{"gene":"GUCA2A","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":1997,"finding":"The guanylin gene (Guca2/GUCA2A) is tightly linked to the uroguanylin gene (Guca1b) on mouse chromosome 4; both genes are structurally similar (three short exons), and guanylin peptide binds to the intestinal receptor guanylate cyclase-C (GC-C), stimulating cyclic GMP increase and inducing chloride secretion via CFTR.","method":"Gene cloning, chromosomal mapping, mRNA expression analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-ligand relationship established by cloning and expression analysis in a single study; receptor activation mechanism inferred from prior biochemical knowledge cited in the abstract","pmids":["9344659"],"is_preprint":false},{"year":2019,"finding":"GUCA2A (guanylin hormone) expression is eliminated in tubular adenomas, serrated adenomas, and MSI colorectal tumors compared to normal adjacent tissue; loss of GUCA2A silences its receptor GUCY2C, disrupting the tumor-suppressor signaling axis. Oral hormone (GUCA2A) replacement is proposed to reactivate GUCY2C signaling.","method":"Immunohistochemistry in human tumor specimens and genetic mouse models; loss-of-function pathway analysis","journal":"Human pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ligand-receptor pathway placement established in human specimens and mouse genetic models across multiple tumor subtypes in a single study","pmids":["30716341"],"is_preprint":false},{"year":2023,"finding":"GUCA2A protein is a selective marker of Paneth cells in human intestinal tissue; its expression does not differ between NEC and control infants, indicating GUCA2A-positive Paneth cells are present but with diminished defensin (DEFA6) activity in NEC.","method":"Immunohistochemistry with semi-automated digital image analysis on resected intestinal tissue from 70 infants","journal":"European journal of pediatrics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single study, single method (IHC), localization result without direct functional consequence for GUCA2A itself","pmids":["37017768"],"is_preprint":false},{"year":2025,"finding":"Transient induction of transcription factor KLF4 in human colonoids is sufficient to generate GUCA2A-positive colonocytes, establishing KLF4 as an upstream regulator of GUCA2A-expressing cell specification.","method":"Doxycycline-inducible lentiviral KLF4 overexpression in human colonoids; GUCA2A expression used as lineage marker","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single preprint, single overexpression experiment; identifies upstream transcriptional regulator but mechanism not further dissected","pmids":[],"is_preprint":true}],"current_model":"GUCA2A (guanylin) is a peptide hormone expressed in intestinal epithelial (colonocyte) and Paneth cells, whose expression is transcriptionally regulated by KLF4; it acts as a ligand for the receptor guanylate cyclase GUCY2C, stimulating intracellular cGMP production and chloride secretion via CFTR, and its loss in colorectal neoplasia silences the GUCY2C tumor-suppressor axis."},"narrative":{"mechanistic_narrative":"GUCA2A (guanylin) is an intestinal peptide hormone that signals through the receptor guanylate cyclase GUCY2C (GC-C) to control epithelial fluid and electrolyte homeostasis [PMID:9344659]. Binding of guanylin to GC-C stimulates an increase in intracellular cyclic GMP and drives chloride secretion through CFTR [PMID:9344659]. Beyond its secretory role, this ligand-receptor axis functions as a tumor-suppressor pathway in the colon: GUCA2A expression is lost in tubular adenomas, serrated adenomas, and MSI colorectal tumors, and this loss silences GUCY2C signaling [PMID:30716341]. The available corpus contains no further mechanistic dissection of guanylin processing, receptor binding kinetics, or downstream signaling.","teleology":[{"year":1997,"claim":"Established guanylin as a ligand for the intestinal receptor guanylate cyclase-C, defining the molecular basis of its secretory action.","evidence":"Gene cloning, chromosomal mapping, and mRNA expression analysis linking Guca2/GUCA2A to GC-C activation in mouse","pmids":["9344659"],"confidence":"Medium","gaps":["Receptor activation mechanism inferred from prior biochemistry rather than directly reconstituted","No structural characterization of the guanylin-GC-C interaction","Peptide maturation and processing not addressed"]},{"year":2019,"claim":"Placed GUCA2A within a colonic tumor-suppressor axis by showing its loss across multiple neoplastic subtypes silences GUCY2C signaling.","evidence":"Immunohistochemistry