{"gene":"CALCR","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2018,"finding":"Collagen V (COLV), produced by muscle satellite cells downstream of Notch/RBPJ transcriptional regulation, acts as a surrogate local ligand for the Calcitonin receptor (CALCR) on satellite cells, maintaining quiescence in a cell-autonomous manner. Conditional deletion of Col5a1 caused cell cycle entry and stem cell pool depletion, and systemic calcitonin derivative administration rescued quiescence defects in COLV-null satellite cells.","method":"Chromatin immunoprecipitation sequencing (ChIP-seq), conditional gene knockout (Col5a1), in vivo pharmacological rescue with calcitonin derivative","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP-seq, genetic KO, pharmacological rescue) in a single rigorous study establishing ligand identity, upstream regulation, and functional consequence","pmids":["29795344"],"is_preprint":false},{"year":2019,"finding":"CALCR (CalcR) signaling maintains muscle satellite cell quiescence via a PKA-Lats1/2-Yap1 axis: CalcR activates PKA, which phosphorylates Lats1/2, thereby inhibiting nuclear accumulation of Yap1 and suppressing Hippo-target cell-cycle genes. Transgenic PKA catalytic domain expression rescued CalcR-mutant satellite cell quiescence defects, and genetic inactivation of Yap1 in CalcR-mutant cells reinstated quiescence.","method":"Transgenic overexpression of PKA catalytic domain, genetic epistasis (CalcR mutant × Yap1 conditional KO), phosphorylation assays for Lats1/2","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with double mutant rescue and multiple orthogonal experiments in a single focused study definitively placing CALCR in a specific signaling cascade","pmids":["31747590"],"is_preprint":false},{"year":2017,"finding":"CALCR acts as a tumor suppressor in glioblastoma: exogenously added calcitonin inhibited glioma cell proliferation and pro-oncogenic signaling in a CALCR-dependent manner, and patient-derived loss-of-function mutations in CALCR abolished these inhibitory functions. Wild-type CALCR, but not mutant versions, inhibited Ras-mediated transformation of immortalized astrocytes in vitro, and calcitonin inhibited patient-derived neurosphere growth and in vivo tumor growth.","method":"Loss-of-function mutation characterization, in vitro transformation assay, patient-derived neurosphere assay, mouse xenograft model","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (in vitro transformation, neurosphere, xenograft) in a single lab establishing tumor-suppressive signaling function","pmids":["29263181"],"is_preprint":false},{"year":2017,"finding":"CALCR (CTR) forms a heterodimer with the prostaglandin E2 receptor EP2 in ovarian granulosa cells and HEK293 cells. EP2-CTR heterodimerization specifically reduces CTR-mediated Ca2+ mobilization by approximately 40% without significantly altering cAMP production by either receptor alone.","method":"Co-immunoprecipitation with LC-MS/MS, Western blot of co-IPs, fluorescence resonance energy transfer (FRET), functional Ca2+ mobilization and cAMP assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP confirmed by FRET and functional assays in a single lab, multiple orthogonal methods","pmids":["29095955"],"is_preprint":false},{"year":1996,"finding":"Homologous regulation of the rat C1a calcitonin receptor (CTR) in nonosteoclastic cells involves ligand-induced receptor down-regulation and uncoupling from adenylate cyclase that is independent of changes in CTR mRNA levels and independent of PKA or PKC activation. Calcitonin treatment reduced cell-surface CTR density and reduced adenylate cyclase responsiveness to a second CT challenge; these effects were recapitulated in CTR-naive HEK293 cells expressing the cloned C1a CTR under a heterologous promoter.","method":"Radioligand binding assays, adenylate cyclase activity assay, receptor down-regulation kinetics in transfected HEK293 cells vs. endogenous expression, PKA/PKC pharmacological activation, reverse transcription-PCR for CTR mRNA","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal assays (binding, cAMP, mRNA, PKA/PKC pharmacology) in a single study; mechanistic conclusions supported by heterologous expression controls","pmids":["8895320"],"is_preprint":false},{"year":2003,"finding":"The mouse Calcr gene is imprinted in a tissue-specific manner, with predominant expression from the maternal allele in the brain, whereas no allelic bias is detected in other tissues.","method":"Allelic expression analysis using F1 mice from reciprocal crosses between B6 and JF strains (imprinting analysis)","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct experimental determination of parent-of-origin allelic expression using reciprocal crosses, single study","pmids":["12730726"],"is_preprint":false},{"year":1995,"finding":"The human CALCR gene was mapped to chromosome band 7q21.3 by