{"gene":"CCKBR","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2025,"finding":"Cryo-EM structures of CCKBR in complex with the endogenous agonist sulfated CCK8 (CCK8s) and three different G protein subtypes (Gs, Gq, Gi) revealed that distinct receptor conformations contribute to selective G protein bias. Leveraging structural insights, synthetic biased agonists were developed: a Gi-biased agonist (z-44) and a Gq-biased agonist (3r1). CCKBR-Gs and -Gq signaling (but not -Gi) were found beneficial for Alzheimer's disease treatment; 3r1 ameliorated cognitive decline in 5×FAD mice, reduced amyloid-β plaques, and promoted LTP via upregulation of ADAM10 and PLCB4.","method":"Cryo-EM structure determination, biased agonist pharmacology, murine AD model (5×FAD), LTP assay, western blot","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures at three G protein subtypes combined with functional biased agonist validation in vitro and in vivo, multiple orthogonal methods in one rigorous study","pmids":["41270732"],"is_preprint":false},{"year":2025,"finding":"A β-arrestin-biased CCKBR agonist (MF-8, IC50 = 0.9 nM) was discovered. Activation of CCKBR with MF-8 failed to induce neocortical long-term potentiation but efficiently induced CCKBR endocytosis. Multi-Electrode Array experiments demonstrated that CCKBR-dependent LTP requires Gαq/11-Ca2+ and Gαs-cAMP signaling pathways, and MF-8 completely blocked the potentiation through β-arrestin signaling. MF-8 also inhibited cue-to-cue associative fear memory formation in vivo.","method":"β-arrestin recruitment assay, multi-electrode array (MEA), calcium signaling assay, cAMP assay, fear memory behavioral test, CCKBR endocytosis imaging","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal functional assays (MEA, Ca2+, cAMP, β-arrestin, endocytosis, in vivo behavior) in a single rigorous study establishing pathway-specific mechanism","pmids":["41360797"],"is_preprint":false},{"year":2005,"finding":"CCK2R activates JAK2 through a Gαq-dependent mechanism involving the conserved NPXXY motif in the receptor. Constitutively active Gαq (Q209L) associates with and activates JAK2 in transfected COS-7 cells. In pancreatic tumor cells expressing endogenous CCK2R, this leads to JAK2/STAT3 pathway activation, which contributes to CCK2R-mediated proliferation. In vivo, targeted CCK2R expression in Elas-CCK2 mouse pancreas activates JAK2 and STAT3.","method":"Constitutively active Gαq transfection, Co-IP (Gαq–JAK2 association), NPXXY motif mutagenesis, western blot (JAK2/STAT3 phosphorylation), transgenic mouse model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — active-site mutagenesis of NPXXY, co-IP, and in vivo transgenic validation across multiple systems in one study","pmids":["15640156"],"is_preprint":false},{"year":2013,"finding":"Progastrin stimulates colonic cell proliferation via CCK2R and β-arrestin 1/2-dependent suppression of BMP2 transcription, leading to decreased Smad1/5/8 phosphorylation and suppression of ID4. This promotes symmetric division of putative cancer stem cells (increased CD44+, BrdU+, NUMB+ cells). CCK2R was necessary and sufficient for progastrin binding and induction of proliferation in human cancer cell lines; effects were blocked by recombinant BMP2.","method":"Microarray, siRNA knockdown (β-arrestin 1/2), CCK2R-knockout mouse colonic crypt cultures, progastrin binding assay, symmetric division analysis (CD44/BrdU/NUMB staining)","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic knockout, siRNA knockdown, and multiple orthogonal cellular readouts establishing pathway position in a single thorough study","pmids":["23891976"],"is_preprint":false},{"year":2014,"finding":"CCK2R marks +4 antral stem cells (Lgr5neg/low) distinct from typical Lgr5high stem cells. Progastrin treatment interconverts Lgr5neg/low CCK2R+ cells into Lgr5high cells, increases CCK2R+ cell numbers, and promotes gland fission and MNU-induced carcinogenesis. Pharmacological inhibition or genetic ablation of CCK2R attenuated progastrin-dependent stem cell expansion and carcinogenesis.","method":"CCK2R-CreERT inducible lineage tracing, 3D organoid culture, CCK2R genetic ablation, CCK2R pharmacological inhibition, MNU carcinogenesis model","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Strong — lineage tracing, genetic ablation, and pharmacological inhibition converge on the same conclusion, replicated across multiple in vivo and in vitro systems","pmids":["24951258"],"is_preprint":false},{"year":2020,"finding":"Hypergastrinemia expands ECL cells primarily from CCK2R+ isthmus progenitors (not from mature Hdc+ ECL cells). Gastrin activates ERK signaling in vivo and in vitro via CCK2R; MEK1 inhibitor U0126 blocked hypergastrinemia-mediated ECL cell hyperplasia, sphere formation, and chromogranin A expression in CCK2R-derived organoids.","method":"Cck2r-CreERT2 lineage tracing, Hdc-CreERT2 lineage tracing, omeprazole/gastrin infusion models, 3D organoid/sphere formation, U0126 MEK inhibitor treatment, in vivo ERK phosphorylation assay","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — lineage tracing combined with pharmacological inhibition and in vitro organoid assays, multiple orthogonal methods","pmids":["32330731"],"is_preprint":false},{"year":2022,"finding":"Intestinal gastrin/CCKBR inhibits NHE3 (Na+/H+ exchanger 3) trafficking and activity through a PKC-mediated activation of NHERF1 and NHERF2, reducing intestinal sodium absorption. Intestinal epithelial cell-specific Cckbr knockout (Cckbrfl/fl villin-Cre) mice showed increased intestinal Na+ absorption and salt-sensitive hypertension. Gastrin-SiO2 microspheres (acting locally on intestinal CCKBR) prevented high-salt-induced hypertension.","method":"Intestinal-specific Cckbr knockout mice, Dahl salt-sensitive rats, in vivo sodium transport assay, gastrin-SiO2 microsphere administration, PKC pathway analysis, NHERF1/NHERF2 interaction studies","journal":"Hypertension","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic knockout model combined with mechanistic pathway dissection (PKC/NHERF1/NHERF2) and pharmacological rescue, multiple orthogonal approaches","pmids":["35674015"],"is_preprint":false},{"year":2025,"finding":"Intestinal gastrin/CCKBR reduces glucose absorption by down-regulating intestinal SGLT1 and GLUT2 expressions and stimulating incretin secretion via the PI3K/Akt/eIF4B signaling pathway. Intestinal epithelial cell-specific Cckbr knockout mice on high-fat diet rapidly progressed from pre-diabetes to T2D. Gastrin-SiO2 microspheres reduced intestinal glucose absorption in duodenum from T2D patients.","method":"Intestinal epithelial Cckbr knockout mice, HFD model, oral glucose tolerance test, PI3K/Akt/eIF4B signaling analysis, human duodenal tissue studies, Gastrin-SiO2 microsphere administration","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with pathway analysis and human tissue validation, but single lab, single publication","pmids":["39950948"],"is_preprint":false},{"year":2024,"finding":"Renal gastrin/CCKBR inhibits SGLT2-mediated glucose reabsorption through the Erk/NF-κB signaling pathway. Renal tubule-specific Cckbr knockout mice showed greater susceptibility to obesity and diabetes on high-fat diet. In HK-2 cells, gastrin intervention attenuated high-glucose-induced upregulation of SGLT2, and this effect was absent in the absence