{"gene":"CALCR","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2018,"finding":"Collagen V (COLV), produced by muscle satellite cells, acts as a surrogate local ligand for the Calcitonin receptor (CALCR) to maintain satellite cell quiescence in a cell-autonomous manner; depletion of COLV leads to anomalous cell cycle entry, and systemic calcitonin administration rescues the quiescence defects in COLV-null satellite cells, placing CALCR downstream of a Notch-COLV signaling cascade.","method":"Conditional deletion (Col5a1 knockout), chromatin immunoprecipitation followed by sequencing (ChIP-seq), systemic calcitonin derivative administration, genetic epistasis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP-seq, conditional KO, rescue experiments) in a high-impact study with clear mechanistic pathway placement","pmids":["29795344"],"is_preprint":false},{"year":2019,"finding":"CalcR activates protein kinase A (PKA), which phosphorylates Lats1/2 (the main effector of Hippo signaling), thereby inhibiting nuclear accumulation of Yap1 and suppressing Hippo-target gene expression including cell-cycle-related molecules, thus maintaining muscle satellite cell quiescence.","method":"Transgenic expression of PKA catalytic domain in CalcR-mutant mice, genetic inactivation of Yap1 in CalcR-mutant cells (epistasis), phosphorylation assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with double-mutant rescue and defined phosphorylation mechanism; Yap1 KO in CalcR-mutant cells reinstates quiescence","pmids":["31747590"],"is_preprint":false},{"year":2017,"finding":"CALCR acts as a tumor suppressor in glioblastoma; calcitonin (CT) inhibits glioma cell properties and pro-oncogenic signaling in a CALCR-dependent manner, and patient-derived loss-of-function mutations in CALCR abolish these functions. WT CALCR inhibits Ras-mediated transformation of immortalized astrocytes.","method":"Patient-derived CALCR mutations, glioma cell lines, mouse xenograft models, calcitonin treatment with CT-CALCR axis functional characterization","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple cell and in vivo models with defined pathway, but single lab study","pmids":["29263181"],"is_preprint":false},{"year":2017,"finding":"CALCR (CTR) forms a heterodimer with the prostaglandin E2 receptor EP2 in ovarian granulosa cells; this heterodimerization specifically decreases CTR-mediated Ca2+ mobilization (~40% reduction) without significantly altering cAMP production by either receptor.","method":"LC-tandem MS/MS of EP2 co-immunoprecipitates, Western blotting of reciprocal co-IPs, fluorescence resonance energy transfer (FRET) in HEK293MSR cells, Ca2+ mobilization and cAMP functional assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP confirmed by FRET with functional consequence; single lab","pmids":["29095955"],"is_preprint":false},{"year":1996,"finding":"Homologous regulation of the calcitonin receptor (CTR) in nonosteoclastic cells involves agonist-induced receptor down-regulation and uncoupling from adenylate cyclase independently of CTR mRNA changes or PKA/PKC activation; the regulation is an inherent property of the receptor itself.","method":"Receptor binding assays, adenylate cyclase activity assays, RT-PCR, phorbol ester and PKA activator treatments in UMR106-06 and transfected HEK293 cells","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal assays establishing receptor-intrinsic mechanism; single lab","pmids":["8895320"],"is_preprint":false},{"year":2003,"finding":"Mouse Calcr is imprinted in a tissue-specific manner, with predominant expression from the maternal allele in the brain but no allelic bias in other tissues.","method":"Imprinting analysis using F1 mice from reciprocal crosses between B6 and JF strains, allelic expression analysis","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 — direct allelic expression measurement with reciprocal crosses; single lab but clear experimental demonstration","pmids":["12730726"],"is_preprint":false},{"year":2023,"finding":"Calcr-expressing neurons in the posterodorsal medial amygdala (MeApd) are GABAergic with female-biased expression; Calcr signaling in the MeApd suppresses social contacts, demonstrating a distinct circuit-level role from Calcr neurons in the medial preoptic area.","method":"AAV-shRNA knockdown of Calcr in MeApd, behavioral assays (social contact during resocialization), locomotor activity measurement","journal":"Molecular brain","confidence":"Medium","confidence_rationale":"Tier 2 — specific regional knockdown with defined behavioral phenotype; single lab","pmids":["36658598"],"is_preprint":false},{"year":2024,"finding":"CALCR directly binds to CD44 protein, preventing its degradation and upregulating CD44 expression; this CALCR-CD44 interaction mediates CALCR's pro-tumorigenic effects on renal cell carcinoma proliferation, migration, and anti-apoptosis.","method":"Co-immunoprecipitation (CALCR-CD44 binding), CALCR depletion experiments, CD44 knockdown epistasis, in vivo tumor formation assay","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP plus epistasis experiment; single lab with defined molecular mechanism","pmids":["38985127"],"is_preprint":false},{"year":2025,"finding":"CALCR interacts with ANTXR1 (via co-immunoprecipitation), and CALCR knockdown leads to decreased AKT phosphorylation; CALCR-ANTXR1 interaction promotes gastric cancer growth and metastasis via the AKT signaling pathway.","method":"Co-immunoprecipitation (CALCR-ANTXR1), CALCR knockdown in GC cell lines and nude mouse xenograft model, AKT phosphorylation western blotting","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP with limited mechanistic follow-up; single lab","pmids":["40195530"],"is_preprint":false},{"year":2024,"finding":"Chicken calcitonin receptor (CTR) and calcitonin receptor-like receptor (CLR), when combined with receptor