PCR, SSCA of somatic cell hybrids, and FISH to metaphase chromosomes; two-color FISH confirmed CALCR maps telomeric to the elastin locus (ELN) and outside the Williams syndrome deletion region.","method":"PCR with somatic cell hybrids, single-strand conformation analysis, fluorescence in situ hybridization (FISH)","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromosomal localization by two orthogonal methods (SSCA + FISH) replicated in multiple patient samples","pmids":["7789182"],"is_preprint":false},{"year":2024,"finding":"CALCR directly binds CD44 protein in renal cell carcinoma cells, preventing CD44 protein degradation and thereby upregulating CD44 expression. CALCR depletion reduced CD44 levels, and CD44 deficiency significantly attenuated the pro-tumorigenic effects of CALCR overexpression on proliferation, migration, and apoptosis resistance.","method":"Co-immunoprecipitation, CALCR knockdown with phenotypic rescue by CD44, in vivo tumor formation assay","journal":"Aging","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP pulldown for binding claim, partial mechanistic follow-up; single lab, single study","pmids":["38985127"],"is_preprint":false},{"year":2024,"finding":"In chickens, CTR (calcitonin receptor) stimulates both the cAMP/PKA and MAPK/ERK signaling pathways upon calcitonin binding, as demonstrated by luciferase reporter assays. RAMP co-expression modifies CTR signaling, and chicken CLR can serve as a functional CT receptor even without RAMPs.","method":"Receptor cloning, luciferase reporter assays for cAMP/PKA and MAPK/ERK pathway activation, RAMP co-expression functional assays","journal":"Animals","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional assays in a non-mammalian ortholog system, single lab, limited mechanistic depth","pmids":["38612299"],"is_preprint":false},{"year":2025,"finding":"In glioblastoma, CT/CTR signaling activates the Hippo tumor-suppressor pathway through a CTR/cAMP/PKA/LATS1 cascade, inhibiting YAP/TAZ oncogenic transcription factors. Patient-derived loss-of-function CTR mutants fail to activate this Hippo pathway. Intranasal delivery of salmon CT inhibited glioma growth initiated by glioma stem cells (GSCs) in an intracranial orthotopic mouse model. All-atom molecular dynamics simulations revealed structural perturbations in CTR mutants that perturb cAMP/PKA signaling.","method":"Patient-derived glioma stem cell assays, phosphorylation assays (LATS1), YAP phosphorylation-resistant mutant epistasis, intracranial orthotopic mouse model with intranasal CT delivery, molecular dynamics simulation of WT and mutant CTR","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (cell assay, phosphorylation assays, epistasis, in vivo model, structural simulation) in a single preprint; partially corroborated by prior peer-reviewed work (PMID:29263181, PMID:31747590)","pmids":[],"is_preprint":true},{"year":2023,"finding":"In the posterodorsal medial amygdala (MeApd), CALCR-expressing neurons are GABAergic and show female-biased expression. Inhibiting CALCR expression in MeApd via AAV-shRNA increased social contacts during resocialization without affecting locomotion, demonstrating that endogenous CALCR signaling in the MeApd suppresses social contact behavior.","method":"Immunohistochemistry for cell-type markers, AAV-shRNA knockdown of Calcr in MeApd, behavioral assay (resocialization paradigm)","journal":"Molecular brain","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single knockdown experiment with behavioral readout, limited molecular pathway characterization, single lab","pmids":["36658598"],"is_preprint":false},{"year":2025,"finding":"In the brainstem dorsal vagal complex (DVC), CALCR-expressing neurons mediate the suppression of food intake and body weight by the amylin analog cagrilintide. Long-term cagrilintide responsiveness involves NTS Calcr/Prlh neurons: cagrilintide promoted increased Prlh expression in NTS Calcr/Prlh cells in cagrilintide-responsive rats but not in poorly-responsive mice. Activating area postrema Calcr cells only transiently reduced food intake without long-term body weight effects.","method":"Single-nucleus RNA sequencing, spatial transcriptomics, cross-species comparison (rat, mouse, non-human primate), in vivo activation of AP Calcr cells","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transcriptional profiling and cell-type characterization with limited direct manipulation of CALCR itself; preprint, single study","pmids":[],"is_preprint":true},{"year":2025,"finding":"CALCR interacts with ANTXR1 in gastric cancer cells, and this interaction leads to decreased AKT phosphorylation. CALCR knockdown reduced GC cell proliferation, increased apoptosis, and inhibited migration/invasion in vitro, and reduced tumor growth and metastasis in a nude mouse xenograft model.","method":"Co-immunoprecipitation (CALCR-ANTXR1 interaction), siRNA