of CCKBR.","method":"Renal tubule-specific Cckbr knockout mice, HFD + streptozotocin model, HK-2 cell culture with high glucose, Erk/NF-κB pathway western blot, glucose uptake assay","journal":"Diabetes & metabolism journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout combined with in vitro pathway analysis, single lab, multiple methods","pmids":["39721589"],"is_preprint":false},{"year":2012,"finding":"CCK2R somatic mutations identified in colorectal and gastric cancers increase receptor activity, activate multiple downstream signaling pathways, increase cell migration, and promote angiogenesis. Six mutations in CCK2R were functionally characterized among 140 colorectal and 44 gastric cancers.","method":"Functional receptor activity assays, cell migration assay, angiogenesis assay, downstream signaling pathway analysis in cancer cell lines expressing mutant CCK2R","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional readouts for gain-of-function mutations, single lab study","pmids":["22516348"],"is_preprint":false},{"year":2012,"finding":"CCK2R activation by gastrin in GIST xenografts leads to hyper-activation of KIT and PKC-θ kinases and PI3K-AKT pathway over-activation (by western blot), with increased tumor cell proliferation (Ki-67 and mitotic activity). In vivo, gastrin stimulation produced a two-fold increase in GIST tumor volume.","method":"GIST xenograft nude mouse model, gastrin administration, western blot (KIT, PKC-θ, PI3K-AKT), IHC (Ki-67, mitotic index)","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo xenograft combined with western blot pathway analysis, single lab","pmids":["22786615"],"is_preprint":false},{"year":2007,"finding":"CCK2R promoter activity requires consensus binding sites for SP1, C/EBP, and GATA transcription factors for transcription in gastric cell lines. Gastrin increases CCK2R transcription through mechanisms partly dependent on PKC and MEK signaling. CCK2R expression is also induced in myofibroblasts (vimentin+, smooth muscle α-actin+, desmin-) adjacent to gastric ulcer repair margins in vivo.","method":"Luciferase promoter-reporter constructs with site-directed mutagenesis, qPCR for endogenous CCK2R mRNA, PKC/MEK pharmacological inhibition, gastric cryoulcer injury model, immunofluorescence co-localization","journal":"Experimental physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay with mutagenesis combined with in vivo injury model, single lab, multiple orthogonal approaches","pmids":["17933865"],"is_preprint":false},{"year":2016,"finding":"miR-148a directly targets the CCKBR 3'UTR (validated by luciferase assay and western blot). CCKBR knockdown by siRNA phenocopied miR-148a overexpression (decreased proliferation and migration). miR-148a anti-oncogenic effects in gastric cancer are mediated through CCKBR-dependent inhibition of STAT3 and Akt activation.","method":"Luciferase reporter assay (3'UTR), western blot, siRNA knockdown, proliferation and migration assays, tumor xenograft","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter and siRNA phenocopy establish direct targeting, single lab","pmids":["27518872"],"is_preprint":false},{"year":2013,"finding":"miR-148a directly targets CCKBR (validated by luciferase reporter assay and western blot) in pancreatic cancer. CCKBR is identified as a functional target mediating miR-148a's effects on proliferation and apoptosis in PANC-1 and AsPC-1 cells.","method":"Luciferase reporter assay (3'UTR), western blot, MTT assay, colony formation assay, Annexin V apoptosis assay, caspase activity assay","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter with functional rescue experiments, single lab","pmids":["23975374"],"is_preprint":false},{"year":2020,"finding":"mTORC1 inhibition by RAD001 (everolimus) increases CCKBR protein levels (~2.2-fold) and enhances internalization of radiolabeled minigastrin analogue in CCKBR-expressing cells. PP-F11N induces recruitment of β-arrestin1/2 and ERK1/2 phosphorylation upon CCKBR activation. In vivo, RAD001 pretreatment significantly enhanced tumor-specific uptake of [177Lu]Lu-PP-F11N in A431/CCKBR xenograft mice.","method":"Kinase inhibitor library screen, western blot (CCKBR protein level, S6 phosphorylation), β-arrestin recruitment assay, ERK1/2 phosphorylation assay, cell internalization assay, xenograft biodistribution, SPECT/CT imaging","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (western blot, β-arrestin assay, in vivo imaging), single lab","pmids":["33042258"],"is_preprint":false},{"year":2015,"finding":"CCKAR and CCKBR have dynamic, largely reciprocal expression in embryonic and postnatal brain. Compound homozygous mutant mice lacking both CCK receptors show additive, synergistic defects in cortical development including abnormalities in midline formation, corpus callosum development, and cortical interneuron migration.","method":"Compound homozygous double-knockout mice, comparative transcriptome analysis of embryonic neocortex, histological analysis of brain development","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic double-knockout with defined anatomical/cellular phenotypes and transcriptomic pathway analysis, single lab","pmids":["25875176"],"is_preprint":false},{"year":2026,"finding":"In the VTA→BLA→BNST circuit, CCK2R in BLA glutamatergic neurons is required for METH-induced conditioned place preference. METH enhanced CCK release from VTA→BLA projections. CCK2R knockout in BLA glutamatergic neurons abolished CPP and normalized synaptic plasticity. CCK2R deletion in this circuit reversed METH-induced increases in AMPA/NMDA ratios, paired-pulse facilitation, and dendritic spine density in BNST.","method":"CCKflox/flox cell-type-specific knockout, optogenetics, chemogenetics (DREADD), electrophysiology (AMPA/NMDA ratio, PPF), Golgi staining (dendritic spine density)","journal":"Translational psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — circuit-specific knockout with multiple orthogonal electrophysiological and structural readouts, single lab","pmids":["41888094"],"is_preprint":false},{"year":2018,"finding":"Low gastrin/CCKBR is associated with inactivation of ERK/P65 signaling in ER+ breast cancer cells. Gastrin or ERK/P65 activators inhibited ER+ BC through CCKBR-mediated activation of ERK/P65. CCKBR/ERK/P65 signaling functions as tumor suppressive in ER+ BC.","method":"CCK-8 proliferation assay, nude mouse xenograft, western blot (ERK, P65 activation), ELISA (serum gastrin)","journal":"BMC cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, cellular and xenograft assays but limited mechanistic dissection of CCKBR-specific pathway","pmids":["30115027"],"is_preprint":false},{"year":2015,"finding":"Trastuzumab upregulates CCKBR protein levels in HER2-negative gastric cancer cells and synergizes with gastrin to enhance CCKBR stability. Combined trastuzumab and gastrin treatment synergistically arrested GC cells at G0/G1 phase and down-regulated AE1, cyclin D1, β-catenin, and cytoplasmic p16, while promoting nuclear translocation of p16 and upregulating AE2.","method":"Western blot (CCKBR, AE1, AE2, cyclin D1, β-catenin, p16), flow cytometry (cell cycle), xenograft in vivo model","journal":"Digestive diseases and sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, western blot-based mechanism without specific CCKBR loss-of-function controls for pathway