{"gene":"HOMER3","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2008,"finding":"Homer3 is phosphorylated by CaMKII (calcium/calmodulin-dependent protein kinase II) both in vitro and in vivo; phosphorylation reduces Homer3 affinity for mGluR1α, causing dissociation from the postsynaptic density (PSD) into the cytosolic fraction, and modulates mGluR1α-induced Ca2+ signaling patterns.","method":"In vitro kinase assay, phospho-specific antibody fractionation, depolarization of primary cultured Purkinje cells with CaMKII inhibitor, in vitro binding kinetics, heterologous Ca2+ signaling assay","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (in vitro phosphorylation, fractionation, live-cell depolarization, binding kinetics, Ca2+ signaling readout) in a single rigorous study with genetic validation (P/Q-type Ca2+ channel KO mice)","pmids":["18480293"],"is_preprint":false},{"year":2003,"finding":"Homer-3 is recruited to the immunological synapse upon TCR engagement, subsequently translocates to the nucleus, suppresses SRE-driven transcription via its EVH1 domain, and co-precipitates with C/EBPβ; its EVH1 domain fragment is sufficient to reduce C/EBPβ transcriptional activation.","method":"Overexpression/knockdown in Jurkat T cells, luciferase SRE reporter assay, co-immunoprecipitation with C/EBPβ, confocal localization to anti-CD3/CD28-coated bead contact sites","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP plus functional reporter and localization in a single lab; multiple orthogonal readouts but no structural or in vitro reconstitution","pmids":["14645007"],"is_preprint":false},{"year":2008,"finding":"Homer2 and Homer3 (but not Homer1) specifically interact with the amyloid precursor protein (APP); their expression decreases APP surface levels, inhibits APP and BACE1 maturation, and reduces Aβ peptide secretion.","method":"Co-immunoprecipitation, cell-surface APP assay, Aβ ELISA in transfected cells","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP plus functional Aβ assays and maturation assays in one lab; multiple readouts but no in vitro reconstitution","pmids":["18387811"],"is_preprint":false},{"year":2012,"finding":"Long Homer-3 proteins specifically interact with the proteasomal S8 ATPase subunit; Homer-3A co-immunoprecipitates with the 26S proteasome and facilitates ubiquitination and proteasomal degradation of mGluR1α; siRNA silencing of Homer-3 increases total and plasma membrane-associated mGluR1α.","method":"Co-immunoprecipitation in vitro and in vivo, siRNA knockdown, ubiquitination assay, cell-surface mGluR1α quantification","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal co-IP plus functional siRNA rescue plus ubiquitination assay; single lab, multiple complementary methods","pmids":["22486777"],"is_preprint":false},{"year":2015,"finding":"Homer3 is identified as a novel Gαi2-binding protein via affinity chromatography; Homer3 knockdown in HL-60 neutrophil-like cells impairs chemotaxis and the establishment of PIP3 and actin polarity, as well as persistence of the WAVE2 complex, while leaving Rac and PI3K activation kinetics intact—placing Homer3 downstream of GPCR/Gαi2 and upstream of spatial actin organization.","method":"Affinity chromatography with primary neutrophil lysate, RNAi knockdown in HL-60 cells, live-cell imaging of PIP3 and F-actin polarity, WAVE2 localization, Rac/PI3K activity assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — affinity chromatography identification plus RNAi epistasis with multiple orthogonal cellular readouts; pathway position defined by showing PI3K/Rac are normal while polarity is lost","pmids":["25739453"],"is_preprint":false},{"year":2010,"finding":"Homer3 specifically associates with a novel ubiquitin-like domain of IKKβ; the IKK complex recruits Homer3 to the immunological synapse following TCR engagement; Homer3 is not required for NF-κB/IKK activation but this association regulates actin dynamics in T cells.","method":"Co-immunoprecipitation of Homer3 with IKKβ, confocal colocalization at immune synapse, T cells from Homer3-deficient mice (NF-κB signaling intact), actin dynamics assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus Homer3-KO cells with defined negative result (IKK activation intact) and positive actin phenotype; single lab","pmids":["20693425"],"is_preprint":false},{"year":2014,"finding":"Extracellular Ca2+ influx (via ionophore A23187), ER Ca2+ store depletion (thapsigargin/SOCE), and PLC-stimulated IP3-mediated ER Ca2+ release each specifically reduce the APP/Homer3 interaction without affecting APP/X11a interaction; membrane depolarization also disrupts the complex in human neuroblastoma cells.","method":"Co-immunoprecipitation under pharmacological Ca2+ perturbations in HEK293 and neuroblastoma cells","journal":"Neurobiology of aging","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP with multiple Ca2+ perturbation conditions in two cell types; single lab, single method type but several orthogonal Ca2+ manipulations","pmids":["24792907"],"is_preprint":false},{"year":2015,"finding":"The cytoplasmic tail of APP is necessary for interaction with Homer3; both the EVH1 domain and the coiled-coil polymerization domain of Homer3 are required for complex assembly; phosphorylation of Homer3 at certain serine residues enhances the interaction with APP.","method":"Domain deletion/mutation analysis by co-immunoprecipitation in transfected cells","journal":"Journal of Alzheimer's disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — domain-deletion co-IP and phospho-site