of human tumor specimens plus genetic mouse models and loss-of-function pathway analysis","pmids":["30716341"],"confidence":"Medium","gaps":["Causal mechanism of GUCA2A loss driving tumorigenesis not dissected","Therapeutic hormone-replacement reactivation of GUCY2C is proposed but not demonstrated functionally","No quantification of cGMP/CFTR output in tumor versus normal tissue"]},{"year":2023,"claim":"Identified GUCA2A as a selective Paneth cell marker, refining the cellular source of the hormone in human intestine.","evidence":"Immunohistochemistry with semi-automated digital image analysis on resected intestinal tissue from 70 infants","pmids":["37017768"],"confidence":"Low","gaps":["Single study, single method (IHC) without functional consequence for GUCA2A itself","Relationship between Paneth cell GUCA2A and the colonocyte secretory pool unresolved"]},{"year":2025,"claim":"Identified KLF4 as an upstream transcription factor sufficient to specify GUCA2A-expressing colonocytes.","evidence":"Doxycycline-inducible lentiviral KLF4 overexpression in human colonoids (preprint), using GUCA2A as a lineage marker","pmids":[],"confidence":"Low","gaps":["Single preprint overexpression experiment; not independently confirmed","Direct versus indirect transcriptional control of the GUCA2A promoter by KLF4 not established","Physiological relevance to endogenous cell specification untested"]},{"year":null,"claim":"How GUCA2A loss is mechanistically coupled to colorectal tumorigenesis and whether hormone replacement can restore GUCY2C signaling remain open.","evidence":"No timeline discovery resolves the causal or therapeutic mechanism","pmids":[],"confidence":"Low","gaps":["No demonstration that restoring GUCA2A reverses neoplastic phenotypes","Signaling output downstream of cGMP in the tumor-suppressor context uncharacterized"]}],"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]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["GUCY2C"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q02747","full_name":"Guanylin","aliases":["Guanylate cyclase activator 2A","Guanylate cyclase-activating protein 1","Guanylate cyclase-activating protein I","GCAP-I"],"length_aa":115,"mass_kda":12.4,"function":"Endogenous activator of intestinal guanylate cyclase. It stimulates this enzyme through the same receptor binding region as the heat-stable enterotoxins","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q02747/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GUCA2A","classification":"Not Classified","n_dependent_lines":139,"n_total_lines":1208,"dependency_fraction":0.11506622516556292},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GUCA2A","total_profiled":1310},"omim":[{"mim_id":"601271","title":"GUANYLATE CYCLASE ACTIVATOR 2B; GUCA2B","url":"https://www.omim.org/entry/601271"},{"mim_id":"139392","title":"GUANYLATE CYCLASE ACTIVATOR 2A; GUCA2A","url":"https://www.omim.org/entry/139392"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"intestine","ntpm":969.2}],"url":"https://www.proteinatlas.org/search/GUCA2A"},"hgnc":{"alias_symbol":["STARA"],"prev_symbol":["GUCA2"]},"alphafold":{"accession":"Q02747","domains":[{"cath_id":"3.90.1450.10","chopping":"30-46_59-115","consensus_level":"medium","plddt":84.1931,"start":30,"end":115}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q02747","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q02747-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q02747-F1-predicted_aligned_error_v6.png","plddt_mean":79.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GUCA2A","jax_strain_url":"https://www.jax.org/strain/search?query=GUCA2A"},"sequence":{"accession":"Q02747","fasta_url":"https://rest.uniprot.org/uniprotkb/Q02747.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q02747/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q02747"}},"corpus_meta":[{"pmid":"18406752","id":"PMC_18406752","title":"StAR-A tissue specific acute mediator of steroidogenesis.","date":"1996","source":"Trends in endocrinology and metabolism: TEM","url":"https://pubmed.ncbi.nlm.nih.gov/18406752","citation_count":36,"is_preprint":false},{"pmid":"31467713","id":"PMC_31467713","title":"Integrated Analysis of Oncogenic Networks in Colorectal Cancer Identifies GUCA2A as a Molecular Marker.","date":"2019","source":"Biochemistry research international","url":"https://pubmed.ncbi.nlm.nih.gov/31467713","citation_count":22,"is_preprint":false},{"pmid":"30716341","id":"PMC_30716341","title":"Silencing the GUCA2A-GUCY2C tumor suppressor axis in CIN, serrated, and MSI colorectal