validation","pmids":["26173505"],"is_preprint":false},{"year":2005,"finding":"The CCK2R fragment CCK(B)-R(352-379) binds CCK8 peptide with a dissociation constant in the micromolar range, as measured by fluorescence titration in a membrane-mimetic solvent system. This confirms the binding mode of CCK8 with its receptor at this extracellular region.","method":"Fluorescence titration spectroscopy in membrane-mimetic solvent","journal":"Biopolymers","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single in vitro binding assay using a receptor fragment, not full receptor, single lab","pmids":["15666329"],"is_preprint":false},{"year":2025,"finding":"An ensemble of RSG glutamatergic neurons expressing CCKBR (RSGGlu-Cckbr) in layer 5 of the granular retrosplenial cortex encodes opioid-associated memories and controls relapse to opioid via innervation of ZI GABAergic neurons. Cckergic neurons from the anterodorsal thalamus orchestrate RSGGlu-Cckbr–ZI circuit function via CCK release in RSG.","method":"Circuit-specific manipulation (optogenetics, chemogenetics), in vivo electrophysiology, opioid CPP behavioral model, calcium imaging","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — preprint, single lab, circuit-level findings mechanistically relevant but not yet peer reviewed","pmids":[],"is_preprint":true}],"current_model":"CCKBR (CCK2R) is a Gq/Gs/Gi-coupled GPCR whose cryo-EM structures in complex with CCK8s and distinct G proteins reveal conformational basis for biased signaling; it activates JAK2/STAT3 via Gαq and the NPXXY motif, drives ERK and PI3K/AKT pathways, recruits β-arrestin1/2 to mediate endocytosis and BMP2 suppression, regulates gastric antral and corpus stem cell expansion and ECL cell hyperplasia via ERK activation, controls intestinal NHE3 activity through PKC/NHERF1/NHERF2, and modulates synaptic plasticity (LTP) via Gαq/11-Ca2+ and Gαs-cAMP signaling in the CNS."},"narrative":{"mechanistic_narrative":"CCKBR (CCK2R) is a gastrin/CCK-responsive G-protein-coupled receptor that couples to Gs, Gq, and Gi to drive proliferative, secretory, and neuromodulatory programs, with distinct receptor conformations dictating G-protein bias [PMID:41270732]. Through a Gαq-dependent mechanism requiring the conserved NPXXY motif, CCKBR activates JAK2/STAT3 to promote cell proliferation [PMID:15640156], and it additionally engages ERK and PI3K/AKT signaling that supports tumor cell growth, migration, and angiogenesis—activities amplified by gain-of-function somatic mutations found in colorectal and gastric cancers [PMID:22516348, PMID:22786615]. Agonist-occupied CCKBR also recruits β-arrestin1/2, which mediates receptor endocytosis and, in colonic epithelium, suppresses BMP2 transcription to promote symmetric cancer stem-cell division [PMID:23891976, PMID:33042258]. In the gastrointestinal tract, CCKBR marks Lgr5neg/low antral +4 stem cells and ECL-cell isthmus progenitors, and gastrin/progastrin signaling through CCKBR-dependent ERK activation drives stem-cell expansion, ECL-cell hyperplasia, and carcinogenesis [PMID:24951258, PMID:32330731]. CCKBR also governs intestinal and renal transport physiology: in intestinal epithelium it inhibits NHE3 via PKC/NHERF1/NHERF2 to limit sodium absorption and protect against salt-sensitive hypertension, and it restrains glucose handling through PI3K/Akt/eIF4B and Erk/NF-κB pathways [PMID:35674015, PMID:39950948, PMID:39721589]. In the CNS, CCKBR is required for cortical development and for circuit-level synaptic plasticity, where Gαq/11-Ca2+ and Gαs-cAMP signaling (but not β-arrestin signaling) underlies long-term potentiation and associative memory [PMID:41360797, PMID:25875176, PMID:41888094].","teleology":[{"year":2005,"claim":"Establishing how CCKBR transduces a proliferative signal, this work showed the receptor activates JAK2/STAT3 through Gαq and the conserved NPXXY motif, linking receptor architecture to a defined kinase cascade.","evidence":"Constitutively active Gαq transfection, Gαq–JAK2 co-IP, NPXXY mutagenesis, and transgenic Elas-CCK2 mouse pancreas","pmids":["15640156"],"confidence":"High","gaps":["Did not resolve how Gαq physically couples to JAK2","Relevance of JAK2/STAT3 across other CCKBR-expressing tissues not addressed"]},{"year":2005,"claim":"To map the ligand-binding mode, an extracellular receptor fragment was shown to bind CCK8 in the micromolar range, providing early biochemical evidence for the agonist contact region.","evidence":"Fluorescence titration of the CCK(B)-R(352-379) peptide with CCK8 in membrane-mimetic solvent","pmids":["15666329"],"confidence":"Low","gaps":["Used a receptor fragment rather than the full receptor","Single in vitro binding assay without functional correlate"]},{"year":2007,"claim":"Addressing how CCKBR expression is controlled, this work defined the SP1/C/EBP/GATA promoter requirements and a gastrin-driven PKC/MEK feed-forward loop regulating receptor transcription.","evidence":"Luciferase promoter-reporter mutagenesis, qPCR, PKC/MEK inhibition, and a gastric cryoulcer injury model","pmids":["17933865"],"confidence":"Medium","gaps":["Functional consequence of myofibroblast CCKBR induction not defined","Direct factor binding to promoter sites inferred from mutagenesis only"]},{"year":2012,"claim":"To clarify CCKBR's contribution to tumorigenesis, somatic mutations from colorectal and gastric cancers were shown to be activating, increasing downstream signaling, migration, and angiogenesis.","evidence":"Functional receptor activity, migration, and angiogenesis assays on six mutant CCK2R variants in cancer cell lines","pmids":["22516348"],"confidence":"Medium","gaps":["Which specific G-protein/effector pathway each mutation biases not resolved","In vivo tumorigenicity of mutants not tested"]},{"year":2012,"claim":"Demonstrating CCKBR signaling in a non-classical tumor type, gastrin stimulation in GIST xenografts hyperactivated KIT, PKC-θ, and PI3K-AKT and doubled tumor volume.","evidence":"GIST xenograft mouse model with gastrin, western blot, and Ki-67/mitotic IHC","pmids":["22786615"],"confidence":"Medium","gaps":["Mechanistic link between CCKBR and KIT activation not dissected","No CCKBR loss-of-function control"]},{"year":2013,"claim":"Defining a β-arrestin-dependent transcriptional output, progastrin/CCKBR signaling was shown to suppress BMP2 via β-arrestin1/2, reducing Smad1/5/8 phosphorylation and ID4 to drive symmetric cancer stem-cell division.","evidence":"Microarray, β-arrestin1/2 siRNA, CCK2R-knockout crypt cultures, progastrin binding, and symmetric division markers","pmids":["23891976"],"confidence":"High","gaps":["How β-arrestin represses BMP2 transcription not resolved","Stem-cell identity markers correlative"]},{"year":2013,"claim":"Connecting CCKBR to microRNA control in pancreatic cancer, miR-148a was shown to directly target the CCKBR 3'UTR to regulate proliferation and apoptosis.","evidence":"Luciferase 3'UTR reporter, western blot, and proliferation/apoptosis assays in PANC-1 and AsPC-1 cells","pmids":["23975374"],"confidence":"Medium","gaps":["Downstream CCKBR effectors mediating the phenotype not fully mapped","Single lab"]},{"year":2014,"claim":"Resolving which gastric epithelial population CCKBR marks, the receptor was shown to label Lgr5neg/low +4 antral stem cells that progastrin interconverts and expands toward carcinogenesis.","evidence":"CCK2R-CreERT lineage