knockdown, CCK-8 proliferation assay, flow cytometry, transwell migration/invasion assay, nude mouse xenograft","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for binding claim, AKT phosphorylation shown but mechanism of CALCR-ANTXR1 interaction on AKT not deeply characterized; single lab","pmids":["40195530"],"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 activating the Hippo tumor-suppressor pathway and inhibiting nuclear YAP/TAZ activity; in muscle satellite cells this cascade maintains quiescence downstream of a Notch-ColV-CALCR axis, while in the brain CALCR is maternally imprinted, modulates social behavior via GABAergic neurons in the medial amygdala, and mediates food intake suppression in brainstem DVC neurons; CALCR also heterodimerizes with the EP2 prostaglandin receptor to attenuate Ca2+ mobilization, and can bind partners such as CD44 and ANTXR1 to influence tumor cell survival."},"narrative":{"mechanistic_narrative":"CALCR encodes the calcitonin receptor, a G protein-coupled receptor that couples ligand binding to cAMP/PKA signaling to control cell-cycle quiescence and tumor-suppressive transcription [PMID:31747590, PMID:29263181]. In muscle satellite cells, CALCR maintains quiescence cell-autonomously through a PKA–LATS1/2–YAP1 axis: PKA activation downstream of the receptor phosphorylates LATS1/2, which restrains nuclear YAP1 and suppresses Hippo-target cell-cycle genes, with both PKA catalytic-domain transgenes and Yap1 inactivation rescuing CALCR-mutant quiescence defects [PMID:31747590]. The local ligand for this satellite-cell program is Collagen V, produced downstream of Notch/RBPJ, and systemic calcitonin derivatives rescue quiescence defects in Collagen V-null cells [PMID:29795344]. The same cAMP/PKA/LATS-Hippo cascade underlies CALCR's tumor-suppressive activity in glioblastoma, where calcitonin inhibits proliferation and Ras-mediated transformation in a receptor-dependent manner and patient-derived loss-of-function mutations abolish these effects [PMID:29263181]. CALCR signaling is subject to homologous desensitization through ligand-induced receptor down-regulation and adenylate cyclase uncoupling independent of PKA/PKC and of receptor mRNA levels [PMID:8895320], and is modulated by heterodimerization with the EP2 prostaglandin receptor, which selectively dampens CALCR-mediated Ca2+ mobilization [PMID:29095955]. The mouse Calcr gene shows brain-specific maternal imprinting [PMID:12730726], and CALCR-expressing neurons function in defined circuits, including GABAergic neurons of the posterodorsal medial amygdala that suppress social contact [PMID:36658598].","teleology":[{"year":1995,"claim":"Before functional dissection, the human CALCR locus had to be physically placed in the genome, establishing it as a distinct gene near but outside the Williams syndrome region.","evidence":"PCR of somatic cell hybrids, single-strand conformation analysis, and two-color FISH to metaphase chromosomes","pmids":["7789182"],"confidence":"Medium","gaps":["No functional or regulatory information from mapping alone","Does not address receptor activity or signaling"]},{"year":1996,"claim":"It was unclear how CALCR responsiveness is regulated after agonist exposure; this work showed receptor desensitization occurs via surface down-regulation and adenylate cyclase uncoupling, not transcriptional control or kinase feedback.","evidence":"Radioligand binding, adenylate cyclase assays, RT-PCR for CTR mRNA, and PKA/PKC pharmacology in transfected HEK293 and endogenous cells","pmids":["8895320"],"confidence":"Medium","gaps":["Molecular machinery of down-regulation (internalization, arrestins) not identified","Studied in rat C1a isoform; human relevance not directly tested"]},{"year":2003,"claim":"The question of whether Calcr is monoallelically expressed was answered by showing tissue-specific maternal imprinting restricted to the brain.","evidence":"Allelic expression analysis in F1 mice from reciprocal B6 × JF crosses","pmids":["12730726"],"confidence":"Medium","gaps":["Imprinting control elements not mapped","Functional consequence of brain-specific maternal expression unknown"]},{"year":2017,"claim":"Whether CALCR has anti-proliferative function was tested in glioblastoma, where calcitonin inhibited transformation and tumor growth in a receptor-dependent manner and patient mutations abolished this, defining CALCR as a tumor suppressor.","evidence":"Loss-of-function mutation characterization, in vitro transformation assay, patient-derived neurosphere assay, and mouse xenograft","pmids":["29263181"],"confidence":"Medium","gaps":["Downstream signaling effectors not resolved in this study","Endogenous tumor-relevant ligand source unclear"]},{"year":2017,"claim":"To explain how CALCR's Ca2+ signaling is tuned, heterodimerization with the EP2 prostaglandin receptor was shown to selectively reduce CALCR-mediated Ca2+ mobilization without altering cAMP output.","evidence":"Reciprocal Co-IP with LC-MS/MS, FRET, and functional Ca2+/cAMP assays in granulosa and HEK293 cells","pmids":["29095955"],"confidence":"Medium","gaps":["Physiological setting of heterodimer beyond granulosa cells not established","Structural basis of biased signaling not resolved"]},{"year":2018,"claim":"The endogenous local ligand and upstream regulation of CALCR in satellite cells were unknown; Collagen V was identified as a Notch/RBPJ-driven surrogate ligand maintaining quiescence.","evidence":"ChIP-seq, conditional Col5a1 knockout, and in vivo pharmacological rescue with a calcitonin derivative","pmids":["29795344"],"confidence":"High","gaps":["Mode of Collagen V engagement of the receptor not structurally defined","Whether Collagen V acts elsewhere as a CALCR ligand untested"]},{"year":2019,"claim":"How CALCR enforces quiescence at the signaling level was resolved by placing it in a PKA–LATS1/2–YAP1 cascade that suppresses Hippo-target cell-cycle genes, via genetic epistasis.","evidence":"PKA catalytic-domain transgenic rescue, CalcR × Yap1 double-mutant epistasis, and LATS1/2 phosphorylation assays","pmids":["31747590"],"confidence":"High","gaps":["G protein/cAMP coupling step linking receptor to PKA not detailed","Generalizability beyond satellite cells not tested here"]},{"year":2023,"claim":"The circuit-level role of CALCR neurons in behavior was probed by showing MeApd CALCR-expressing GABAergic neurons suppress social contact.","evidence":"Immunohistochemistry for cell-type markers, AAV-shRNA Calcr knockdown, and resocialization behavioral assay","pmids":["36658598"],"confidence":"Low","gaps":["Single knockdown experiment with limited molecular pathway characterization","Ligand and downstream signaling in these neurons unidentified"]},{"year":2024,"claim":"Additional protein partners in cancer were sought; CALCR was shown to bind CD44 and stabilize it against degradation, supporting pro-tumorigenic phenotypes in renal cell carcinoma.","evidence":"Co-IP, CALCR knockdown with CD44 rescue, and in vivo tumor formation assay","pmids":["38985127"],"confidence":"Low","gaps":["Single Co-IP for binding claim without reciprocal/structural validation","Mechanism of CD44 stabilization unresolved","Apparent pro-tumor role conflicts with tumor-suppressor data in other tissues"]},{"year":2025,"claim":"The glioblastoma tumor-suppressor mechanism was unified with the satellite-cell cascade by showing CTR/cAMP/PKA/LATS1 activation of Hippo suppresses YAP/TAZ, with structural rationale for mutant inactivity.","evidence":"Patient-derived glioma stem cell assays, LATS1/YAP phosphorylation and epistasis, intracranial orthotopic model with intranasal calcitonin, and all-atom molecular dynamics (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","In vivo efficacy across diverse patient tumors not established"]},{"year":2025,"claim":"The role of brainstem CALCR neurons in energy balance was characterized, identifying NTS Calcr/Prlh cells as mediators of long-term amylin-analog responsiveness.","evidence":"Single-nucleus RNA-seq, spatial transcriptomics, cross-species comparison, and in vivo activation of AP Calcr cells (preprint)","pmids":[],"confidence":"Low","gaps":["Preprint with limited direct manipulation of CALCR itself","Receptor-intrinsic signaling in these neurons not dissected"]},{"year":2025,"claim":"Another cancer interaction was reported, with CALCR binding ANTXR1 and decreasing AKT phosphorylation to promote gastric cancer growth.","evidence":"Co-IP, siRNA knockdown, proliferation/apoptosis/migration assays, and nude mouse xenograft","pmids":["40195530"],"confidence":"Low","gaps":["Single Co-IP for binding claim without reciprocal validation","Mechanistic link from ANTXR1 interaction to AKT not characterized"]},{"year":null,"claim":"How CALCR can act as a tumor suppressor via Hippo in some contexts yet appear pro-tumorigenic through CD44/ANTXR1 in others, and what determines its tissue-specific signaling outputs, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying model reconciling tumor-suppressive and pro-tumor roles","Receptor structure and G-protein coupling determinants not defined in the corpus","Endogenous ligands outside muscle Collagen V not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,2,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1]}],"complexes":[],"partners":["PTGER2","CD44","ANTXR1","COL5A1"],"other_free_text":[]}},"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":207,"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":81,"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":71,"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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Conditional deletion of Col5a1 caused cell cycle entry and stem cell pool depletion, and systemic calcitonin derivative administration rescued quiescence defects in COLV-null satellite cells.