mutagenesis; single lab, multiple domain constructs","pmids":["25589726"],"is_preprint":false},{"year":2014,"finding":"NMR spectroscopy and pull-down assays revealed that the IP3R suppressor domain uses its PPKKF motif to bind the Homer3 EVH1 domain; additionally, a new set of residues on the opposite face of the previously reported EVH1 binding site also participates in binding, with F40 acting as a conformational lock-switch.","method":"NMR chemical shift mapping, biochemical pull-down with EVH1 domain mutants","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — NMR structure plus mutant pull-down in a single study; no functional cellular validation reported","pmids":["24901889"],"is_preprint":false},{"year":2016,"finding":"In SCA1 Purkinje cells, impaired climbing fiber-mediated synaptic transmission reduces mTORC1 signaling, which in turn decreases Homer-3 expression; pharmacological or genetic mTORC1 inhibition reduces Homer-3 levels, placing Homer-3 as a downstream target of mTORC1; reinstating Homer-3 expression in SCA1 Purkinje cells attenuates cellular dysfunction and improves motor deficits.","method":"Proteomic profiling of SCA1 Purkinje cells, mTORC1 pharmacological inhibition (rapamycin), Purkinje cell-specific mTORC1 knockout, AAV-mediated Homer-3 re-expression with motor behavioral readout","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic epistasis (mTORC1 KO), pharmacological inhibition, and functional rescue (Homer-3 AAV re-expression improving motor phenotype) in multiple orthogonal experiments","pmids":["26748090"],"is_preprint":false},{"year":2019,"finding":"Homer2 and Homer3 interact with NFATc1 and calcineurin; deletion of Homer2/3 facilitates RANKL-induced osteoclast differentiation by increasing NFATc1 nuclear translocation without altering Ca2+ oscillations; RANKL treatment disrupts Homer interaction with NFATc1 but this is restored by calcineurin inhibition with cyclosporin A.","method":"Homer2/3 double-knockout BMMs, RANKL-induced osteoclastogenesis assay, NFATc1 nuclear translocation imaging, Ca2+ oscillation measurement, co-immunoprecipitation of Homer with NFATc1/calcineurin, bone density measurement","journal":"The Journal of endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic DKO plus pharmacological rescue (CsA) plus co-IP plus multiple cellular phenotypes; multiple orthogonal methods in a single rigorous study","pmids":["31319381"],"is_preprint":false},{"year":2005,"finding":"HOMER3 interacts with the C-terminal peptide of PAX6 in a yeast two-hybrid screen; three C-terminal PAX6 mutations associated with eye malformations reduce or abolish this interaction.","method":"Yeast two-hybrid library screen, interaction confirmed with disease-associated PAX6 C-terminal mutants","journal":"BMC genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid only, single lab, no in vivo or biochemical validation of the interaction","pmids":["16098226"],"is_preprint":false},{"year":2021,"finding":"HOMER3 interacts with both c-Src and β-Catenin (by co-immunoprecipitation), providing a scaffold that facilitates c-Src-induced tyrosine phosphorylation of β-Catenin under EGF stimulation, promoting β-Catenin nuclear translocation and transcriptional activation, and driving TNBC metastasis in vitro and in vivo.","method":"Reciprocal co-immunoprecipitation, tyrosine phosphorylation assay, TOP/FOP flash reporter, in vitro migration/invasion assays, mouse xenograft tumor model","journal":"Journal of hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus functional reporter plus in vivo model in a single lab; multiple orthogonal methods","pmids":["33407765"],"is_preprint":false},{"year":2025,"finding":"HOMER3 acts as a scaffold in prostate cancer that disrupts LATS1-mediated YAP1 phosphorylation and facilitates SRC kinase-mediated YAP1 phosphorylation, maintaining YAP1 nuclear localization and transcriptional activity; this upregulates CD274 (PD-L1) and creates an immunosuppressive phenotype; SRC kinase inhibition rescues immunotherapy sensitivity.","method":"Co-immunoprecipitation, YAP1 phosphorylation assays, nuclear/cytoplasmic fractionation, transcriptome analysis, in vitro proliferation, in vivo tumor growth, pharmacological SRC inhibition","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP plus phosphorylation assay plus gain-of-function in vivo model plus transcriptome; single lab, multiple complementary methods","pmids":["40849586"],"is_preprint":false},{"year":2025,"finding":"In OSCC, HOMER3 forms two distinct scaffolding complexes: HOMER3-CAMKK1-TRPV6 (mediating calcium influx activating AMPK/AKT/mTOR and B-Raf/MEK/ERK) and HOMER3-CAMKK1-TUBB3 (regulating microtubule dynamics and conferring docetaxel resistance); HOMER3 knockdown reduces ECM stiffness and collagen deposition and increases docetaxel sensitivity.","method":"Co-immunoprecipitation, calcium influx assay, signaling pathway western blots (AMPK/AKT/mTOR, ERK), microtubule dynamics assay, docetaxel sensitivity assay, HOMER3 KD/OE functional assays in vitro and in vivo","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP-defined complexes plus multiple downstream pathway readouts plus in vivo model; single lab","pmids":["41326663"],"is_preprint":false}],"current_model":"HOMER3 is a multifunctional postsynaptic scaffold protein that: (1) couples mGluR1α, IP3R, and other targets in Purkinje cell PSD via its EVH1 and coiled-coil domains, with coupling state reversibly regulated by CaMKII-mediated phosphorylation that reduces ligand affinity and promotes cytosolic redistribution; (2) mediates proteasomal degradation of mGluR1α by bridging it to the 26S proteasome via the S8 ATPase subunit; (3) in immune cells, is recruited to the immunological synapse via IKKβ association to regulate actin dynamics, and suppresses SRE transcription by binding C/EBPβ through its EVH1 domain; (4) acts as a Gαi2-binding scaffold in neutrophils that spatially organizes actin and PIP3 polarity downstream of GPCR activation; (5) regulates NFATc1 activity through interaction with calcineurin to control osteoclastogenesis; (6) interacts with APP in a Ca2+-regulated manner to inhibit Aβ production; and (7) in cancer contexts, scaffolds c-Src/β-Catenin, SRC/YAP1, and CAMKK1/TRPV6-TUBB3 complexes to promote oncogenic signaling."