activity-modifying proteins (RAMPs), activate both cAMP/PKA and MAPK/ERK signaling pathways upon calcitonin stimulation; notably chicken CLR can act as a functional calcitonin receptor independently and with RAMPs.","method":"Cloning of chicken CTR and CLR, luciferase reporter assays for cAMP/PKA and MAPK/ERK pathways, RAMP co-expression functional assays","journal":"Animals","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro functional reconstitution with reporter assays and defined signaling pathway outcomes; single lab","pmids":["38612299"],"is_preprint":false},{"year":2025,"finding":"CT/CALCR signaling activates the Hippo tumor suppressor pathway via CTR/cAMP/PKA/LATS1 cascade, inhibiting YAP/TAZ oncogenic transcription factors in glioblastoma stem cells; loss-of-function CTR mutants fail to activate this pathway, and intranasal salmon CT delivery inhibits glioma growth in orthotopic mouse models.","method":"Patient-derived glioma stem cells (GSCs), PKA/LATS1 phosphorylation assays, YAP phosphorylation-resistant mutant rescue experiments, intracranial mouse model, all-atom molecular dynamics simulation of mutant CTR","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods including in vitro signaling, genetic rescue, and in vivo; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.11.20.689524"],"is_preprint":true},{"year":2025,"finding":"CALCR-expressing neurons in the nucleus of the solitary tract (NTS Calcr/Prlh cells) in the brainstem dorsal vagal complex mediate long-term cagrilintide (amylin analog)-induced food intake suppression and body weight loss; activation of area postrema Calcr cells provides only acute but not sustained suppression.","method":"Single-nucleus RNA sequencing, spatial transcriptomics, cagrilintide treatment with transcriptional response profiling in rats and mice, chemogenetic/optogenetic neuron activation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — cross-species single-nucleus RNA-seq with spatial profiling and functional neuron activation; preprint","pmids":["bio_10.1101_2025.01.13.632726"],"is_preprint":true},{"year":1995,"finding":"The human calcitonin receptor gene (CALCR) was mapped to chromosome band 7q21.3 by PCR analysis of somatic cell hybrids and two-color fluorescence in situ hybridization (FISH), placing it telomeric to the elastin locus and outside the Williams syndrome deletion region.","method":"PCR of somatic cell hybrids, single-strand conformation analysis, two-color FISH on metaphase chromosome spreads","journal":"Cytogenetics and cell genetics","confidence":"High","confidence_rationale":"Tier 2 — direct genomic mapping with multiple orthogonal methods (PCR + FISH)","pmids":["7789182"],"is_preprint":false}],"current_model":"CALCR (calcitonin receptor) is a G protein-coupled receptor that, upon activation by calcitonin or surrogate ligands such as Collagen V, signals through cAMP/PKA to phosphorylate LATS1/2, thereby suppressing YAP1/TAZ nuclear accumulation via the Hippo pathway to maintain stem cell quiescence; it also activates MAPK/ERK pathways, forms functional heterodimers with EP2 that modulate Ca2+ signaling, interacts with binding partners such as CD44 and ANTXR1 to regulate cancer cell proliferation and AKT signaling, and is expressed from the maternal allele in a tissue-specific imprinted manner in the brain."},"narrative":{"teleology":[{"year":1995,"claim":"Establishing the chromosomal location of CALCR at 7q21.3 provided the foundational genomic context for subsequent functional and disease-association studies.","evidence":"PCR of somatic cell hybrids and two-color FISH on human metaphase chromosomes","pmids":["7789182"],"confidence":"High","gaps":["No functional information derived from mapping alone","Regulatory elements and promoter architecture uncharacterized"]},{"year":1996,"claim":"Demonstrating that calcitonin-induced receptor down-regulation and adenylate cyclase uncoupling occur independently of mRNA changes and PKA/PKC activation established that homologous desensitization is an intrinsic property of CALCR itself.","evidence":"Receptor binding assays, adenylate cyclase activity measurements, RT-PCR, and pharmacological inhibitor studies in UMR106-06 and transfected HEK293 cells","pmids":["8895320"],"confidence":"Medium","gaps":["Molecular mechanism of receptor-intrinsic uncoupling (e.g., phosphorylation sites, arrestin involvement) not identified","Not tested in primary cells or in vivo"]},{"year":2003,"claim":"Discovery of tissue-specific maternal imprinting of Calcr in the brain revealed an epigenetic regulatory layer, raising the question of whether monoallelic expression influences CALCR-dependent neural functions.","evidence":"Allelic expression analysis in F1 mice from reciprocal crosses between B6 and JF strains","pmids":["12730726"],"confidence":"Medium","gaps":["Functional consequence of monoallelic brain expression unknown","Imprinting control region not mapped","Not confirmed in human tissues"]},{"year":2017,"claim":"Two studies established CALCR's roles in heterodimer signaling and tumor suppression: CALCR forms heterodimers with EP2 that selectively attenuate Ca²⁺ signaling, and patient-derived loss-of-function CALCR mutations abolish its tumor-suppressive activity in glioblastoma by failing to inhibit Ras-mediated transformation.","evidence":"Reciprocal co-IP, FRET, and Ca²⁺/cAMP functional assays in HEK293 cells (heterodimerization); patient-derived mutations in glioma cell lines, xenografts, and calcitonin treatment (tumor suppression)","pmids":["29095955","29263181"],"confidence":"Medium","gaps":["Structural basis of EP2-CALCR heterodimer selectivity unknown","Which downstream effectors mediate CALCR tumor suppression in glioma beyond Ras not fully defined","In vivo relevance of EP2-CALCR heterodimerization not established"]},{"year":2018,"claim":"Identification of Collagen