\",\n      \"method\": \"Chromatin immunoprecipitation sequencing (ChIP-seq), conditional gene knockout (Col5a1), in vivo pharmacological rescue with calcitonin derivative\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP-seq, genetic KO, pharmacological rescue) in a single rigorous study establishing ligand identity, upstream regulation, and functional consequence\",\n      \"pmids\": [\"29795344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CALCR (CalcR) signaling maintains muscle satellite cell quiescence via a PKA-Lats1/2-Yap1 axis: CalcR activates PKA, which phosphorylates Lats1/2, thereby inhibiting nuclear accumulation of Yap1 and suppressing Hippo-target cell-cycle genes. Transgenic PKA catalytic domain expression rescued CalcR-mutant satellite cell quiescence defects, and genetic inactivation of Yap1 in CalcR-mutant cells reinstated quiescence.\",\n      \"method\": \"Transgenic overexpression of PKA catalytic domain, genetic epistasis (CalcR mutant × Yap1 conditional KO), phosphorylation assays for Lats1/2\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with double mutant rescue and multiple orthogonal experiments in a single focused study definitively placing CALCR in a specific signaling cascade\",\n      \"pmids\": [\"31747590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CALCR acts as a tumor suppressor in glioblastoma: exogenously added calcitonin inhibited glioma cell proliferation and pro-oncogenic signaling in a CALCR-dependent manner, and patient-derived loss-of-function mutations in CALCR abolished these inhibitory functions. Wild-type CALCR, but not mutant versions, inhibited Ras-mediated transformation of immortalized astrocytes in vitro, and calcitonin inhibited patient-derived neurosphere growth and in vivo tumor growth.\",\n      \"method\": \"Loss-of-function mutation characterization, in vitro transformation assay, patient-derived neurosphere assay, mouse xenograft model\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (in vitro transformation, neurosphere, xenograft) in a single lab establishing tumor-suppressive signaling function\",\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 and HEK293 cells. EP2-CTR heterodimerization specifically reduces CTR-mediated Ca2+ mobilization by approximately 40% without significantly altering cAMP production by either receptor alone.\",\n      \"method\": \"Co-immunoprecipitation with LC-MS/MS, Western blot of co-IPs, fluorescence resonance energy transfer (FRET), functional Ca2+ mobilization and cAMP assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP confirmed by FRET and functional assays in a single lab, multiple orthogonal methods\",\n      \"pmids\": [\"29095955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Homologous regulation of the rat C1a calcitonin receptor (CTR) in nonosteoclastic cells involves ligand-induced receptor down-regulation and uncoupling from adenylate cyclase that is independent of changes in CTR mRNA levels and independent of PKA or PKC activation. Calcitonin treatment reduced cell-surface CTR density and reduced adenylate cyclase responsiveness to a second CT challenge; these effects were recapitulated in CTR-naive HEK293 cells expressing the cloned C1a CTR under a heterologous promoter.\",\n      \"method\": \"Radioligand binding assays, adenylate cyclase activity assay, receptor down-regulation kinetics in transfected HEK293 cells vs. endogenous expression, PKA/PKC pharmacological activation, reverse transcription-PCR for CTR mRNA\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal assays (binding, cAMP, mRNA, PKA/PKC pharmacology) in a single study; mechanistic conclusions supported by heterologous expression controls\",\n      \"pmids\": [\"8895320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The mouse Calcr gene is imprinted in a tissue-specific manner, with predominant expression from the maternal allele in the brain, whereas no allelic bias is detected in other tissues.\",\n      \"method\": \"Allelic expression analysis using F1 mice from reciprocal crosses between B6 and JF strains (imprinting analysis)\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct experimental determination of parent-of-origin allelic expression using reciprocal crosses, single study\",\n      \"pmids\": [\"12730726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The human CALCR gene was mapped to chromosome band 7q21.3 by PCR, SSCA of somatic cell hybrids, and FISH to metaphase chromosomes; two-color FISH confirmed CALCR maps telomeric to the elastin locus (ELN) and outside the Williams syndrome deletion region.