},"narrative":{"mechanistic_narrative":"HOMER3 is a multidomain scaffold protein that couples signaling receptors to downstream effectors through its EVH1 ligand-binding and coiled-coil polymerization domains, organizing complexes across neuronal, immune, and cancer contexts [PMID:18480293, PMID:25589726]. In Purkinje cells it links mGluR1α and the IP3R suppressor domain via the EVH1 domain, with the IP3R engaging a PPKKF motif and an F40 conformational switch on the EVH1 surface [PMID:24901889]; CaMKII phosphorylation of HOMER3 lowers its affinity for mGluR1α, driving dissociation from the postsynaptic density into the cytosol and reshaping mGluR1α-induced Ca2+ signaling [PMID:18480293]. Beyond scaffolding the receptor, long HOMER3 isoforms bridge mGluR1α to the 26S proteasome through the S8 ATPase subunit, promoting its ubiquitination and degradation [PMID:22486777]. HOMER3 also acts downstream of mTORC1 in Purkinje cells, and restoring its expression in SCA1 model neurons attenuates cellular dysfunction and motor deficits [PMID:26748090]. In immune cells, HOMER3 is recruited to the immunological synapse by association with a ubiquitin-like domain of IKKβ to regulate actin dynamics independently of NF-κB activation [PMID:20693425], translocates to the nucleus to suppress SRE-driven transcription via C/EBPβ binding [PMID:14645007], and serves as a Gαi2-binding scaffold in neutrophils that organizes PIP3 and actin polarity downstream of GPCR activation while leaving Rac and PI3K kinetics intact [PMID:25739453]. HOMER3 binds the cytoplasmic tail of APP in a Ca2+-regulated manner to inhibit APP/BACE1 maturation and reduce Aβ secretion [PMID:18387811, PMID:24792907, PMID:25589726], and it interacts with NFATc1 and calcineurin to restrain RANKL-induced osteoclast differentiation [PMID:31319381]. In cancer, HOMER3 scaffolds oncogenic complexes—c-Src/β-Catenin in triple-negative breast cancer [PMID:33407765], SRC/YAP1 in prostate cancer [PMID:40849586], and CAMKK1/TRPV6 and CAMKK1/TUBB3 in oral squamous cell carcinoma [PMID:41326663]—promoting tumor signaling, metastasis, and chemoresistance.","teleology":[{"year":2003,"claim":"Established that HOMER3 functions beyond neurons by linking TCR engagement to transcriptional control, answering whether this scaffold acts in immune signaling.","evidence":"Overexpression/knockdown, SRE luciferase reporter, co-IP with C/EBPβ, and confocal localization in Jurkat T cells","pmids":["14645007"],"confidence":"Medium","gaps":["No structural definition of the EVH1–C/EBPβ interface","Nuclear translocation mechanism not defined"]},{"year":2005,"claim":"Raised the possibility that HOMER3 binds PAX6, addressing whether it engages transcription factors implicated in eye development.","evidence":"Yeast two-hybrid screen with disease-associated PAX6 C-terminal mutants","pmids":["16098226"],"confidence":"Low","gaps":["Yeast two-hybrid only, no biochemical or in vivo validation","Functional consequence of the interaction untested"]},{"year":2008,"claim":"Defined how synaptic activity dynamically regulates HOMER3 scaffolding, showing that CaMKII phosphorylation toggles its receptor coupling state.","evidence":"In vitro kinase assay, phospho-specific fractionation, Purkinje cell depolarization with CaMKII inhibitor, binding kinetics, and Ca2+ signaling readout","pmids":["18480293"],"confidence":"High","gaps":["Specific phosphosites controlling mGluR1α affinity not fully mapped","In vivo behavioral consequence not addressed"]},{"year":2008,"claim":"Identified a HOMER3 role in APP processing, answering whether the scaffold modulates amyloidogenic pathways.","evidence":"Co-IP, cell-surface APP assay, and Aβ ELISA in transfected cells","pmids":["18387811"],"confidence":"Medium","gaps":["No in vivo validation of Aβ effect","Mechanism of maturation inhibition not resolved"]},{"year":2010,"claim":"Resolved how HOMER3 reaches the immunological synapse and distinguished its actin role from NF-κB signaling.","evidence":"Co-IP with IKKβ ubiquitin-like domain, confocal colocalization, and Homer3-KO T cells with intact NF-κB","pmids":["20693425"],"confidence":"Medium","gaps":["Molecular link from IKKβ recruitment to actin remodeling unknown","Single lab"]},{"year":2012,"claim":"Showed HOMER3 not only scaffolds mGluR1α but targets it for degradation, revealing a receptor turnover function.","evidence":"Reciprocal co-IP with proteasomal S8 ATPase, siRNA knockdown, and ubiquitination/surface mGluR1α assays","pmids":["22486777"],"confidence":"Medium","gaps":["E3 ligase mediating ubiquitination not identified","Isoform specificity mechanism not detailed"]},{"year":2014,"claim":"Provided structural and Ca2+-regulatory detail of HOMER3 EVH1 ligand binding, defining the IP3R-binding surface and the Ca2+ sensitivity of the APP complex.","evidence":"NMR chemical shift