V as a surrogate local ligand for CALCR in satellite cells, downstream of Notch, resolved how quiescence is maintained cell-autonomously and placed CALCR within a Notch–COLV signaling cascade.","evidence":"Conditional Col5a1 knockout, ChIP-seq, systemic calcitonin rescue of COLV-null satellite cells, genetic epistasis in mice","pmids":["29795344"],"confidence":"High","gaps":["Direct binding of Collagen V to CALCR not biochemically demonstrated","Whether other collagens can substitute as CALCR ligands not tested"]},{"year":2019,"claim":"Elucidation of the PKA–LATS1/2–YAP1 axis downstream of CALCR provided the complete intracellular signaling cascade by which CALCR enforces satellite cell quiescence through Hippo pathway activation.","evidence":"Transgenic PKA catalytic domain expression in CalcR-mutant mice, Yap1 genetic inactivation in CalcR-mutant cells (double-mutant rescue), phosphorylation assays","pmids":["31747590"],"confidence":"High","gaps":["Whether this PKA–LATS–YAP axis operates in non-satellite-cell contexts not established","Identity of YAP1 transcriptional targets driving quiescence exit not fully cataloged"]},{"year":2023,"claim":"Identification of Calcr-expressing GABAergic neurons in the medial amygdala that suppress social contacts expanded CALCR's role beyond endocrine/stem cell biology into circuit-level behavioral regulation.","evidence":"AAV-shRNA knockdown of Calcr in MeApd, behavioral assays during resocialization in mice","pmids":["36658598"],"confidence":"Medium","gaps":["Downstream signaling in MeApd Calcr neurons not characterized","Whether calcitonin itself is the relevant ligand in this circuit is unclear","Specificity of shRNA knockdown not independently confirmed"]},{"year":2024,"claim":"Discovery that CALCR directly binds CD44 to prevent its degradation and that CALCR couples to MAPK/ERK in addition to cAMP/PKA broadened understanding of CALCR's context-dependent signaling repertoire and its dual tumor-suppressive versus pro-tumorigenic roles.","evidence":"Co-IP of CALCR-CD44 with epistasis experiments and in vivo tumor assays in renal carcinoma (CD44 interaction); luciferase reporter assays for cAMP/PKA and MAPK/ERK with RAMP co-expression in chicken CTR system (dual pathway activation)","pmids":["38985127","38612299"],"confidence":"Medium","gaps":["Structural determinants of CALCR-CD44 binding unknown","How tissue context determines whether CALCR acts as tumor suppressor or promoter not resolved","RAMP-dependent pathway switching in mammalian systems not confirmed"]},{"year":2025,"claim":"Interaction of CALCR with ANTXR1 and subsequent AKT activation was reported as a mechanism for CALCR-driven gastric cancer progression, though this rests on limited validation.","evidence":"Co-IP of CALCR-ANTXR1, CALCR knockdown with AKT phosphorylation western blotting, nude mouse xenograft","pmids":["40195530"],"confidence":"Low","gaps":["Single Co-IP without reciprocal validation or domain-mapping","Causal link between ANTXR1 binding and AKT activation not mechanistically dissected","Not independently replicated"]},{"year":null,"claim":"Key unresolved questions include the structural basis of CALCR ligand promiscuity (calcitonin vs. Collagen V), how tissue context switches CALCR between tumor-suppressive and pro-tumorigenic signaling, and the physiological ligand(s) activating CALCR in brain circuits controlling behavior.","evidence":"","pmids":[],"confidence":"High","gaps":["No co-crystal or cryo-EM structure of CALCR with Collagen V","Mechanism governing context-dependent oncogenic vs. tumor-suppressive output undefined","Endogenous ligand for neuronal CALCR populations not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,9]}],"complexes":[],"partners":["EP2","CD44","LATS1","YAP1","ANTXR1","RAMP1"],"other_free_text":[]},"mechanistic_narrative":"CALCR (calcitonin receptor) is a G protein-coupled receptor that transduces calcitonin and surrogate ligand signals through cAMP/PKA and MAPK/ERK pathways to regulate cell quiescence, proliferation, and neural circuit function. In muscle satellite cells, CALCR activation by calcitonin or Collagen V (downstream of Notch signaling) engages PKA to phosphorylate LATS1/2, suppressing YAP1 nuclear accumulation via the Hippo pathway and thereby maintaining quiescence [PMID:29795344, PMID:31747590]. CALCR functions as a tumor suppressor in glioblastoma, where patient-derived loss-of-function mutations abolish its ability to inhibit Ras-mediated transformation and pro-oncogenic signaling, while in renal and gastric cancers it instead promotes proliferation through stabilization of CD44 and interaction with ANTXR1/AKT signaling [PMID:29263181, PMID:38985127, PMID:40195530]. CALCR also forms functional heterodimers with the prostaglandin EP2 receptor that selectively attenuate Ca²⁺ mobilization, exhibits tissue-specific maternal imprinting in the brain, and marks neuronal populations in the medial amygdala and brainstem that regulate social behavior and food intake [PMID:29095955, PMID:12730726, PMID:36658598]."},"prefetch_data":{"uniprot":{"accession":"P30988","full_name":"Calcitonin receptor","aliases":[],"length_aa":474,"mass_kda":55.3,"function":"G protein-coupled receptor activated by ligand peptides amylin (IAPP), calcitonin (CT/CALCA) and calcitonin gene-related peptide type 1 (CGRP1/CALCA) (PubMed:35324283, PubMed:38603770). CALCR interacts with receptor-activity-modifying proteins RAMP1, 2 and 3 to form receptor complexes AMYR1, 2 and 3, respectively (PubMed:35324283, PubMed:38603770). IAPP, CT and CGRP1 activate CALCR and AMYRs with distinct modes of receptor activation resulting in specific phenotypes (PubMed:35324283, PubMed:38603770). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors. Activates cAMP-dependent pathway (PubMed:35324283, PubMed:7476993) Non-functional protein. Unable to couple to G proteins and activate adenylyl cyclase (PubMed:7476993). Does not undergo receptor internalization following ligand binding (PubMed:7476993)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P30988/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CALCR","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CALCR","total_profiled":1310},"omim":[{"mim_id":"616499","title":"TRANSMEMBRANE PROTEIN 203; TMEM203","url":"https://www.omim.org/entry/616499"},{"mim_id":"614523","title":"MICRO RNA 489; MIR489","url":"https://www.omim.org/entry/614523"},{"mim_id":"611902","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 136; CCDC136","url":"https://www.omim.org/entry/611902"},{"mim_id":"610562","title":"ZINC FINGER CCCH DOMAIN-CONTAINING PROTEIN 12A; ZC3H12A","url":"https://www.omim.org/entry/610562"},{"mim_id":"605155","title":"RECEPTOR ACTIVITY-MODIFYING PROTEIN 3; RAMP3","url":"https://www.omim.org/entry/605155"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cell Junctions","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Centriolar satellite","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":4.0},{"tissue":"kidney","ntpm":1.4}],"url":"https://www.proteinatlas.org/search/CALCR"},"hgnc":{"alias_symbol":["CTR","CT-R"],"prev_symbol":[]},"alphafold":{"accession":"P30988","domains":[{"cath_id":"4.10.1240.10","chopping":"38-135","consensus_level":"high","plddt":89.019,"start":38,"end":135},{"cath_id":"1.20.1070.10","chopping":"137-401","consensus_level":"high","plddt":84.2045,"start":137,"end":401}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P30988","model_url":"https://alphafold.ebi.ac.uk/files/AF-P30988-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P30988-F1-predicted_aligned_error_v6.png","plddt_mean":78.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CALCR","jax_strain_url":"https://www.jax.org/strain/search?query=CALCR"},"sequence":{"accession":"P30988","fasta_url":"https://rest.uniprot.org/uniprotkb/P30988.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P30988/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P30988"}},"corpus_meta":[{"pmid":"29795344","id":"PMC_29795344","title":"Reciprocal signalling by Notch-Collagen V-CALCR retains muscle stem cells in their niche.","date":"2018","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/29795344","citation_count":205,"is_preprint":false},{"pmid":"21510855","id":"PMC_21510855","title":"Molecular and functional analyses of COPT/Ctr-type copper transporter-like gene family in rice.","date":"2011","source":"BMC plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/21510855","citation_count":118,"is_preprint":false},{"pmid":"15385536","id":"PMC_15385536","title":"Eukaryotic CTR copper uptake transporters require two faces of the third transmembrane domain for helix packing, oligomerization, and function.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15385536","citation_count":89,"is_preprint":false},{"pmid":"19318609","id":"PMC_19318609","title":"Two Chlamydomonas CTR copper transporters with a novel cys-met motif are localized to the plasma membrane and function in copper assimilation.","date":"2009","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/19318609","citation_count":79,"is_preprint":false},{"pmid":"18349053","id":"PMC_18349053","title":"Tomato ethylene receptor-CTR interactions: visualization of NEVER-RIPE interactions with multiple CTRs at the endoplasmic reticulum.","date":"2008","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/18349053","citation_count":75,"is_preprint":false},{"pmid":"12827356","id":"PMC_12827356","title":"The SLC31 (Ctr) copper transporter family.","date":"2003","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12827356","citation_count":73,"is_preprint":false},{"pmid":"22796944","id":"PMC_22796944","title":"Pol II CTD kinases Bur1 and Kin28 promote Spt5 CTR-independent recruitment of Paf1 complex.","date":"2012","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/22796944","citation_count":70,"is_preprint":false},{"pmid":"16844735","id":"PMC_16844735","title":"Transcriptional regulation of ethylene receptor and CTR genes involved in ethylene-induced flower opening in cut rose (Rosa hybrida) cv. 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signaling cascade.\",\n      \"method\": \"Conditional deletion (Col5a1 knockout), chromatin immunoprecipitation followed by sequencing (ChIP-seq), systemic calcitonin derivative administration, genetic epistasis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP-seq, conditional KO, rescue experiments) in a high-impact study with clear mechanistic pathway placement\",\n      \"pmids\": [\"29795344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CalcR activates protein kinase A (PKA), which phosphorylates Lats1/2 (the main effector of Hippo signaling), thereby inhibiting nuclear accumulation of Yap1 and suppressing Hippo-target gene expression including cell-cycle-related molecules, thus maintaining muscle satellite cell quiescence.\",\n      \"method\": \"Transgenic expression of PKA catalytic domain in CalcR-mutant mice, genetic inactivation of Yap1 in CalcR-mutant cells (epistasis), phosphorylation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with double-mutant rescue and defined phosphorylation mechanism; Yap1 KO in CalcR-mutant cells reinstates quiescence\",\n      \"pmids\": [\"31747590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CALCR acts as a tumor suppressor in glioblastoma; calcitonin (CT) inhibits glioma cell properties and pro-oncogenic signaling in a CALCR-dependent manner, and patient-derived loss-of-function mutations in CALCR abolish these functions. WT CALCR inhibits Ras-mediated transformation of immortalized astrocytes.