tracing, organoid culture, genetic ablation, pharmacological inhibition, and MNU carcinogenesis","pmids":["24951258"],"confidence":"High","gaps":["Signaling pathway driving interconversion not defined here","Human relevance of +4 population not established"]},{"year":2015,"claim":"Establishing a developmental role, dual deletion of CCKAR and CCKBR produced synergistic cortical patterning, corpus callosum, and interneuron migration defects.","evidence":"Compound double-knockout mice with embryonic neocortex transcriptomics and histology","pmids":["25875176"],"confidence":"Medium","gaps":["CCKBR-specific contribution not separated from CCKAR","Cell-autonomous mechanism unresolved"]},{"year":2016,"claim":"Extending miR-148a regulation to gastric cancer, CCKBR was confirmed as a direct target whose knockdown phenocopies miR-148a anti-oncogenic effects via reduced STAT3/Akt activation.","evidence":"Luciferase 3'UTR reporter, siRNA phenocopy, proliferation/migration assays, and xenograft","pmids":["27518872"],"confidence":"Medium","gaps":["Other miR-148a targets may contribute","Single lab"]},{"year":2020,"claim":"Identifying the ECL-cell hyperplasia origin, CCK2R+ isthmus progenitors were shown to expand under hypergastrinemia via CCKBR-driven ERK signaling, blocked by MEK inhibition.","evidence":"Cck2r-CreERT2 and Hdc-CreERT2 lineage tracing, gastrin/omeprazole infusion, organoids, and U0126","pmids":["32330731"],"confidence":"High","gaps":["Upstream coupling of CCKBR to ERK in this niche not detailed","Reversibility of hyperplasia not addressed"]},{"year":2020,"claim":"Revealing a regulator of receptor abundance relevant to radiotheranostics, mTORC1 inhibition was shown to raise CCKBR protein and enhance β-arrestin1/2 recruitment, ERK phosphorylation, and minigastrin internalization in vivo.","evidence":"Kinase inhibitor screen, western blot, β-arrestin/ERK assays, and CCKBR xenograft SPECT/CT biodistribution","pmids":["33042258"],"confidence":"Medium","gaps":["Mechanism by which mTORC1 controls CCKBR levels unresolved","Single lab"]},{"year":2022,"claim":"Defining a transport-regulatory function, intestinal CCKBR was shown to inhibit NHE3 through PKC-mediated NHERF1/NHERF2 to limit sodium absorption and protect against salt-sensitive hypertension.","evidence":"Intestinal-specific Cckbr knockout mice, Dahl salt-sensitive rats, sodium transport assays, and gastrin-SiO2 microsphere rescue","pmids":["35674015"],"confidence":"High","gaps":["Direct CCKBR–NHERF physical coupling not structurally defined","Human translation limited"]},{"year":2024,"claim":"Extending CCKBR transport control to the kidney, renal tubular CCKBR was shown to inhibit SGLT2-mediated glucose reabsorption via Erk/NF-κB, with knockout increasing diabetes susceptibility.","evidence":"Renal tubule-specific Cckbr knockout mice, HFD/STZ model, and HK-2 high-glucose assays with pathway western blot","pmids":["39721589"],"confidence":"Medium","gaps":["Direct mechanism linking CCKBR to SGLT2 downregulation not resolved","Single lab"]},{"year":2025,"claim":"Providing the structural basis of CCKBR signaling bias, cryo-EM of CCK8s-bound receptor with Gs, Gq, and Gi revealed conformation-encoded G-protein selectivity and enabled biased agonists, with Gs/Gq signaling shown beneficial in an Alzheimer's model.","evidence":"Cryo-EM at three G-protein subtypes, biased agonist pharmacology, 5×FAD mice, LTP, and western blot","pmids":["41270732"],"confidence":"High","gaps":["Endogenous determinants of bias selection in vivo unknown","Downstream ADAM10/PLCB4 regulation not mechanistically dissected"]},{"year":2025,"claim":"Dissecting which signaling arm supports synaptic plasticity, a β-arrestin-biased agonist showed CCKBR-dependent LTP requires Gαq/11-Ca2+ and Gαs-cAMP, while β-arrestin signaling drives endocytosis and blocks potentiation.","evidence":"β-arrestin recruitment, MEA, Ca2+ and cAMP assays, endocytosis imaging, and fear memory behavior","pmids":["41360797"],"confidence":"High","gaps":["Neuronal G-protein vs arrestin balance under physiological CCK release not measured","Circuit specificity not addressed"]},{"year":2025,"claim":"Extending CCKBR's metabolic role, intestinal CCKBR was shown to reduce glucose absorption by downregulating SGLT1/GLUT2 and stimulating incretin secretion via PI3K/Akt/eIF4B.","evidence":"Intestinal-specific Cckbr knockout mice, HFD model, OGTT, pathway analysis, human duodenal tissue, and gastrin-SiO2 microspheres","pmids":["39950948"],"confidence":"Medium","gaps":["Direct CCKBR-to-transporter regulatory link not resolved","Single lab"]},{"year":2026,"claim":"Placing CCKBR in a reward circuit, CCK2R in BLA glutamatergic neurons was shown to be required for methamphetamine conditioned place preference and the associated synaptic remodeling in the VTA→BLA→BNST pathway.","evidence":"Cell-type-specific Cck knockout, optogenetics, chemogenetics, electrophysiology, and Golgi spine analysis","pmids":["41888094"],"confidence":"Medium","gaps":["Receptor-proximal signaling in BLA neurons not defined","Single lab"]},{"year":null,"claim":"How the structurally defined conformational basis of G-protein bias is selected physiologically across CCKBR's diverse tissues—and how the same receptor partitions between proliferative, transport-regulatory, and synaptic outputs—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model of tissue-specific effector selection","Endogenous determinants of Gs/Gq/Gi/arrestin partitioning unknown","In vivo structural state of the receptor not captured"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,14]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,15,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,10,12]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[6,7,8]}],"complexes":[],"partners":["GNAQ","GNAS","JAK2","ARRB1","ARRB2","NHERF1","NHERF2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P32239","full_name":"Gastrin/cholecystokinin type B receptor","aliases":["Cholecystokinin-2 receptor","CCK2-R"],"length_aa":447,"mass_kda":48.4,"function":"Receptor for the peptide hormones gastrin and cholecystokinin (CCK). Expressed throughout the central nervous system, where it modulates processes such as anxiety, analgesia, arousal and neuroleptic activity. Couples to both GNAI1 and GNAQ signaling pathways, but not to GNAS (PubMed:34556863). Upon gastrin activation, reduces glucose absorption in intestinal epithelial cells by downregulating SGLT1 and GLUT2 expression through suppression of the PI3K/Akt/eIF4B pathway (By similarity). In the kidney, decreases SGLT2 expression under high-glucose conditions via ERK/NF-kappa-B signaling (By similarity) Isoform 2 is constitutively activated and may regulate cancer cell proliferation via a gastrin-independent mechanism","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P32239/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCKBR","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CCKBR","total_profiled":1310},"omim":[{"mim_id":"614215","title":"ACTIVATING SIGNAL COINTEGRATOR 1 COMPLEX, SUBUNIT 1; ASCC1","url":"https://www.omim.org/entry/614215"},{"mim_id":"604592","title":"T CELL IMMUNE REGULATOR 1; TCIRG1","url":"https://www.omim.org/entry/604592"},{"mim_id":"604501","title":"THYROID HORMONE RECEPTOR INTERACTOR 4; TRIP4","url":"https://www.omim.org/entry/604501"},{"mim_id":"600999","title":"MYC-ASSOCIATED ZINC FINGER PROTEIN; MAZ","url":"https://www.omim.org/entry/600999"},{"mim_id":"190090","title":"SRC PROTOONCOGENE, NONRECEPTOR TYROSINE KINASE; SRC","url":"https://www.omim.org/entry/190090"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":21.1},{"tissue":"pancreas","ntpm":25.5},{"tissue":"stomach 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Leveraging structural insights, synthetic biased agonists were developed: a Gi-biased agonist (z-44) and a Gq-biased agonist (3r1). CCKBR-Gs and -Gq signaling (but not -Gi) were found beneficial for Alzheimer's disease treatment; 3r1 ameliorated cognitive decline in 5×FAD mice, reduced amyloid-β plaques, and promoted LTP via upregulation of ADAM10 and PLCB4.