mapping with EVH1 mutants; co-IP under Ca2+ perturbations in HEK293 and neuroblastoma cells","pmids":["24901889","24792907"],"confidence":"Medium","gaps":["EVH1 NMR study lacks cellular functional validation","Ca2+ sensor coupling APP complex to influx not identified"]},{"year":2015,"claim":"Established HOMER3 as a Gαi2-binding scaffold positioning it downstream of GPCRs in neutrophil polarity, and mapped APP-binding determinants.","evidence":"Affinity chromatography and RNAi epistasis in HL-60 cells with PIP3/F-actin imaging; domain-deletion and phospho-mutant co-IP for APP","pmids":["25739453","25589726"],"confidence":"High","gaps":["How HOMER3 organizes WAVE2 persistence mechanistically unknown","Gαi2 binding interface not structurally defined"]},{"year":2016,"claim":"Placed HOMER3 as a functional effector downstream of mTORC1 whose restoration rescues neurodegenerative phenotype, linking its expression level to disease.","evidence":"SCA1 Purkinje cell proteomics, rapamycin treatment, mTORC1 conditional KO, and AAV Homer-3 re-expression with motor behavior","pmids":["26748090"],"confidence":"High","gaps":["Transcriptional/translational mechanism of mTORC1 control of Homer-3 unclear","Downstream targets mediating rescue not defined"]},{"year":2019,"claim":"Demonstrated HOMER3 restrains osteoclastogenesis through calcineurin/NFATc1, revealing a brake on NFAT nuclear translocation.","evidence":"Homer2/3 DKO BMMs, RANKL osteoclast assay, NFATc1 imaging, co-IP, and cyclosporin A rescue with bone density measurement","pmids":["31319381"],"confidence":"High","gaps":["Relative contributions of Homer2 vs Homer3 not separated","Direct calcineurin-binding interface undefined"]},{"year":2025,"claim":"Extended HOMER3 scaffolding into oncogenic signaling, showing it assembles SRC/YAP1 and CAMKK1/TRPV6/TUBB3 complexes driving immunosuppression and chemoresistance.","evidence":"Co-IP, YAP1 phosphorylation and fractionation, calcium influx and pathway westerns, microtubule and docetaxel assays, and in vivo tumor models","pmids":["40849586","41326663"],"confidence":"Medium","gaps":["Domain requirements for these cancer complexes not mapped","Whether scaffolding is constitutive or regulated unclear"]},{"year":null,"claim":"It remains unknown what unifying biochemical principle governs HOMER3 partner selection across its neuronal, immune, and oncogenic complexes, and how phosphorylation and Ca2+ jointly set its scaffolding state in each tissue.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated structural model of HOMER3 complex assembly across contexts","Isoform-specific roles incompletely defined","Physiological selection between competing partners unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,4,8,12,13,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,10]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,13]},{"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":[0,4,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,5]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,13,14]}],"complexes":["HOMER3-CAMKK1-TRPV6","HOMER3-CAMKK1-TUBB3"],"partners":["MGLUR1Α","IP3R","APP","IKKΒ","GΑI2","NFATC1","C-SRC","YAP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NSC5","full_name":"Homer protein homolog 3","aliases":[],"length_aa":361,"mass_kda":39.8,"function":"Postsynaptic density scaffolding protein. Binds and cross-links cytoplasmic regions of GRM1, GRM5, ITPR1, DNM3, RYR1, RYR2, SHANK1 and SHANK3. By physically linking GRM1 and GRM5 with ER-associated ITPR1 receptors, it aids the coupling of surface receptors to intracellular calcium release. Isoforms can be differently regulated and may play an important role in maintaining the plasticity at glutamatergic synapses. Negatively regulates T cell activation by inhibiting the calcineurin-NFAT pathway. Acts by competing with calcineurin/PPP3CA for NFAT protein binding, hence preventing NFAT activation by PPP3CA (PubMed:18218901)","subcellular_location":"Cytoplasm; Postsynaptic density; Synapse","url":"https://www.uniprot.org/uniprotkb/Q9NSC5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HOMER3","classification":"Not Classified","n_dependent_lines":44,"n_total_lines":1208,"dependency_fraction":0.03642384105960265},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HOMER1","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/HOMER3","total_profiled":1310},"omim":[{"mim_id":"604800","title":"HOMER SCAFFOLD PROTEIN 3; HOMER3","url":"https://www.omim.org/entry/604800"},{"mim_id":"604799","title":"HOMER SCAFFOLD PROTEIN 2; HOMER2","url":"https://www.omim.org/entry/604799"},{"mim_id":"604798","title":"HOMER SCAFFOLD PROTEIN 1; HOMER1","url":"https://www.omim.org/entry/604798"},{"mim_id":"601517","title":"ATAXIN 2; ATXN2","url":"https://www.omim.org/entry/601517"},{"mim_id":"600489","title":"NUCLEAR FACTOR OF ACTIVATED T CELLS, CYTOPLASMIC, CALCINEURIN-DEPENDENT 1; NFATC1","url":"https://www.omim.org/entry/600489"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cytoplasmic bodies","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HOMER3"},"hgnc":{"alias_symbol":["HOMER-3"],"prev_symbol":[]},"alphafold":{"accession":"Q9NSC5","domains":[{"cath_id":"2.30.29.30","chopping":"9-121","consensus_level":"medium","plddt":95.0338,"start":9,"end":121}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NSC5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NSC5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NSC5-F1-predicted_aligned_error_v6.png","plddt_mean":82.