\",\n      \"method\": \"PCR with somatic cell hybrids, single-strand conformation analysis, fluorescence in situ hybridization (FISH)\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromosomal localization by two orthogonal methods (SSCA + FISH) replicated in multiple patient samples\",\n      \"pmids\": [\"7789182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CALCR directly binds CD44 protein in renal cell carcinoma cells, preventing CD44 protein degradation and thereby upregulating CD44 expression. CALCR depletion reduced CD44 levels, and CD44 deficiency significantly attenuated the pro-tumorigenic effects of CALCR overexpression on proliferation, migration, and apoptosis resistance.\",\n      \"method\": \"Co-immunoprecipitation, CALCR knockdown with phenotypic rescue by CD44, in vivo tumor formation assay\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP pulldown for binding claim, partial mechanistic follow-up; single lab, single study\",\n      \"pmids\": [\"38985127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In chickens, CTR (calcitonin receptor) stimulates both the cAMP/PKA and MAPK/ERK signaling pathways upon calcitonin binding, as demonstrated by luciferase reporter assays. RAMP co-expression modifies CTR signaling, and chicken CLR can serve as a functional CT receptor even without RAMPs.\",\n      \"method\": \"Receptor cloning, luciferase reporter assays for cAMP/PKA and MAPK/ERK pathway activation, RAMP co-expression functional assays\",\n      \"journal\": \"Animals\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional assays in a non-mammalian ortholog system, single lab, limited mechanistic depth\",\n      \"pmids\": [\"38612299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In glioblastoma, CT/CTR signaling activates the Hippo tumor-suppressor pathway through a CTR/cAMP/PKA/LATS1 cascade, inhibiting YAP/TAZ oncogenic transcription factors. Patient-derived loss-of-function CTR mutants fail to activate this Hippo pathway. Intranasal delivery of salmon CT inhibited glioma growth initiated by glioma stem cells (GSCs) in an intracranial orthotopic mouse model. All-atom molecular dynamics simulations revealed structural perturbations in CTR mutants that perturb cAMP/PKA signaling.\",\n      \"method\": \"Patient-derived glioma stem cell assays, phosphorylation assays (LATS1), YAP phosphorylation-resistant mutant epistasis, intracranial orthotopic mouse model with intranasal CT delivery, molecular dynamics simulation of WT and mutant CTR\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (cell assay, phosphorylation assays, epistasis, in vivo model, structural simulation) in a single preprint; partially corroborated by prior peer-reviewed work (PMID:29263181, PMID:31747590)\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In the posterodorsal medial amygdala (MeApd), CALCR-expressing neurons are GABAergic and show female-biased expression. Inhibiting CALCR expression in MeApd via AAV-shRNA increased social contacts during resocialization without affecting locomotion, demonstrating that endogenous CALCR signaling in the MeApd suppresses social contact behavior.\",\n      \"method\": \"Immunohistochemistry for cell-type markers, AAV-shRNA knockdown of Calcr in MeApd, behavioral assay (resocialization paradigm)\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single knockdown experiment with behavioral readout, limited molecular pathway characterization, single lab\",\n      \"pmids\": [\"36658598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In the brainstem dorsal vagal complex (DVC), CALCR-expressing neurons mediate the suppression of food intake and body weight by the amylin analog cagrilintide. Long-term cagrilintide responsiveness involves NTS Calcr/Prlh neurons: cagrilintide promoted increased Prlh expression in NTS Calcr/Prlh cells in cagrilintide-responsive rats but not in poorly-responsive mice. Activating area postrema Calcr cells only transiently reduced food intake without long-term body weight effects.\",\n      \"method\": \"Single-nucleus RNA sequencing, spatial transcriptomics, cross-species comparison (rat, mouse, non-human primate), in vivo activation of AP Calcr cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcriptional profiling and cell-type characterization with limited direct manipulation of CALCR itself; preprint, single study\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CALCR interacts with ANTXR1 in gastric cancer cells, and this interaction leads to decreased AKT phosphorylation. CALCR knockdown reduced GC cell proliferation, increased apoptosis, and inhibited migration/invasion in vitro, and reduced tumor growth and metastasis in a nude mouse xenograft model.