\",\n      \"method\": \"Cryo-EM structure determination, biased agonist pharmacology, murine AD model (5×FAD), LTP assay, western blot\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures at three G protein subtypes combined with functional biased agonist validation in vitro and in vivo, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"41270732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A β-arrestin-biased CCKBR agonist (MF-8, IC50 = 0.9 nM) was discovered. Activation of CCKBR with MF-8 failed to induce neocortical long-term potentiation but efficiently induced CCKBR endocytosis. Multi-Electrode Array experiments demonstrated that CCKBR-dependent LTP requires Gαq/11-Ca2+ and Gαs-cAMP signaling pathways, and MF-8 completely blocked the potentiation through β-arrestin signaling. MF-8 also inhibited cue-to-cue associative fear memory formation in vivo.\",\n      \"method\": \"β-arrestin recruitment assay, multi-electrode array (MEA), calcium signaling assay, cAMP assay, fear memory behavioral test, CCKBR endocytosis imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal functional assays (MEA, Ca2+, cAMP, β-arrestin, endocytosis, in vivo behavior) in a single rigorous study establishing pathway-specific mechanism\",\n      \"pmids\": [\"41360797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CCK2R activates JAK2 through a Gαq-dependent mechanism involving the conserved NPXXY motif in the receptor. Constitutively active Gαq (Q209L) associates with and activates JAK2 in transfected COS-7 cells. In pancreatic tumor cells expressing endogenous CCK2R, this leads to JAK2/STAT3 pathway activation, which contributes to CCK2R-mediated proliferation. In vivo, targeted CCK2R expression in Elas-CCK2 mouse pancreas activates JAK2 and STAT3.\",\n      \"method\": \"Constitutively active Gαq transfection, Co-IP (Gαq–JAK2 association), NPXXY motif mutagenesis, western blot (JAK2/STAT3 phosphorylation), transgenic mouse model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — active-site mutagenesis of NPXXY, co-IP, and in vivo transgenic validation across multiple systems in one study\",\n      \"pmids\": [\"15640156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Progastrin stimulates colonic cell proliferation via CCK2R and β-arrestin 1/2-dependent suppression of BMP2 transcription, leading to decreased Smad1/5/8 phosphorylation and suppression of ID4. This promotes symmetric division of putative cancer stem cells (increased CD44+, BrdU+, NUMB+ cells). CCK2R was necessary and sufficient for progastrin binding and induction of proliferation in human cancer cell lines; effects were blocked by recombinant BMP2.\",\n      \"method\": \"Microarray, siRNA knockdown (β-arrestin 1/2), CCK2R-knockout mouse colonic crypt cultures, progastrin binding assay, symmetric division analysis (CD44/BrdU/NUMB staining)\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout, siRNA knockdown, and multiple orthogonal cellular readouts establishing pathway position in a single thorough study\",\n      \"pmids\": [\"23891976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CCK2R marks +4 antral stem cells (Lgr5neg/low) distinct from typical Lgr5high stem cells. Progastrin treatment interconverts Lgr5neg/low CCK2R+ cells into Lgr5high cells, increases CCK2R+ cell numbers, and promotes gland fission and MNU-induced carcinogenesis. Pharmacological inhibition or genetic ablation of CCK2R attenuated progastrin-dependent stem cell expansion and carcinogenesis.\",\n      \"method\": \"CCK2R-CreERT inducible lineage tracing, 3D organoid culture, CCK2R genetic ablation, CCK2R pharmacological inhibition, MNU carcinogenesis model\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — lineage tracing, genetic ablation, and pharmacological inhibition converge on the same conclusion, replicated across multiple in vivo and in vitro systems\",\n      \"pmids\": [\"24951258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Hypergastrinemia expands ECL cells primarily from CCK2R+ isthmus progenitors (not from mature Hdc+ ECL cells). Gastrin activates ERK signaling in vivo and in vitro via CCK2R; MEK1 inhibitor U0126 blocked hypergastrinemia-mediated ECL cell hyperplasia, sphere formation, and chromogranin A expression in CCK2R-derived organoids.\",\n      \"method\": \"Cck2r-CreERT2 lineage tracing, Hdc-CreERT2 lineage tracing, omeprazole/gastrin infusion models, 3D organoid/sphere formation, U0126 MEK inhibitor treatment, in vivo ERK phosphorylation assay\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lineage tracing combined with pharmacological inhibition and in vitro organoid assays, multiple orthogonal methods\",\n      \"pmids\": [\"32330731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Intestinal gastrin/CCKBR inhibits NHE3 (Na+/H+ exchanger 3) trafficking and activity through a PKC-mediated activation of NHERF1 and NHERF2, reducing intestinal sodium absorption. Intestinal epithelial cell-specific Cckbr knockout (Cckbrfl/fl villin-Cre) mice showed increased intestinal Na+ absorption and salt-sensitive hypertension. Gastrin-SiO2 microspheres (acting locally on intestinal CCKBR) prevented high-salt-induced hypertension.\",\n      \"method\": \"Intestinal-specific Cckbr knockout mice, Dahl salt-sensitive rats, in vivo sodium transport assay, gastrin-SiO2 microsphere administration, PKC pathway analysis, NHERF1/NHERF2 interaction studies\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout model combined with mechanistic pathway dissection (PKC/NHERF1/NHERF2) and pharmacological rescue, multiple orthogonal approaches\",\n      \"pmids\": [\"35674015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Intestinal gastrin/CCKBR reduces glucose absorption by down-regulating intestinal SGLT1 and GLUT2 expressions and stimulating incretin secretion via the PI3K/Akt/eIF4B signaling pathway. Intestinal epithelial cell-specific Cckbr knockout mice on high-fat diet rapidly progressed from pre-diabetes to T2D. Gastrin-SiO2 microspheres reduced intestinal glucose absorption in duodenum from T2D patients.\",\n      \"method\": \"Intestinal epithelial Cckbr knockout mice, HFD model, oral glucose tolerance test, PI3K/Akt/eIF4B signaling analysis, human duodenal tissue studies, Gastrin-SiO2 microsphere administration\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with pathway analysis and human tissue validation, but single lab, single publication\",\n      \"pmids\": [\"39950948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Renal gastrin/CCKBR inhibits SGLT2-mediated glucose reabsorption through the Erk/NF-κB signaling pathway. Renal tubule-specific Cckbr knockout mice showed greater susceptibility to obesity and diabetes on high-fat diet. In HK-2 cells, gastrin intervention attenuated high-glucose-induced upregulation of SGLT2, and this effect was absent in the absence of CCKBR.