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HOMER3","jax_strain_url":"https://www.jax.org/strain/search?query=HOMER3"},"sequence":{"accession":"Q9NSC5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NSC5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NSC5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NSC5"}},"corpus_meta":[{"pmid":"26377085","id":"PMC_26377085","title":"'Medusa-head ataxia': the expanding spectrum of Purkinje cell antibodies in autoimmune cerebellar ataxia. 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1950)","url":"https://pubmed.ncbi.nlm.nih.gov/20693425","citation_count":6,"is_preprint":false},{"pmid":"36672107","id":"PMC_36672107","title":"Cerebrospinal Fluid Homer-3 Autoantibodies in a Patient with Amnestic Mild Cognitive Impairment.","date":"2023","source":"Brain sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36672107","citation_count":6,"is_preprint":false},{"pmid":"35871640","id":"PMC_35871640","title":"Anti-Homer-3 antibodies in cerebrospinal fluid and serum samples from a 58-year-old woman with subacute cerebellar degeneration and diffuse breast adenocarcinoma.","date":"2022","source":"Neurological research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/35871640","citation_count":6,"is_preprint":false},{"pmid":"40849586","id":"PMC_40849586","title":"HOMER3 orchestrates SRC-YAP1 activity that promotes tumor cell growth and antagonizes anti-tumor immunotherapy in prostate 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in vivo; phosphorylation reduces Homer3 affinity for mGluR1α, causing dissociation from the postsynaptic density (PSD) into the cytosolic fraction, and modulates mGluR1α-induced Ca2+ signaling patterns.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibody fractionation, depolarization of primary cultured Purkinje cells with CaMKII inhibitor, in vitro binding kinetics, heterologous Ca2+ signaling assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (in vitro phosphorylation, fractionation, live-cell depolarization, binding kinetics, Ca2+ signaling readout) in a single rigorous study with genetic validation (P/Q-type Ca2+ channel KO mice)\",\n      \"pmids\": [\"18480293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Homer-3 is recruited to the immunological synapse upon TCR engagement, subsequently translocates to the nucleus, suppresses SRE-driven transcription via its EVH1 domain, and co-precipitates with C/EBPβ; its EVH1 domain fragment is sufficient to reduce C/EBPβ transcriptional activation.\",\n      \"method\": \"Overexpression/knockdown in Jurkat T cells, luciferase SRE reporter assay, co-immunoprecipitation with C/EBPβ, confocal localization to anti-CD3/CD28-coated bead contact sites\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP plus functional reporter and localization in a single lab; multiple orthogonal readouts but no structural or in vitro reconstitution\",\n      \"pmids\": [\"14645007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Homer2 and Homer3 (but not Homer1) specifically interact with the amyloid precursor protein (APP); their expression decreases APP surface levels, inhibits APP and BACE1 maturation, and reduces Aβ peptide secretion.\",\n      \"method\": \"Co-immunoprecipitation, cell-surface APP assay, Aβ ELISA in transfected cells\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP plus functional Aβ assays and maturation assays in one lab; multiple readouts but no in vitro reconstitution\",\n      \"pmids\": [\"18387811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Long Homer-3 proteins specifically interact with the proteasomal S8 ATPase subunit; Homer-3A co-immunoprecipitates with the 26S proteasome and facilitates ubiquitination and proteasomal degradation of mGluR1α; siRNA silencing of Homer-3 increases total and plasma membrane-associated mGluR1α.\",\n      \"method\": \"Co-immunoprecipitation in vitro and in vivo, siRNA knockdown, ubiquitination assay, cell-surface mGluR1α quantification\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal co-IP plus functional siRNA rescue plus ubiquitination assay; single lab, multiple complementary methods\",\n      \"pmids\": [\"22486777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Homer3 is identified as a novel Gαi2-binding protein via affinity chromatography; Homer3 knockdown in HL-60 neutrophil-like cells impairs chemotaxis and the establishment of PIP3 and actin polarity, as well as persistence of the WAVE2 complex, while leaving Rac and PI3K activation kinetics intact—placing Homer3 downstream of GPCR/Gαi2 and upstream of spatial actin organization.\",\n      \"method\": \"Affinity chromatography with primary neutrophil lysate, RNAi knockdown in HL-60 cells, live-cell imaging of PIP3 and F-actin polarity, WAVE2 localization, Rac/PI3K activity assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — affinity chromatography identification plus RNAi epistasis with multiple orthogonal cellular readouts; pathway position defined by showing PI3K/Rac are normal while polarity is lost\",\n      \"pmids\": [\"25739453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Homer3 specifically associates with a novel ubiquitin-like domain of IKKβ; the IKK complex recruits Homer3 to the immunological synapse following TCR engagement; Homer3 is not required for NF-κB/IKK activation but this association regulates actin dynamics in T cells.