivo physiological relevance of the FAM237A–GPR83 axis not demonstrated"]},{"year":2023,"claim":"Quantitative binding and functional assays confirmed FAM237A as the primary endogenous ligand for GPR83 — not PEN or proCCK56-63 — and revealed a complete agonist profile including nanomolar binding, β-arrestin recruitment, and receptor internalization, consolidating the deorphanization.","evidence":"NanoBiT-based ligand-binding, β-arrestin recruitment, and fluorescent ligand internalization assays with negative-control peptides in HEK293T cells","pmids":["36853120"],"confidence":"High","gaps":["G-protein coupling specificity (Gi, Gq, Gs) of GPR83 upon FAM237A binding not determined","Endogenous tissue-level confirmation of the interaction (e.g., in hypothalamic neurons) not yet reported","Structural basis of FAM237A–GPR83 recognition unknown"]},{"year":null,"claim":"The in vivo physiological functions mediated by the FAM237A–GPR83 signaling axis — including roles in energy homeostasis, neuroendocrine regulation, or immune modulation — remain uncharacterized at the mechanistic level.","evidence":"","pmids":[],"confidence":"Low","gaps":["No loss-of-function or gain-of-function animal models reported for FAM237A","G-protein coupling pathway and downstream transcriptional consequences undefined","Whether FAM237A signals through additional receptors beyond GPR83 is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["GPR83"],"other_free_text":[]},"mechanistic_narrative":"FAM237A encodes a preprohormone that is post-translationally processed via C-terminal cleavage and amidation into a mature ~9 kDa secreted neuropeptide that functions as the primary endogenous agonist of the orphan GPCR GPR83 [PMID:32713278]. Mature FAM237A binds GPR83 with nanomolar affinity, induces β-arrestin recruitment, and triggers receptor internalization [PMID:36853120]."},"prefetch_data":{"uniprot":{"accession":"A0A1B0GTK4","full_name":"Protein FAM237A","aliases":[],"length_aa":181,"mass_kda":20.6,"function":"May be capable of activating GPR83 via the GNAQ signaling pathway","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/A0A1B0GTK4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FAM237A","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":74,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FAM237A","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"brain","ntpm":1.8}],"url":"https://www.proteinatlas.org/search/FAM237A"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"A0A1B0GTK4","domains":[{"cath_id":"-","chopping":"46-113","consensus_level":"medium","plddt":89.4713,"start":46,"end":113}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A0A1B0GTK4","model_url":"https://alphafold.ebi.ac.uk/files/AF-A0A1B0GTK4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A0A1B0GTK4-F1-predicted_aligned_error_v6.png","plddt_mean":64.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FAM237A","jax_strain_url":"https://www.jax.org/strain/search?query=FAM237A"},"sequence":{"accession":"A0A1B0GTK4","fasta_url":"https://rest.uniprot.org/uniprotkb/A0A1B0GTK4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A0A1B0GTK4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A0A1B0GTK4"}},"corpus_meta":[{"pmid":"36853120","id":"PMC_36853120","title":"FAM237A, rather than peptide PEN and proCCK56-63, binds to and activates the orphan receptor GPR83.","date":"2023","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/36853120","citation_count":10,"is_preprint":false},{"pmid":"32713278","id":"PMC_32713278","title":"A Pilot Screen of a Novel Peptide Hormone Library Identified Candidate GPR83 Ligands.","date":"2020","source":"SLAS discovery : advancing life sciences R & D","url":"https://pubmed.ncbi.nlm.nih.gov/32713278","citation_count":9,"is_preprint":false},{"pmid":"37689599","id":"PMC_37689599","title":"Nanomolar range of FAM237B can activate receptor GPR83.","date":"2023","source":"Amino acids","url":"https://pubmed.ncbi.nlm.nih.gov/37689599","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":2669,"output_tokens":583,"usd":0.008376},"stage2":{"model":"claude-opus-4-6","input_tokens":3754,"output_tokens":934,"usd":0.06318},"total_usd":0.071556,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"FAM237A was identified as a specific activator of GPR83 (a GPCR implicated in CNS and regulatory T-cell function); the active form of FAM237A is a C-terminally cleaved, amidated 9 kDa secreted protein produced via posttranslational processing in the regulated secretory pathway.