\",\n      \"method\": \"Co-immunoprecipitation (CALCR-ANTXR1 interaction), siRNA knockdown, CCK-8 proliferation assay, flow cytometry, transwell migration/invasion assay, nude mouse xenograft\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for binding claim, AKT phosphorylation shown but mechanism of CALCR-ANTXR1 interaction on AKT not deeply characterized; single lab\",\n      \"pmids\": [\"40195530\"],\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 activating the Hippo tumor-suppressor pathway and inhibiting nuclear YAP/TAZ activity; in muscle satellite cells this cascade maintains quiescence downstream of a Notch-ColV-CALCR axis, while in the brain CALCR is maternally imprinted, modulates social behavior via GABAergic neurons in the medial amygdala, and mediates food intake suppression in brainstem DVC neurons; CALCR also heterodimerizes with the EP2 prostaglandin receptor to attenuate Ca2+ mobilization, and can bind partners such as CD44 and ANTXR1 to influence tumor cell survival.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CALCR encodes the calcitonin receptor, a G protein-coupled receptor that couples ligand binding to cAMP/PKA signaling to control cell-cycle quiescence and tumor-suppressive transcription [#1, #2]. In muscle satellite cells, CALCR maintains quiescence cell-autonomously through a PKA–LATS1/2–YAP1 axis: PKA activation downstream of the receptor phosphorylates LATS1/2, which restrains nuclear YAP1 and suppresses Hippo-target cell-cycle genes, with both PKA catalytic-domain transgenes and Yap1 inactivation rescuing CALCR-mutant quiescence defects [#1]. The local ligand for this satellite-cell program is Collagen V, produced downstream of Notch/RBPJ, and systemic calcitonin derivatives rescue quiescence defects in Collagen V-null cells [#0]. The same cAMP/PKA/LATS-Hippo cascade underlies CALCR's tumor-suppressive activity in glioblastoma, where calcitonin inhibits proliferation and Ras-mediated transformation in a receptor-dependent manner and patient-derived loss-of-function mutations abolish these effects [#2]. CALCR signaling is subject to homologous desensitization through ligand-induced receptor down-regulation and adenylate cyclase uncoupling independent of PKA/PKC and of receptor mRNA levels [#4], and is modulated by heterodimerization with the EP2 prostaglandin receptor, which selectively dampens CALCR-mediated Ca2+ mobilization [#3]. The mouse Calcr gene shows brain-specific maternal imprinting [#5], and CALCR-expressing neurons function in defined circuits, including GABAergic neurons of the posterodorsal medial amygdala that suppress social contact [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Before functional dissection, the human CALCR locus had to be physically placed in the genome, establishing it as a distinct gene near but outside the Williams syndrome region.\",\n      \"evidence\": \"PCR of somatic cell hybrids, single-strand conformation analysis, and two-color FISH to metaphase chromosomes\",\n      \"pmids\": [\"7789182\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional or regulatory information from mapping alone\", \"Does not address receptor activity or signaling\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"It was unclear how CALCR responsiveness is regulated after agonist exposure; this work showed receptor desensitization occurs via surface down-regulation and adenylate cyclase uncoupling, not transcriptional control or kinase feedback.\",\n      \"evidence\": \"Radioligand binding, adenylate cyclase assays, RT-PCR for CTR mRNA, and PKA/PKC pharmacology in transfected HEK293 and endogenous cells\",\n      \"pmids\": [\"8895320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular machinery of down-regulation (internalization, arrestins) not identified\", \"Studied in rat C1a isoform; human relevance not directly tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The question of whether Calcr is monoallelically expressed was answered by showing tissue-specific maternal imprinting restricted to the brain.\",\n      \"evidence\": \"Allelic expression analysis in F1 mice from reciprocal B6 × JF crosses\",\n      \"pmids\": [\"12730726\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Imprinting control elements not mapped\", \"Functional consequence of brain-specific maternal expression unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Whether CALCR has anti-proliferative function was tested in glioblastoma, where calcitonin inhibited transformation and tumor growth in a receptor-dependent manner and patient mutations abolished this, defining CALCR as a tumor suppressor.\",\n      \"evidence\": \"Loss-of-function mutation characterization, in vitro transformation assay, patient-derived neurosphere assay, and mouse xenograft\",\n      \"pmids\": [\"29263181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling effectors not resolved in this study\", \"Endogenous tumor-relevant ligand source unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"To explain how CALCR's Ca2+ signaling is tuned, heterodimerization with the EP2 prostaglandin receptor was shown to selectively reduce CALCR-mediated Ca2+ mobilization without altering cAMP output.