\",\n      \"method\": \"Co-immunoprecipitation of Homer3 with IKKβ, confocal colocalization at immune synapse, T cells from Homer3-deficient mice (NF-κB signaling intact), actin dynamics assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus Homer3-KO cells with defined negative result (IKK activation intact) and positive actin phenotype; single lab\",\n      \"pmids\": [\"20693425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Extracellular Ca2+ influx (via ionophore A23187), ER Ca2+ store depletion (thapsigargin/SOCE), and PLC-stimulated IP3-mediated ER Ca2+ release each specifically reduce the APP/Homer3 interaction without affecting APP/X11a interaction; membrane depolarization also disrupts the complex in human neuroblastoma cells.\",\n      \"method\": \"Co-immunoprecipitation under pharmacological Ca2+ perturbations in HEK293 and neuroblastoma cells\",\n      \"journal\": \"Neurobiology of aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP with multiple Ca2+ perturbation conditions in two cell types; single lab, single method type but several orthogonal Ca2+ manipulations\",\n      \"pmids\": [\"24792907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The cytoplasmic tail of APP is necessary for interaction with Homer3; both the EVH1 domain and the coiled-coil polymerization domain of Homer3 are required for complex assembly; phosphorylation of Homer3 at certain serine residues enhances the interaction with APP.\",\n      \"method\": \"Domain deletion/mutation analysis by co-immunoprecipitation in transfected cells\",\n      \"journal\": \"Journal of Alzheimer's disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — domain-deletion co-IP and phospho-site mutagenesis; single lab, multiple domain constructs\",\n      \"pmids\": [\"25589726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NMR spectroscopy and pull-down assays revealed that the IP3R suppressor domain uses its PPKKF motif to bind the Homer3 EVH1 domain; additionally, a new set of residues on the opposite face of the previously reported EVH1 binding site also participates in binding, with F40 acting as a conformational lock-switch.\",\n      \"method\": \"NMR chemical shift mapping, biochemical pull-down with EVH1 domain mutants\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — NMR structure plus mutant pull-down in a single study; no functional cellular validation reported\",\n      \"pmids\": [\"24901889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In SCA1 Purkinje cells, impaired climbing fiber-mediated synaptic transmission reduces mTORC1 signaling, which in turn decreases Homer-3 expression; pharmacological or genetic mTORC1 inhibition reduces Homer-3 levels, placing Homer-3 as a downstream target of mTORC1; reinstating Homer-3 expression in SCA1 Purkinje cells attenuates cellular dysfunction and improves motor deficits.\",\n      \"method\": \"Proteomic profiling of SCA1 Purkinje cells, mTORC1 pharmacological inhibition (rapamycin), Purkinje cell-specific mTORC1 knockout, AAV-mediated Homer-3 re-expression with motor behavioral readout\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic epistasis (mTORC1 KO), pharmacological inhibition, and functional rescue (Homer-3 AAV re-expression improving motor phenotype) in multiple orthogonal experiments\",\n      \"pmids\": [\"26748090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Homer2 and Homer3 interact with NFATc1 and calcineurin; deletion of Homer2/3 facilitates RANKL-induced osteoclast differentiation by increasing NFATc1 nuclear translocation without altering Ca2+ oscillations; RANKL treatment disrupts Homer interaction with NFATc1 but this is restored by calcineurin inhibition with cyclosporin A.\",\n      \"method\": \"Homer2/3 double-knockout BMMs, RANKL-induced osteoclastogenesis assay, NFATc1 nuclear translocation imaging, Ca2+ oscillation measurement, co-immunoprecipitation of Homer with NFATc1/calcineurin, bone density measurement\",\n      \"journal\": \"The Journal of endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic DKO plus pharmacological rescue (CsA) plus co-IP plus multiple cellular phenotypes; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"31319381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HOMER3 interacts with the C-terminal peptide of PAX6 in a yeast two-hybrid screen; three C-terminal PAX6 mutations associated with eye malformations reduce or abolish this interaction.\",\n      \"method\": \"Yeast two-hybrid library screen, interaction confirmed with disease-associated PAX6 C-terminal mutants\",\n      \"journal\": \"BMC genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid only, single lab, no in vivo or biochemical validation of the interaction\",\n      \"pmids\": [\"16098226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HOMER3 interacts with both c-Src and β-Catenin (by co-immunoprecipitation), providing a scaffold that facilitates c-Src-induced tyrosine phosphorylation of β-Catenin under EGF stimulation, promoting β-Catenin nuclear translocation and transcriptional activation, and driving TNBC metastasis in vitro and in vivo.\",\n      \"method\": \"Reciprocal co-immunoprecipitation, tyrosine phosphorylation assay, TOP/FOP flash reporter, in vitro migration/invasion assays, mouse xenograft tumor model\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus functional reporter plus in vivo model in a single lab; multiple orthogonal methods\",\n      \"pmids\": [\"33407765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HOMER3 acts as a scaffold in prostate cancer that disrupts LATS1-mediated YAP1 phosphorylation and facilitates SRC kinase-mediated YAP1 phosphorylation, maintaining YAP1 nuclear localization and transcriptional activity; this upregulates CD274 (PD-L1) and creates an immunosuppressive phenotype; SRC kinase inhibition rescues immunotherapy sensitivity.