\",\n      \"method\": \"Functional GPCR screen using endocrine host cells expressing preprohormones; posttranslational processing characterization\",\n      \"journal\": \"SLAS discovery : advancing life sciences R & D\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional cell-based screen with biochemical characterization of processed form, single lab\",\n      \"pmids\": [\"32713278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Mature human FAM237A binds to GPR83 with nanomolar affinity, activates this receptor, and induces its internalization in transfected HEK293T cells; PEN and proCCK56-63 do not interact with GPR83 under the same assay conditions, establishing FAM237A as the primary endogenous agonist of GPR83.\",\n      \"method\": \"NanoLuc Binary Technology (NanoBiT)-based ligand-binding assay, fluorescent ligand-based visualization, and NanoBiT-based β-arrestin recruitment assay in HEK293T cells\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal cell-based assays (binding, activation, internalization) in a single study, with rigorous negative controls\",\n      \"pmids\": [\"36853120\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FAM237A (also known as neurosecretory protein GL/NPGL) is processed from a preprohormone into a C-terminally cleaved and amidated ~9 kDa mature neuropeptide that binds to and activates the brain-enriched orphan GPCR GPR83 with nanomolar affinity, inducing β-arrestin recruitment and receptor internalization.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FAM237A encodes a preprohormone that is post-translationally processed via C-terminal cleavage and amidation into a mature ~9 kDa secreted neuropeptide that functions as the primary endogenous agonist of the orphan GPCR GPR83 [PMID:32713278]. Mature FAM237A binds GPR83 with nanomolar affinity, induces β-arrestin recruitment, and triggers receptor internalization [PMID:36853120].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing that the FAM237A gene product is not merely a precursor but undergoes regulated secretory pathway processing to yield a C-terminally amidated ~9 kDa neuropeptide that specifically activates the orphan receptor GPR83 resolved the ligand identity question for this brain-enriched GPCR.\",\n      \"evidence\": \"Functional GPCR screen using endocrine host cells co-expressing preprohormones with biochemical characterization of the processed form\",\n      \"pmids\": [\"32713278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab discovery without independent replication at the time\",\n        \"Downstream signaling cascades beyond GPCR activation not characterized\",\n        \"In vivo physiological relevance of the FAM237A–GPR83 axis not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Quantitative binding and functional assays confirmed FAM237A as the primary endogenous ligand for GPR83 — not PEN or proCCK56-63 — and revealed a complete agonist profile including nanomolar binding, β-arrestin recruitment, and receptor internalization, consolidating the deorphanization.\",\n      \"evidence\": \"NanoBiT-based ligand-binding, β-arrestin recruitment, and fluorescent ligand internalization assays with negative-control peptides in HEK293T cells\",\n      \"pmids\": [\"36853120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"G-protein coupling specificity (Gi, Gq, Gs) of GPR83 upon FAM237A binding not determined\",\n        \"Endogenous tissue-level confirmation of the interaction (e.g., in hypothalamic neurons) not yet reported\",\n        \"Structural basis of FAM237A–GPR83 recognition unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The in vivo physiological functions mediated by the FAM237A–GPR83 signaling axis — including roles in energy homeostasis, neuroendocrine regulation, or immune modulation — remain uncharacterized at the mechanistic level.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No loss-of-function or gain-of-function animal models reported for FAM237A\",\n        \"G-protein coupling pathway and downstream transcriptional consequences undefined\",\n        \"Whether FAM237A signals through additional receptors beyond GPR83 is untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GPR83\"],\n    \"other_free_text\": []\n  }\n}\n```"}