\",\n      \"method\": \"Patient-derived CALCR mutations, glioma cell lines, mouse xenograft models, calcitonin treatment with CT-CALCR axis functional characterization\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple cell and in vivo models with defined pathway, but single lab study\",\n      \"pmids\": [\"29263181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CALCR (CTR) forms a heterodimer with the prostaglandin E2 receptor EP2 in ovarian granulosa cells; this heterodimerization specifically decreases CTR-mediated Ca2+ mobilization (~40% reduction) without significantly altering cAMP production by either receptor.\",\n      \"method\": \"LC-tandem MS/MS of EP2 co-immunoprecipitates, Western blotting of reciprocal co-IPs, fluorescence resonance energy transfer (FRET) in HEK293MSR cells, Ca2+ mobilization and cAMP functional assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP confirmed by FRET with functional consequence; single lab\",\n      \"pmids\": [\"29095955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Homologous regulation of the calcitonin receptor (CTR) in nonosteoclastic cells involves agonist-induced receptor down-regulation and uncoupling from adenylate cyclase independently of CTR mRNA changes or PKA/PKC activation; the regulation is an inherent property of the receptor itself.\",\n      \"method\": \"Receptor binding assays, adenylate cyclase activity assays, RT-PCR, phorbol ester and PKA activator treatments in UMR106-06 and transfected HEK293 cells\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal assays establishing receptor-intrinsic mechanism; single lab\",\n      \"pmids\": [\"8895320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mouse Calcr is imprinted in a tissue-specific manner, with predominant expression from the maternal allele in the brain but no allelic bias in other tissues.\",\n      \"method\": \"Imprinting analysis using F1 mice from reciprocal crosses between B6 and JF strains, allelic expression analysis\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct allelic expression measurement with reciprocal crosses; single lab but clear experimental demonstration\",\n      \"pmids\": [\"12730726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Calcr-expressing neurons in the posterodorsal medial amygdala (MeApd) are GABAergic with female-biased expression; Calcr signaling in the MeApd suppresses social contacts, demonstrating a distinct circuit-level role from Calcr neurons in the medial preoptic area.\",\n      \"method\": \"AAV-shRNA knockdown of Calcr in MeApd, behavioral assays (social contact during resocialization), locomotor activity measurement\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — specific regional knockdown with defined behavioral phenotype; single lab\",\n      \"pmids\": [\"36658598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CALCR directly binds to CD44 protein, preventing its degradation and upregulating CD44 expression; this CALCR-CD44 interaction mediates CALCR's pro-tumorigenic effects on renal cell carcinoma proliferation, migration, and anti-apoptosis.\",\n      \"method\": \"Co-immunoprecipitation (CALCR-CD44 binding), CALCR depletion experiments, CD44 knockdown epistasis, in vivo tumor formation assay\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP plus epistasis experiment; single lab with defined molecular mechanism\",\n      \"pmids\": [\"38985127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CALCR interacts with ANTXR1 (via co-immunoprecipitation), and CALCR knockdown leads to decreased AKT phosphorylation; CALCR-ANTXR1 interaction promotes gastric cancer growth and metastasis via the AKT signaling pathway.\",\n      \"method\": \"Co-immunoprecipitation (CALCR-ANTXR1), CALCR knockdown in GC cell lines and nude mouse xenograft model, AKT phosphorylation western blotting\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with limited mechanistic follow-up; single lab\",\n      \"pmids\": [\"40195530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Chicken calcitonin receptor (CTR) and calcitonin receptor-like receptor (CLR), when combined with receptor activity-modifying proteins (RAMPs), activate both cAMP/PKA and MAPK/ERK signaling pathways upon calcitonin stimulation; notably chicken CLR can act as a functional calcitonin receptor independently and with RAMPs.\",\n      \"method\": \"Cloning of chicken CTR and CLR, luciferase reporter assays for cAMP/PKA and MAPK/ERK pathways, RAMP co-expression functional assays\",\n      \"journal\": \"Animals\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro functional reconstitution with reporter assays and defined signaling pathway outcomes; single lab\",\n      \"pmids\": [\"38612299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CT/CALCR signaling activates the Hippo tumor suppressor pathway via CTR/cAMP/PKA/LATS1 cascade, inhibiting YAP/TAZ oncogenic transcription factors in glioblastoma stem cells; loss-of-function CTR mutants fail to activate this pathway, and intranasal salmon CT delivery inhibits glioma growth in orthotopic mouse models.\",\n      \"method\": \"Patient-derived glioma stem cells (GSCs), PKA/LATS1 phosphorylation assays, YAP phosphorylation-resistant mutant rescue experiments, intracranial mouse model, all-atom molecular dynamics simulation of mutant CTR\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including in vitro signaling, genetic rescue, and in vivo; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.11.20.689524\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CALCR-expressing neurons in the nucleus of the solitary tract (NTS Calcr/Prlh cells) in the brainstem dorsal vagal complex mediate long-term cagrilintide (amylin analog)-induced food intake suppression and body weight loss; activation of area postrema Calcr cells provides only acute but not sustained suppression.