\",\n      \"method\": \"Co-immunoprecipitation, YAP1 phosphorylation assays, nuclear/cytoplasmic fractionation, transcriptome analysis, in vitro proliferation, in vivo tumor growth, pharmacological SRC inhibition\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP plus phosphorylation assay plus gain-of-function in vivo model plus transcriptome; single lab, multiple complementary methods\",\n      \"pmids\": [\"40849586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In OSCC, HOMER3 forms two distinct scaffolding complexes: HOMER3-CAMKK1-TRPV6 (mediating calcium influx activating AMPK/AKT/mTOR and B-Raf/MEK/ERK) and HOMER3-CAMKK1-TUBB3 (regulating microtubule dynamics and conferring docetaxel resistance); HOMER3 knockdown reduces ECM stiffness and collagen deposition and increases docetaxel sensitivity.\",\n      \"method\": \"Co-immunoprecipitation, calcium influx assay, signaling pathway western blots (AMPK/AKT/mTOR, ERK), microtubule dynamics assay, docetaxel sensitivity assay, HOMER3 KD/OE functional assays in vitro and in vivo\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP-defined complexes plus multiple downstream pathway readouts plus in vivo model; single lab\",\n      \"pmids\": [\"41326663\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HOMER3 is a multifunctional postsynaptic scaffold protein that: (1) couples mGluR1α, IP3R, and other targets in Purkinje cell PSD via its EVH1 and coiled-coil domains, with coupling state reversibly regulated by CaMKII-mediated phosphorylation that reduces ligand affinity and promotes cytosolic redistribution; (2) mediates proteasomal degradation of mGluR1α by bridging it to the 26S proteasome via the S8 ATPase subunit; (3) in immune cells, is recruited to the immunological synapse via IKKβ association to regulate actin dynamics, and suppresses SRE transcription by binding C/EBPβ through its EVH1 domain; (4) acts as a Gαi2-binding scaffold in neutrophils that spatially organizes actin and PIP3 polarity downstream of GPCR activation; (5) regulates NFATc1 activity through interaction with calcineurin to control osteoclastogenesis; (6) interacts with APP in a Ca2+-regulated manner to inhibit Aβ production; and (7) in cancer contexts, scaffolds c-Src/β-Catenin, SRC/YAP1, and CAMKK1/TRPV6-TUBB3 complexes to promote oncogenic signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HOMER3 is a multidomain scaffold protein that couples signaling receptors to downstream effectors through its EVH1 ligand-binding and coiled-coil polymerization domains, organizing complexes across neuronal, immune, and cancer contexts [#0, #7]. In Purkinje cells it links mGluR1\\u03b1 and the IP3R suppressor domain via the EVH1 domain, with the IP3R engaging a PPKKF motif and an F40 conformational switch on the EVH1 surface [#8]; CaMKII phosphorylation of HOMER3 lowers its affinity for mGluR1\\u03b1, driving dissociation from the postsynaptic density into the cytosol and reshaping mGluR1\\u03b1-induced Ca2+ signaling [#0]. Beyond scaffolding the receptor, long HOMER3 isoforms bridge mGluR1\\u03b1 to the 26S proteasome through the S8 ATPase subunit, promoting its ubiquitination and degradation [#3]. HOMER3 also acts downstream of mTORC1 in Purkinje cells, and restoring its expression in SCA1 model neurons attenuates cellular dysfunction and motor deficits [#9]. In immune cells, HOMER3 is recruited to the immunological synapse by association with a ubiquitin-like domain of IKK\\u03b2 to regulate actin dynamics independently of NF-\\u03baB activation [#5], translocates to the nucleus to suppress SRE-driven transcription via C/EBP\\u03b2 binding [#1], and serves as a G\\u03b1i2-binding scaffold in neutrophils that organizes PIP3 and actin polarity downstream of GPCR activation while leaving Rac and PI3K kinetics intact [#4]. HOMER3 binds the cytoplasmic tail of APP in a Ca2+-regulated manner to inhibit APP/BACE1 maturation and reduce A\\u03b2 secretion [#2, #6, #7], and it interacts with NFATc1 and calcineurin to restrain RANKL-induced osteoclast differentiation [#10]. In cancer, HOMER3 scaffolds oncogenic complexes\\u2014c-Src/\\u03b2-Catenin in triple-negative breast cancer [#12], SRC/YAP1 in prostate cancer [#13], and CAMKK1/TRPV6 and CAMKK1/TUBB3 in oral squamous cell carcinoma [#14]\\u2014promoting tumor signaling, metastasis, and chemoresistance.\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that HOMER3 functions beyond neurons by linking TCR engagement to transcriptional control, answering whether this scaffold acts in immune signaling.\",\n      \"evidence\": \"Overexpression/knockdown, SRE luciferase reporter, co-IP with C/EBP\\u03b2, and confocal localization in Jurkat T cells\",\n      \"pmids\": [\"14645007\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural definition of the EVH1\\u2013C/EBP\\u03b2 interface\", \"Nuclear translocation mechanism not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Raised the possibility that HOMER3 binds PAX6, addressing whether it engages transcription factors implicated in eye development.\",\n      \"evidence\": \"Yeast two-hybrid screen with disease-associated PAX6 C-terminal mutants\",\n      \"pmids\": [\"16098226\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Yeast two-hybrid only, no biochemical or in vivo validation\", \"Functional consequence of the interaction untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined how synaptic activity dynamically regulates HOMER3 scaffolding, showing that CaMKII phosphorylation toggles its receptor coupling state.