\",\n      \"evidence\": \"Reciprocal Co-IP with LC-MS/MS, FRET, and functional Ca2+/cAMP assays in granulosa and HEK293 cells\",\n      \"pmids\": [\"29095955\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological setting of heterodimer beyond granulosa cells not established\", \"Structural basis of biased signaling not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The endogenous local ligand and upstream regulation of CALCR in satellite cells were unknown; Collagen V was identified as a Notch/RBPJ-driven surrogate ligand maintaining quiescence.\",\n      \"evidence\": \"ChIP-seq, conditional Col5a1 knockout, and in vivo pharmacological rescue with a calcitonin derivative\",\n      \"pmids\": [\"29795344\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mode of Collagen V engagement of the receptor not structurally defined\", \"Whether Collagen V acts elsewhere as a CALCR ligand untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"How CALCR enforces quiescence at the signaling level was resolved by placing it in a PKA–LATS1/2–YAP1 cascade that suppresses Hippo-target cell-cycle genes, via genetic epistasis.\",\n      \"evidence\": \"PKA catalytic-domain transgenic rescue, CalcR × Yap1 double-mutant epistasis, and LATS1/2 phosphorylation assays\",\n      \"pmids\": [\"31747590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"G protein/cAMP coupling step linking receptor to PKA not detailed\", \"Generalizability beyond satellite cells not tested here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The circuit-level role of CALCR neurons in behavior was probed by showing MeApd CALCR-expressing GABAergic neurons suppress social contact.\",\n      \"evidence\": \"Immunohistochemistry for cell-type markers, AAV-shRNA Calcr knockdown, and resocialization behavioral assay\",\n      \"pmids\": [\"36658598\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single knockdown experiment with limited molecular pathway characterization\", \"Ligand and downstream signaling in these neurons unidentified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Additional protein partners in cancer were sought; CALCR was shown to bind CD44 and stabilize it against degradation, supporting pro-tumorigenic phenotypes in renal cell carcinoma.\",\n      \"evidence\": \"Co-IP, CALCR knockdown with CD44 rescue, and in vivo tumor formation assay\",\n      \"pmids\": [\"38985127\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP for binding claim without reciprocal/structural validation\", \"Mechanism of CD44 stabilization unresolved\", \"Apparent pro-tumor role conflicts with tumor-suppressor data in other tissues\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The glioblastoma tumor-suppressor mechanism was unified with the satellite-cell cascade by showing CTR/cAMP/PKA/LATS1 activation of Hippo suppresses YAP/TAZ, with structural rationale for mutant inactivity.\",\n      \"evidence\": \"Patient-derived glioma stem cell assays, LATS1/YAP phosphorylation and epistasis, intracranial orthotopic model with intranasal calcitonin, and all-atom molecular dynamics (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"In vivo efficacy across diverse patient tumors not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The role of brainstem CALCR neurons in energy balance was characterized, identifying NTS Calcr/Prlh cells as mediators of long-term amylin-analog responsiveness.\",\n      \"evidence\": \"Single-nucleus RNA-seq, spatial transcriptomics, cross-species comparison, and in vivo activation of AP Calcr cells (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint with limited direct manipulation of CALCR itself\", \"Receptor-intrinsic signaling in these neurons not dissected\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Another cancer interaction was reported, with CALCR binding ANTXR1 and decreasing AKT phosphorylation to promote gastric cancer growth.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, proliferation/apoptosis/migration assays, and nude mouse xenograft\",\n      \"pmids\": [\"40195530\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP for binding claim without reciprocal validation\", \"Mechanistic link from ANTXR1 interaction to AKT not characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CALCR can act as a tumor suppressor via Hippo in some contexts yet appear pro-tumorigenic through CD44/ANTXR1 in others, and what determines its tissue-specific signaling outputs, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying model reconciling tumor-suppressive and pro-tumor roles\", \"Receptor structure and G-protein coupling determinants not defined in the corpus\", \"Endogenous ligands outside muscle Collagen V not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 2, 4]},\n      {\"term_id\": \"GO:0004930\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PTGER2\",\n      \"CD44\",\n      \"ANTXR1\",\n      \"COL5A1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}