\",\n      \"method\": \"Single-nucleus RNA sequencing, spatial transcriptomics, cagrilintide treatment with transcriptional response profiling in rats and mice, chemogenetic/optogenetic neuron activation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cross-species single-nucleus RNA-seq with spatial profiling and functional neuron activation; preprint\",\n      \"pmids\": [\"bio_10.1101_2025.01.13.632726\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The human calcitonin receptor gene (CALCR) was mapped to chromosome band 7q21.3 by PCR analysis of somatic cell hybrids and two-color fluorescence in situ hybridization (FISH), placing it telomeric to the elastin locus and outside the Williams syndrome deletion region.\",\n      \"method\": \"PCR of somatic cell hybrids, single-strand conformation analysis, two-color FISH on metaphase chromosome spreads\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct genomic mapping with multiple orthogonal methods (PCR + FISH)\",\n      \"pmids\": [\"7789182\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CALCR (calcitonin receptor) is a G protein-coupled receptor that, upon activation by calcitonin or surrogate ligands such as Collagen V, signals through cAMP/PKA to phosphorylate LATS1/2, thereby suppressing YAP1/TAZ nuclear accumulation via the Hippo pathway to maintain stem cell quiescence; it also activates MAPK/ERK pathways, forms functional heterodimers with EP2 that modulate Ca2+ signaling, interacts with binding partners such as CD44 and ANTXR1 to regulate cancer cell proliferation and AKT signaling, and is expressed from the maternal allele in a tissue-specific imprinted manner in the brain.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CALCR (calcitonin receptor) is a G protein-coupled receptor that transduces calcitonin and surrogate ligand signals through cAMP/PKA and MAPK/ERK pathways to regulate cell quiescence, proliferation, and neural circuit function. In muscle satellite cells, CALCR activation by calcitonin or Collagen V (downstream of Notch signaling) engages PKA to phosphorylate LATS1/2, suppressing YAP1 nuclear accumulation via the Hippo pathway and thereby maintaining quiescence [PMID:29795344, PMID:31747590]. CALCR functions as a tumor suppressor in glioblastoma, where patient-derived loss-of-function mutations abolish its ability to inhibit Ras-mediated transformation and pro-oncogenic signaling, while in renal and gastric cancers it instead promotes proliferation through stabilization of CD44 and interaction with ANTXR1/AKT signaling [PMID:29263181, PMID:38985127, PMID:40195530]. CALCR also forms functional heterodimers with the prostaglandin EP2 receptor that selectively attenuate Ca²⁺ mobilization, exhibits tissue-specific maternal imprinting in the brain, and marks neuronal populations in the medial amygdala and brainstem that regulate social behavior and food intake [PMID:29095955, PMID:12730726, PMID:36658598].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing the chromosomal location of CALCR at 7q21.3 provided the foundational genomic context for subsequent functional and disease-association studies.\",\n      \"evidence\": \"PCR of somatic cell hybrids and two-color FISH on human metaphase chromosomes\",\n      \"pmids\": [\"7789182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No functional information derived from mapping alone\", \"Regulatory elements and promoter architecture uncharacterized\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstrating that calcitonin-induced receptor down-regulation and adenylate cyclase uncoupling occur independently of mRNA changes and PKA/PKC activation established that homologous desensitization is an intrinsic property of CALCR itself.\",\n      \"evidence\": \"Receptor binding assays, adenylate cyclase activity measurements, RT-PCR, and pharmacological inhibitor studies in UMR106-06 and transfected HEK293 cells\",\n      \"pmids\": [\"8895320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of receptor-intrinsic uncoupling (e.g., phosphorylation sites, arrestin involvement) not identified\", \"Not tested in primary cells or in vivo\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Discovery of tissue-specific maternal imprinting of Calcr in the brain revealed an epigenetic regulatory layer, raising the question of whether monoallelic expression influences CALCR-dependent neural functions.\",\n      \"evidence\": \"Allelic expression analysis in F1 mice from reciprocal crosses between B6 and JF strains\",\n      \"pmids\": [\"12730726\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of monoallelic brain expression unknown\", \"Imprinting control region not mapped\", \"Not confirmed in human tissues\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two studies established CALCR's roles in heterodimer signaling and tumor suppression: CALCR forms heterodimers with EP2 that selectively attenuate Ca²⁺ signaling, and patient-derived loss-of-function CALCR mutations abolish its tumor-suppressive activity in glioblastoma by failing to inhibit Ras-mediated transformation.\",\n      \"evidence\": \"Reciprocal co-IP, FRET, and Ca²⁺/cAMP functional assays in HEK293 cells (heterodimerization); patient-derived mutations in glioma cell lines, xenografts, and calcitonin treatment (tumor suppression)\",\n      \"pmids\": [\"29095955\", \"29263181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of EP2-CALCR heterodimer selectivity unknown\", \"Which downstream effectors mediate CALCR tumor suppression in glioma beyond Ras not fully defined\", \"In vivo relevance of EP2-CALCR heterodimerization not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of Collagen V as a surrogate local ligand for CALCR in satellite cells, downstream of Notch, resolved how quiescence is maintained cell-autonomously and placed CALCR within a Notch–COLV signaling cascade.