\",\n      \"evidence\": \"In vitro kinase assay, phospho-specific fractionation, Purkinje cell depolarization with CaMKII inhibitor, binding kinetics, and Ca2+ signaling readout\",\n      \"pmids\": [\"18480293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific phosphosites controlling mGluR1\\u03b1 affinity not fully mapped\", \"In vivo behavioral consequence not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified a HOMER3 role in APP processing, answering whether the scaffold modulates amyloidogenic pathways.\",\n      \"evidence\": \"Co-IP, cell-surface APP assay, and A\\u03b2 ELISA in transfected cells\",\n      \"pmids\": [\"18387811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo validation of A\\u03b2 effect\", \"Mechanism of maturation inhibition not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved how HOMER3 reaches the immunological synapse and distinguished its actin role from NF-\\u03baB signaling.\",\n      \"evidence\": \"Co-IP with IKK\\u03b2 ubiquitin-like domain, confocal colocalization, and Homer3-KO T cells with intact NF-\\u03baB\",\n      \"pmids\": [\"20693425\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link from IKK\\u03b2 recruitment to actin remodeling unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed HOMER3 not only scaffolds mGluR1\\u03b1 but targets it for degradation, revealing a receptor turnover function.\",\n      \"evidence\": \"Reciprocal co-IP with proteasomal S8 ATPase, siRNA knockdown, and ubiquitination/surface mGluR1\\u03b1 assays\",\n      \"pmids\": [\"22486777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating ubiquitination not identified\", \"Isoform specificity mechanism not detailed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided structural and Ca2+-regulatory detail of HOMER3 EVH1 ligand binding, defining the IP3R-binding surface and the Ca2+ sensitivity of the APP complex.\",\n      \"evidence\": \"NMR chemical shift mapping with EVH1 mutants; co-IP under Ca2+ perturbations in HEK293 and neuroblastoma cells\",\n      \"pmids\": [\"24901889\", \"24792907\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"EVH1 NMR study lacks cellular functional validation\", \"Ca2+ sensor coupling APP complex to influx not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established HOMER3 as a G\\u03b1i2-binding scaffold positioning it downstream of GPCRs in neutrophil polarity, and mapped APP-binding determinants.\",\n      \"evidence\": \"Affinity chromatography and RNAi epistasis in HL-60 cells with PIP3/F-actin imaging; domain-deletion and phospho-mutant co-IP for APP\",\n      \"pmids\": [\"25739453\", \"25589726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HOMER3 organizes WAVE2 persistence mechanistically unknown\", \"G\\u03b1i2 binding interface not structurally defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed HOMER3 as a functional effector downstream of mTORC1 whose restoration rescues neurodegenerative phenotype, linking its expression level to disease.\",\n      \"evidence\": \"SCA1 Purkinje cell proteomics, rapamycin treatment, mTORC1 conditional KO, and AAV Homer-3 re-expression with motor behavior\",\n      \"pmids\": [\"26748090\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional/translational mechanism of mTORC1 control of Homer-3 unclear\", \"Downstream targets mediating rescue not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated HOMER3 restrains osteoclastogenesis through calcineurin/NFATc1, revealing a brake on NFAT nuclear translocation.\",\n      \"evidence\": \"Homer2/3 DKO BMMs, RANKL osteoclast assay, NFATc1 imaging, co-IP, and cyclosporin A rescue with bone density measurement\",\n      \"pmids\": [\"31319381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of Homer2 vs Homer3 not separated\", \"Direct calcineurin-binding interface undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended HOMER3 scaffolding into oncogenic signaling, showing it assembles SRC/YAP1 and CAMKK1/TRPV6/TUBB3 complexes driving immunosuppression and chemoresistance.\",\n      \"evidence\": \"Co-IP, YAP1 phosphorylation and fractionation, calcium influx and pathway westerns, microtubule and docetaxel assays, and in vivo tumor models\",\n      \"pmids\": [\"40849586\", \"41326663\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Domain requirements for these cancer complexes not mapped\", \"Whether scaffolding is constitutive or regulated unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown what unifying biochemical principle governs HOMER3 partner selection across its neuronal, immune, and oncogenic complexes, and how phosphorylation and Ca2+ jointly set its scaffolding state in each tissue.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated structural model of HOMER3 complex assembly across contexts\", \"Isoform-specific roles incompletely defined\", \"Physiological selection between competing partners unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 4, 8, 12, 13, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 10]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 13]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 13, 14]}\n    ],\n    \"complexes\": [\n      \"HOMER3-CAMKK1-TRPV6\",\n      \"HOMER3-CAMKK1-TUBB3\"\n    ],\n    \"partners\": [\n      \"mGluR1\\u03b1\",\n      \"IP3R\",\n      \"APP\",\n      \"IKK\\u03b2\",\n      \"G\\u03b1i2\",\n      \"NFATc1\",\n      \"c-Src\",\n      \"YAP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}