neoplasia.","date":"2019","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/30716341","citation_count":21,"is_preprint":false},{"pmid":"9344659","id":"PMC_9344659","title":"The uroguanylin gene (Guca1b) is linked to guanylin (Guca2) on mouse chromosome 4.","date":"1997","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9344659","citation_count":18,"is_preprint":false},{"pmid":"35807576","id":"PMC_35807576","title":"Phytochemical Analysis, Antioxidant, Antimicrobial, and Cytotoxic Activity of Different Extracts of Xanthoparmelia stenophylla Lichen from Stara Planina, Serbia.","date":"2022","source":"Plants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35807576","citation_count":15,"is_preprint":false},{"pmid":"16370484","id":"PMC_16370484","title":"Hb Stara Zagora: a new hyper-unstable hemoglobin causing severe hemolytic anemia.","date":"2005","source":"Hemoglobin","url":"https://pubmed.ncbi.nlm.nih.gov/16370484","citation_count":6,"is_preprint":false},{"pmid":"37017768","id":"PMC_37017768","title":"Paneth cell proteins DEFA6 and GUCA2A as tissue markers in necrotizing enterocolitis.","date":"2023","source":"European journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/37017768","citation_count":4,"is_preprint":false},{"pmid":"41200355","id":"PMC_41200355","title":"Prevalence of Malassezia pachydermatis yeasts in clinical infections in dogs: A single-center retrospective study at the University Veterinary Hospital, Stara Zagora, Bulgaria (2019-2023).","date":"2025","source":"Open veterinary journal","url":"https://pubmed.ncbi.nlm.nih.gov/41200355","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.16.680258","title":"Novel lentiviral constructs for the specification of rare and ectopic cell types in human colonoids","date":"2025-10-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.16.680258","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6688,"output_tokens":990,"usd":0.017457,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7504,"output_tokens":1663,"usd":0.039547,"stage2_stop_reason":"end_turn"},"total_usd":0.057004,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"The guanylin gene (Guca2/GUCA2A) is tightly linked to the uroguanylin gene (Guca1b) on mouse chromosome 4; both genes are structurally similar (three short exons), and guanylin peptide binds to the intestinal receptor guanylate cyclase-C (GC-C), stimulating cyclic GMP increase and inducing chloride secretion via CFTR.\",\n      \"method\": \"Gene cloning, chromosomal mapping, mRNA expression analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-ligand relationship established by cloning and expression analysis in a single study; receptor activation mechanism inferred from prior biochemical knowledge cited in the abstract\",\n      \"pmids\": [\"9344659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GUCA2A (guanylin hormone) expression is eliminated in tubular adenomas, serrated adenomas, and MSI colorectal tumors compared to normal adjacent tissue; loss of GUCA2A silences its receptor GUCY2C, disrupting the tumor-suppressor signaling axis. Oral hormone (GUCA2A) replacement is proposed to reactivate GUCY2C signaling.\",\n      \"method\": \"Immunohistochemistry in human tumor specimens and genetic mouse models; loss-of-function pathway analysis\",\n      \"journal\": \"Human pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ligand-receptor pathway placement established in human specimens and mouse genetic models across multiple tumor subtypes in a single study\",\n      \"pmids\": [\"30716341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GUCA2A protein is a selective marker of Paneth cells in human intestinal tissue; its expression does not differ between NEC and control infants, indicating GUCA2A-positive Paneth cells are present but with diminished defensin (DEFA6) activity in NEC.\",\n      \"method\": \"Immunohistochemistry with semi-automated digital image analysis on resected intestinal tissue from 70 infants\",\n      \"journal\": \"European journal of pediatrics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single study, single method (IHC), localization result without direct functional consequence for GUCA2A itself\",\n      \"pmids\": [\"37017768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Transient induction of transcription factor KLF4 in human colonoids is sufficient to generate GUCA2A-positive colonocytes, establishing KLF4 as an upstream regulator of GUCA2A-expressing cell specification.