\",\n      \"evidence\": \"Conditional Col5a1 knockout, ChIP-seq, systemic calcitonin rescue of COLV-null satellite cells, genetic epistasis in mice\",\n      \"pmids\": [\"29795344\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding of Collagen V to CALCR not biochemically demonstrated\", \"Whether other collagens can substitute as CALCR ligands not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Elucidation of the PKA–LATS1/2–YAP1 axis downstream of CALCR provided the complete intracellular signaling cascade by which CALCR enforces satellite cell quiescence through Hippo pathway activation.\",\n      \"evidence\": \"Transgenic PKA catalytic domain expression in CalcR-mutant mice, Yap1 genetic inactivation in CalcR-mutant cells (double-mutant rescue), phosphorylation assays\",\n      \"pmids\": [\"31747590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this PKA–LATS–YAP axis operates in non-satellite-cell contexts not established\", \"Identity of YAP1 transcriptional targets driving quiescence exit not fully cataloged\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of Calcr-expressing GABAergic neurons in the medial amygdala that suppress social contacts expanded CALCR's role beyond endocrine/stem cell biology into circuit-level behavioral regulation.\",\n      \"evidence\": \"AAV-shRNA knockdown of Calcr in MeApd, behavioral assays during resocialization in mice\",\n      \"pmids\": [\"36658598\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling in MeApd Calcr neurons not characterized\", \"Whether calcitonin itself is the relevant ligand in this circuit is unclear\", \"Specificity of shRNA knockdown not independently confirmed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that CALCR directly binds CD44 to prevent its degradation and that CALCR couples to MAPK/ERK in addition to cAMP/PKA broadened understanding of CALCR's context-dependent signaling repertoire and its dual tumor-suppressive versus pro-tumorigenic roles.\",\n      \"evidence\": \"Co-IP of CALCR-CD44 with epistasis experiments and in vivo tumor assays in renal carcinoma (CD44 interaction); luciferase reporter assays for cAMP/PKA and MAPK/ERK with RAMP co-expression in chicken CTR system (dual pathway activation)\",\n      \"pmids\": [\"38985127\", \"38612299\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural determinants of CALCR-CD44 binding unknown\", \"How tissue context determines whether CALCR acts as tumor suppressor or promoter not resolved\", \"RAMP-dependent pathway switching in mammalian systems not confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Interaction of CALCR with ANTXR1 and subsequent AKT activation was reported as a mechanism for CALCR-driven gastric cancer progression, though this rests on limited validation.\",\n      \"evidence\": \"Co-IP of CALCR-ANTXR1, CALCR knockdown with AKT phosphorylation western blotting, nude mouse xenograft\",\n      \"pmids\": [\"40195530\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation or domain-mapping\", \"Causal link between ANTXR1 binding and AKT activation not mechanistically dissected\", \"Not independently replicated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of CALCR ligand promiscuity (calcitonin vs. Collagen V), how tissue context switches CALCR between tumor-suppressive and pro-tumorigenic signaling, and the physiological ligand(s) activating CALCR in brain circuits controlling behavior.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal or cryo-EM structure of CALCR with Collagen V\", \"Mechanism governing context-dependent oncogenic vs. tumor-suppressive output undefined\", \"Endogenous ligand for neuronal CALCR populations not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [1, 2, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EP2\", \"CD44\", \"LATS1\", \"YAP1\", \"ANTXR1\", \"RAMP1\"],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I need to fix the pathway term_ids. Let me correct:\n\n```json\n{\n  \"mechanistic_narrative\": \"CALCR (calcitonin receptor) is a G protein-coupled receptor that transduces calcitonin and surrogate ligand signals through cAMP/PKA and MAPK/ERK pathways to regulate cell quiescence, proliferation, and neural circuit function. In muscle satellite cells, CALCR activation by calcitonin or Collagen V (downstream of Notch signaling) engages PKA to phosphorylate LATS1/2, suppressing YAP1 nuclear accumulation via the Hippo pathway and thereby maintaining quiescence [PMID:29795344, PMID:31747590]. CALCR functions as a tumor suppressor in glioblastoma, where patient-derived loss-of-function mutations abolish its ability to inhibit Ras-mediated transformation, while in renal and gastric cancers it promotes proliferation through stabilization of CD44 and interaction with ANTXR1/AKT signaling [PMID:29263181, PMID:38985127, PMID:40195530]. CALCR also forms functional heterodimers with the prostaglandin EP2 receptor that selectively attenuate Ca²⁺ mobilization, exhibits tissue-specific maternal imprinting in the brain, and marks neuronal populations in the medial amygdala and brainstem that regulate social behavior and food intake [PMID:29095955, PMID:12730726, PMID:36658598].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing the chromosomal location of CALCR at 7q21.3 provided the foundational genomic context for subsequent functional and disease-association studies.\",\n      \"evidence\": \"PCR of somatic cell hybrids and two-color FISH on human metaphase chromosomes\",\n      \"pmids\": [\"7789182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No functional information derived from mapping alone\", \"Regulatory elements and promoter architecture uncharacterized\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstrating that calcitonin-induced receptor down-regulation and adenylate cyclase uncoupling occur independently of mRNA changes and PKA/PKC activation established that homologous desensitization is an intrinsic property of CALCR itself.