\",\n      \"method\": \"Renal tubule-specific Cckbr knockout mice, HFD + streptozotocin model, HK-2 cell culture with high glucose, Erk/NF-κB pathway western blot, glucose uptake assay\",\n      \"journal\": \"Diabetes & metabolism journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout combined with in vitro pathway analysis, single lab, multiple methods\",\n      \"pmids\": [\"39721589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CCK2R somatic mutations identified in colorectal and gastric cancers increase receptor activity, activate multiple downstream signaling pathways, increase cell migration, and promote angiogenesis. Six mutations in CCK2R were functionally characterized among 140 colorectal and 44 gastric cancers.\",\n      \"method\": \"Functional receptor activity assays, cell migration assay, angiogenesis assay, downstream signaling pathway analysis in cancer cell lines expressing mutant CCK2R\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional readouts for gain-of-function mutations, single lab study\",\n      \"pmids\": [\"22516348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CCK2R activation by gastrin in GIST xenografts leads to hyper-activation of KIT and PKC-θ kinases and PI3K-AKT pathway over-activation (by western blot), with increased tumor cell proliferation (Ki-67 and mitotic activity). In vivo, gastrin stimulation produced a two-fold increase in GIST tumor volume.\",\n      \"method\": \"GIST xenograft nude mouse model, gastrin administration, western blot (KIT, PKC-θ, PI3K-AKT), IHC (Ki-67, mitotic index)\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo xenograft combined with western blot pathway analysis, single lab\",\n      \"pmids\": [\"22786615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CCK2R promoter activity requires consensus binding sites for SP1, C/EBP, and GATA transcription factors for transcription in gastric cell lines. Gastrin increases CCK2R transcription through mechanisms partly dependent on PKC and MEK signaling. CCK2R expression is also induced in myofibroblasts (vimentin+, smooth muscle α-actin+, desmin-) adjacent to gastric ulcer repair margins in vivo.\",\n      \"method\": \"Luciferase promoter-reporter constructs with site-directed mutagenesis, qPCR for endogenous CCK2R mRNA, PKC/MEK pharmacological inhibition, gastric cryoulcer injury model, immunofluorescence co-localization\",\n      \"journal\": \"Experimental physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay with mutagenesis combined with in vivo injury model, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"17933865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-148a directly targets the CCKBR 3'UTR (validated by luciferase assay and western blot). CCKBR knockdown by siRNA phenocopied miR-148a overexpression (decreased proliferation and migration). miR-148a anti-oncogenic effects in gastric cancer are mediated through CCKBR-dependent inhibition of STAT3 and Akt activation.\",\n      \"method\": \"Luciferase reporter assay (3'UTR), western blot, siRNA knockdown, proliferation and migration assays, tumor xenograft\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter and siRNA phenocopy establish direct targeting, single lab\",\n      \"pmids\": [\"27518872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"miR-148a directly targets CCKBR (validated by luciferase reporter assay and western blot) in pancreatic cancer. CCKBR is identified as a functional target mediating miR-148a's effects on proliferation and apoptosis in PANC-1 and AsPC-1 cells.\",\n      \"method\": \"Luciferase reporter assay (3'UTR), western blot, MTT assay, colony formation assay, Annexin V apoptosis assay, caspase activity assay\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter with functional rescue experiments, single lab\",\n      \"pmids\": [\"23975374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"mTORC1 inhibition by RAD001 (everolimus) increases CCKBR protein levels (~2.2-fold) and enhances internalization of radiolabeled minigastrin analogue in CCKBR-expressing cells. PP-F11N induces recruitment of β-arrestin1/2 and ERK1/2 phosphorylation upon CCKBR activation. In vivo, RAD001 pretreatment significantly enhanced tumor-specific uptake of [177Lu]Lu-PP-F11N in A431/CCKBR xenograft mice.\",\n      \"method\": \"Kinase inhibitor library screen, western blot (CCKBR protein level, S6 phosphorylation), β-arrestin recruitment assay, ERK1/2 phosphorylation assay, cell internalization assay, xenograft biodistribution, SPECT/CT imaging\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (western blot, β-arrestin assay, in vivo imaging), single lab\",\n      \"pmids\": [\"33042258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CCKAR and CCKBR have dynamic, largely reciprocal expression in embryonic and postnatal brain. Compound homozygous mutant mice lacking both CCK receptors show additive, synergistic defects in cortical development including abnormalities in midline formation, corpus callosum development, and cortical interneuron migration.\",\n      \"method\": \"Compound homozygous double-knockout mice, comparative transcriptome analysis of embryonic neocortex, histological analysis of brain development\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic double-knockout with defined anatomical/cellular phenotypes and transcriptomic pathway analysis, single lab\",\n      \"pmids\": [\"25875176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In the VTA→BLA→BNST circuit, CCK2R in BLA glutamatergic neurons is required for METH-induced conditioned place preference. METH enhanced CCK release from VTA→BLA projections. CCK2R knockout in BLA glutamatergic neurons abolished CPP and normalized synaptic plasticity. CCK2R deletion in this circuit reversed METH-induced increases in AMPA/NMDA ratios, paired-pulse facilitation, and dendritic spine density in BNST.\",\n      \"method\": \"CCKflox/flox cell-type-specific knockout, optogenetics, chemogenetics (DREADD), electrophysiology (AMPA/NMDA ratio, PPF), Golgi staining (dendritic spine density)\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — circuit-specific knockout with multiple orthogonal electrophysiological and structural readouts, single lab\",\n      \"pmids\": [\"41888094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Low gastrin/CCKBR is associated with inactivation of ERK/P65 signaling in ER+ breast cancer cells. Gastrin or ERK/P65 activators inhibited ER+ BC through CCKBR-mediated activation of ERK/P65. CCKBR/ERK/P65 signaling functions as tumor suppressive in ER+ BC.\",\n      \"method\": \"CCK-8 proliferation assay, nude mouse xenograft, western blot (ERK, P65 activation), ELISA (serum gastrin)\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, cellular and xenograft assays but limited mechanistic dissection of CCKBR-specific pathway\",\n      \"pmids\": [\"30115027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Trastuzumab upregulates CCKBR protein levels in HER2-negative gastric cancer cells and synergizes with gastrin to enhance CCKBR stability. Combined trastuzumab and gastrin treatment synergistically arrested GC cells at G0/G1 phase and down-regulated AE1, cyclin D1, β-catenin, and cytoplasmic p16, while promoting nuclear translocation of p16 and upregulating AE2.