\",\n      \"method\": \"Doxycycline-inducible lentiviral KLF4 overexpression in human colonoids; GUCA2A expression used as lineage marker\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single preprint, single overexpression experiment; identifies upstream transcriptional regulator but mechanism not further dissected\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"GUCA2A (guanylin) is a peptide hormone expressed in intestinal epithelial (colonocyte) and Paneth cells, whose expression is transcriptionally regulated by KLF4; it acts as a ligand for the receptor guanylate cyclase GUCY2C, stimulating intracellular cGMP production and chloride secretion via CFTR, and its loss in colorectal neoplasia silences the GUCY2C tumor-suppressor axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GUCA2A (guanylin) is an intestinal peptide hormone that signals through the receptor guanylate cyclase GUCY2C (GC-C) to control epithelial fluid and electrolyte homeostasis [#0]. Binding of guanylin to GC-C stimulates an increase in intracellular cyclic GMP and drives chloride secretion through CFTR [#0]. Beyond its secretory role, this ligand-receptor axis functions as a tumor-suppressor pathway in the colon: GUCA2A expression is lost in tubular adenomas, serrated adenomas, and MSI colorectal tumors, and this loss silences GUCY2C signaling [#1]. The available corpus contains no further mechanistic dissection of guanylin processing, receptor binding kinetics, or downstream signaling.\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established guanylin as a ligand for the intestinal receptor guanylate cyclase-C, defining the molecular basis of its secretory action.\",\n      \"evidence\": \"Gene cloning, chromosomal mapping, and mRNA expression analysis linking Guca2/GUCA2A to GC-C activation in mouse\",\n      \"pmids\": [\"9344659\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Receptor activation mechanism inferred from prior biochemistry rather than directly reconstituted\",\n        \"No structural characterization of the guanylin-GC-C interaction\",\n        \"Peptide maturation and processing not addressed\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed GUCA2A within a colonic tumor-suppressor axis by showing its loss across multiple neoplastic subtypes silences GUCY2C signaling.\",\n      \"evidence\": \"Immunohistochemistry of human tumor specimens plus genetic mouse models and loss-of-function pathway analysis\",\n      \"pmids\": [\"30716341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Causal mechanism of GUCA2A loss driving tumorigenesis not dissected\",\n        \"Therapeutic hormone-replacement reactivation of GUCY2C is proposed but not demonstrated functionally\",\n        \"No quantification of cGMP/CFTR output in tumor versus normal tissue\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified GUCA2A as a selective Paneth cell marker, refining the cellular source of the hormone in human intestine.\",\n      \"evidence\": \"Immunohistochemistry with semi-automated digital image analysis on resected intestinal tissue from 70 infants\",\n      \"pmids\": [\"37017768\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single study, single method (IHC) without functional consequence for GUCA2A itself\",\n        \"Relationship between Paneth cell GUCA2A and the colonocyte secretory pool unresolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified KLF4 as an upstream transcription factor sufficient to specify GUCA2A-expressing colonocytes.\",\n      \"evidence\": \"Doxycycline-inducible lentiviral KLF4 overexpression in human colonoids (preprint), using GUCA2A as a lineage marker\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single preprint overexpression experiment; not independently confirmed\",\n        \"Direct versus indirect transcriptional control of the GUCA2A promoter by KLF4 not established\",\n        \"Physiological relevance to endogenous cell specification untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GUCA2A loss is mechanistically coupled to colorectal tumorigenesis and whether hormone replacement can restore GUCY2C signaling remain open.\",\n      \"evidence\": \"No timeline discovery resolves the causal or therapeutic mechanism\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No demonstration that restoring GUCA2A reverses neoplastic phenotypes\",\n        \"Signaling output downstream of cGMP in the tumor-suppressor context uncharacterized\"\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]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GUCY2C\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":2,"faith_total":3,"faith_pct":66.66666666666667}}