\",\n      \"evidence\": \"Receptor binding assays, adenylate cyclase activity measurements, RT-PCR, and pharmacological inhibitor studies in UMR106-06 and transfected HEK293 cells\",\n      \"pmids\": [\"8895320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of receptor-intrinsic uncoupling (e.g., phosphorylation sites, arrestin involvement) not identified\", \"Not tested in primary cells or in vivo\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Discovery of tissue-specific maternal imprinting of Calcr in the brain revealed an epigenetic regulatory layer, raising the question of whether monoallelic expression influences CALCR-dependent neural functions.\",\n      \"evidence\": \"Allelic expression analysis in F1 mice from reciprocal crosses between B6 and JF strains\",\n      \"pmids\": [\"12730726\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of monoallelic brain expression unknown\", \"Imprinting control region not mapped\", \"Not confirmed in human tissues\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two studies established CALCR's roles in heterodimer signaling and tumor suppression: CALCR forms heterodimers with EP2 that selectively attenuate Ca²⁺ signaling, and patient-derived loss-of-function CALCR mutations abolish its tumor-suppressive activity in glioblastoma.\",\n      \"evidence\": \"Reciprocal co-IP, FRET, and Ca²⁺/cAMP functional assays in HEK293 cells (heterodimerization); patient-derived mutations in glioma cell lines, xenografts, and calcitonin treatment (tumor suppression)\",\n      \"pmids\": [\"29095955\", \"29263181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of EP2-CALCR heterodimer selectivity unknown\", \"Which downstream effectors mediate CALCR tumor suppression in glioma beyond Ras not fully defined\", \"In vivo relevance of EP2-CALCR heterodimerization not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of Collagen V as a surrogate local ligand for CALCR in satellite cells, downstream of Notch, resolved how quiescence is maintained cell-autonomously and placed CALCR within a Notch–COLV signaling cascade.\",\n      \"evidence\": \"Conditional Col5a1 knockout, ChIP-seq, systemic calcitonin rescue of COLV-null satellite cells, genetic epistasis in mice\",\n      \"pmids\": [\"29795344\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding of Collagen V to CALCR not biochemically demonstrated\", \"Whether other collagens can substitute as CALCR ligands not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Elucidation of the PKA–LATS1/2–YAP1 axis downstream of CALCR provided the complete intracellular signaling cascade by which CALCR enforces satellite cell quiescence through Hippo pathway activation.\",\n      \"evidence\": \"Transgenic PKA catalytic domain expression in CalcR-mutant mice, Yap1 genetic inactivation in CalcR-mutant cells (double-mutant rescue), phosphorylation assays\",\n      \"pmids\": [\"31747590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this PKA–LATS–YAP axis operates in non-satellite-cell contexts not established\", \"Identity of YAP1 transcriptional targets driving quiescence exit not fully cataloged\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of Calcr-expressing GABAergic neurons in the medial amygdala that suppress social contacts expanded CALCR's role beyond endocrine/stem cell biology into circuit-level behavioral regulation.\",\n      \"evidence\": \"AAV-shRNA knockdown of Calcr in MeApd, behavioral assays during resocialization in mice\",\n      \"pmids\": [\"36658598\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling in MeApd Calcr neurons not characterized\", \"Whether calcitonin itself is the relevant ligand in this circuit is unclear\", \"Specificity of shRNA knockdown not independently confirmed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that CALCR directly binds CD44 to prevent its degradation and that CALCR couples to MAPK/ERK in addition to cAMP/PKA broadened understanding of CALCR's context-dependent signaling repertoire and its dual tumor-suppressive versus pro-tumorigenic roles.\",\n      \"evidence\": \"Co-IP of CALCR-CD44 with epistasis experiments and in vivo tumor assays in renal carcinoma; luciferase reporter assays for cAMP/PKA and MAPK/ERK with RAMP co-expression in chicken CTR system\",\n      \"pmids\": [\"38985127\", \"38612299\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural determinants of CALCR-CD44 binding unknown\", \"How tissue context determines whether CALCR acts as tumor suppressor or promoter not resolved\", \"RAMP-dependent pathway switching in mammalian systems not confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Interaction of CALCR with ANTXR1 and subsequent AKT activation was reported as a mechanism for CALCR-driven gastric cancer progression, though this rests on limited validation.\",\n      \"evidence\": \"Co-IP of CALCR-ANTXR1, CALCR knockdown with AKT phosphorylation western blotting, nude mouse xenograft\",\n      \"pmids\": [\"40195530\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation or domain-mapping\", \"Causal link between ANTXR1 binding and AKT activation not mechanistically dissected\", \"Not independently replicated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of CALCR ligand promiscuity (calcitonin vs. Collagen V), how tissue context switches CALCR between tumor-suppressive and pro-tumorigenic signaling, and the physiological ligand(s) activating CALCR in brain circuits controlling behavior.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal or cryo-EM structure of CALCR with Collagen V\", \"Mechanism governing context-dependent oncogenic vs. tumor-suppressive output undefined\", \"Endogenous ligand for neuronal CALCR populations not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EP2\", \"CD44\", \"LATS1\", \"YAP1\", \"ANTXR1\", \"RAMP1\"],\n    \"other_free_text\": []\n  }\n}\n```"}