\",\n      \"method\": \"Western blot (CCKBR, AE1, AE2, cyclin D1, β-catenin, p16), flow cytometry (cell cycle), xenograft in vivo model\",\n      \"journal\": \"Digestive diseases and sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, western blot-based mechanism without specific CCKBR loss-of-function controls for pathway validation\",\n      \"pmids\": [\"26173505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The CCK2R fragment CCK(B)-R(352-379) binds CCK8 peptide with a dissociation constant in the micromolar range, as measured by fluorescence titration in a membrane-mimetic solvent system. This confirms the binding mode of CCK8 with its receptor at this extracellular region.\",\n      \"method\": \"Fluorescence titration spectroscopy in membrane-mimetic solvent\",\n      \"journal\": \"Biopolymers\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single in vitro binding assay using a receptor fragment, not full receptor, single lab\",\n      \"pmids\": [\"15666329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"An ensemble of RSG glutamatergic neurons expressing CCKBR (RSGGlu-Cckbr) in layer 5 of the granular retrosplenial cortex encodes opioid-associated memories and controls relapse to opioid via innervation of ZI GABAergic neurons. Cckergic neurons from the anterodorsal thalamus orchestrate RSGGlu-Cckbr–ZI circuit function via CCK release in RSG.\",\n      \"method\": \"Circuit-specific manipulation (optogenetics, chemogenetics), in vivo electrophysiology, opioid CPP behavioral model, calcium imaging\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint, single lab, circuit-level findings mechanistically relevant but not yet peer reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CCKBR (CCK2R) is a Gq/Gs/Gi-coupled GPCR whose cryo-EM structures in complex with CCK8s and distinct G proteins reveal conformational basis for biased signaling; it activates JAK2/STAT3 via Gαq and the NPXXY motif, drives ERK and PI3K/AKT pathways, recruits β-arrestin1/2 to mediate endocytosis and BMP2 suppression, regulates gastric antral and corpus stem cell expansion and ECL cell hyperplasia via ERK activation, controls intestinal NHE3 activity through PKC/NHERF1/NHERF2, and modulates synaptic plasticity (LTP) via Gαq/11-Ca2+ and Gαs-cAMP signaling in the CNS.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCKBR (CCK2R) is a gastrin/CCK-responsive G-protein-coupled receptor that couples to Gs, Gq, and Gi to drive proliferative, secretory, and neuromodulatory programs, with distinct receptor conformations dictating G-protein bias [#0]. Through a Gαq-dependent mechanism requiring the conserved NPXXY motif, CCKBR activates JAK2/STAT3 to promote cell proliferation [#2], and it additionally engages ERK and PI3K/AKT signaling that supports tumor cell growth, migration, and angiogenesis—activities amplified by gain-of-function somatic mutations found in colorectal and gastric cancers [#9, #10]. Agonist-occupied CCKBR also recruits β-arrestin1/2, which mediates receptor endocytosis and, in colonic epithelium, suppresses BMP2 transcription to promote symmetric cancer stem-cell division [#3, #14]. In the gastrointestinal tract, CCKBR marks Lgr5neg/low antral +4 stem cells and ECL-cell isthmus progenitors, and gastrin/progastrin signaling through CCKBR-dependent ERK activation drives stem-cell expansion, ECL-cell hyperplasia, and carcinogenesis [#4, #5]. CCKBR also governs intestinal and renal transport physiology: in intestinal epithelium it inhibits NHE3 via PKC/NHERF1/NHERF2 to limit sodium absorption and protect against salt-sensitive hypertension, and it restrains glucose handling through PI3K/Akt/eIF4B and Erk/NF-κB pathways [#6, #7, #8]. In the CNS, CCKBR is required for cortical development and for circuit-level synaptic plasticity, where Gαq/11-Ca2+ and Gαs-cAMP signaling (but not β-arrestin signaling) underlies long-term potentiation and associative memory [#1, #15, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing how CCKBR transduces a proliferative signal, this work showed the receptor activates JAK2/STAT3 through Gαq and the conserved NPXXY motif, linking receptor architecture to a defined kinase cascade.\",\n      \"evidence\": \"Constitutively active Gαq transfection, Gαq–JAK2 co-IP, NPXXY mutagenesis, and transgenic Elas-CCK2 mouse pancreas\",\n      \"pmids\": [\"15640156\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how Gαq physically couples to JAK2\", \"Relevance of JAK2/STAT3 across other CCKBR-expressing tissues not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"To map the ligand-binding mode, an extracellular receptor fragment was shown to bind CCK8 in the micromolar range, providing early biochemical evidence for the agonist contact region.\",\n      \"evidence\": \"Fluorescence titration of the CCK(B)-R(352-379) peptide with CCK8 in membrane-mimetic solvent\",\n      \"pmids\": [\"15666329\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Used a receptor fragment rather than the full receptor\", \"Single in vitro binding assay without functional correlate\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Addressing how CCKBR expression is controlled, this work defined the SP1/C/EBP/GATA promoter requirements and a gastrin-driven PKC/MEK feed-forward loop regulating receptor transcription.\",\n      \"evidence\": \"Luciferase promoter-reporter mutagenesis, qPCR, PKC/MEK inhibition, and a gastric cryoulcer injury model\",\n      \"pmids\": [\"17933865\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of myofibroblast CCKBR induction not defined\", \"Direct factor binding to promoter sites inferred from mutagenesis only\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"To clarify CCKBR's contribution to tumorigenesis, somatic mutations from colorectal and gastric cancers were shown to be activating, increasing downstream signaling, migration, and angiogenesis.\",\n      \"evidence\": \"Functional receptor activity, migration, and angiogenesis assays on six mutant CCK2R variants in cancer cell lines\",\n      \"pmids\": [\"22516348\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which specific G-protein/effector pathway each mutation biases not resolved\", \"In vivo tumorigenicity of mutants not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating CCKBR signaling in a non-classical tumor type, gastrin stimulation in GIST xenografts hyperactivated KIT, PKC-θ, and PI3K-AKT and doubled tumor volume.\",\n      \"evidence\": \"GIST xenograft mouse model with gastrin, western blot, and Ki-67/mitotic IHC\",\n      \"pmids\": [\"22786615\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between CCKBR and KIT activation not dissected\", \"No CCKBR loss-of-function control\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defining a β-arrestin-dependent transcriptional output, progastrin/CCKBR signaling was shown to suppress BMP2 via β-arrestin1/2, reducing Smad1/5/8 phosphorylation and ID4 to drive symmetric cancer stem-cell division.\",\n      \"evidence\": \"Microarray, β-arrestin1/2 siRNA, CCK2R-knockout crypt cultures, progastrin binding, and symmetric division markers\",\n      \"pmids\": [\"23891976\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How β-arrestin represses BMP2 transcription not resolved\", \"Stem-cell identity markers correlative\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connecting CCKBR to microRNA control in pancreatic cancer, miR-148a was shown to directly target the CCKBR 3'UTR to regulate proliferation and apoptosis.\",\n      \"evidence\": \"Luciferase 3'UTR reporter, western blot, and proliferation/apoptosis assays in PANC-1 and AsPC-1 cells\",\n      \"pmids\": [\"23975374\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream CCKBR effectors mediating the phenotype not fully mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolving which gastric epithelial population CCKBR marks, the receptor was shown to label Lgr5neg/low +4 antral stem cells that progastrin interconverts and expands toward carcinogenesis.\",\n      \"evidence\": \"CCK2R-CreERT lineage tracing, organoid culture, genetic ablation, pharmacological inhibition, and MNU carcinogenesis\",\n      \"pmids\": [\"24951258\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway driving interconversion not defined here\", \"Human relevance of +4 population not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Establishing a developmental role, dual deletion of CCKAR and CCKBR produced synergistic cortical patterning, corpus callosum, and interneuron migration defects.\",\n      \"evidence\": \"Compound double-knockout mice with embryonic neocortex transcriptomics and histology\",\n      \"pmids\": [\"25875176\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CCKBR-specific contribution not separated from CCKAR\", \"Cell-autonomous mechanism unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extending miR-148a regulation to gastric cancer, CCKBR was confirmed as a direct target whose knockdown phenocopies miR-148a anti-oncogenic effects via reduced STAT3/Akt activation.\",\n      \"evidence\": \"Luciferase 3'UTR reporter, siRNA phenocopy, proliferation/migration assays, and xenograft\",\n      \"pmids\": [\"27518872\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Other miR-148a targets may contribute\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying the ECL-cell hyperplasia origin, CCK2R+ isthmus progenitors were shown to expand under hypergastrinemia via CCKBR-driven ERK signaling, blocked by MEK inhibition.\",\n      \"evidence\": \"Cck2r-CreERT2 and Hdc-CreERT2 lineage tracing, gastrin/omeprazole infusion, organoids, and U0126\",\n      \"pmids\": [\"32330731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream coupling of CCKBR to ERK in this niche not detailed\", \"Reversibility of hyperplasia not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealing a regulator of receptor abundance relevant to radiotheranostics, mTORC1 inhibition was shown to raise CCKBR protein and enhance β-arrestin1/2 recruitment, ERK phosphorylation, and minigastrin internalization in vivo.\",\n      \"evidence\": \"Kinase inhibitor screen, western blot, β-arrestin/ERK assays, and CCKBR xenograft SPECT/CT biodistribution\",\n      \"pmids\": [\"33042258\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which mTORC1 controls CCKBR levels unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defining a transport-regulatory function, intestinal CCKBR was shown to inhibit NHE3 through PKC-mediated NHERF1/NHERF2 to limit sodium absorption and protect against salt-sensitive hypertension.\",\n      \"evidence\": \"Intestinal-specific Cckbr knockout mice, Dahl salt-sensitive rats, sodium transport assays, and gastrin-SiO2 microsphere rescue\",\n      \"pmids\": [\"35674015\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CCKBR–NHERF physical coupling not structurally defined\", \"Human translation limited\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extending CCKBR transport control to the kidney, renal tubular CCKBR was shown to inhibit SGLT2-mediated glucose reabsorption via Erk/NF-κB, with knockout increasing diabetes susceptibility.\",\n      \"evidence\": \"Renal tubule-specific Cckbr knockout mice, HFD/STZ model, and HK-2 high-glucose assays with pathway western blot\",\n      \"pmids\": [\"39721589\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism linking CCKBR to SGLT2 downregulation not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Providing the structural basis of CCKBR signaling bias, cryo-EM of CCK8s-bound receptor with Gs, Gq, and Gi revealed conformation-encoded G-protein selectivity and enabled biased agonists, with Gs/Gq signaling shown beneficial in an Alzheimer's model.\",\n      \"evidence\": \"Cryo-EM at three G-protein subtypes, biased agonist pharmacology, 5×FAD mice, LTP, and western blot\",\n      \"pmids\": [\"41270732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous determinants of bias selection in vivo unknown\", \"Downstream ADAM10/PLCB4 regulation not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Dissecting which signaling arm supports synaptic plasticity, a β-arrestin-biased agonist showed CCKBR-dependent LTP requires Gαq/11-Ca2+ and Gαs-cAMP, while β-arrestin signaling drives endocytosis and blocks potentiation.\",\n      \"evidence\": \"β-arrestin recruitment, MEA, Ca2+ and cAMP assays, endocytosis imaging, and fear memory behavior\",\n      \"pmids\": [\"41360797\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Neuronal G-protein vs arrestin balance under physiological CCK release not measured\", \"Circuit specificity not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extending CCKBR's metabolic role, intestinal CCKBR was shown to reduce glucose absorption by downregulating SGLT1/GLUT2 and stimulating incretin secretion via PI3K/Akt/eIF4B.\",\n      \"evidence\": \"Intestinal-specific Cckbr knockout mice, HFD model, OGTT, pathway analysis, human duodenal tissue, and gastrin-SiO2 microspheres\",\n      \"pmids\": [\"39950948\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CCKBR-to-transporter regulatory link not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Placing CCKBR in a reward circuit, CCK2R in BLA glutamatergic neurons was shown to be required for methamphetamine conditioned place preference and the associated synaptic remodeling in the VTA→BLA→BNST pathway.\",\n      \"evidence\": \"Cell-type-specific Cck knockout, optogenetics, chemogenetics, electrophysiology, and Golgi spine analysis\",\n      \"pmids\": [\"41888094\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor-proximal signaling in BLA neurons not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the structurally defined conformational basis of G-protein bias is selected physiologically across CCKBR's diverse tissues—and how the same receptor partitions between proliferative, transport-regulatory, and synaptic outputs—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model of tissue-specific effector selection\", \"Endogenous determinants of Gs/Gq/Gi/arrestin partitioning unknown\", \"In vivo structural state of the receptor not captured\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0004930\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 15, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 10, 12]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [6, 7, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GNAQ\", \"GNAS\", \"JAK2\", \"ARRB1\", \"ARRB2\", \"NHERF1\", \"NHERF2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}