{"gene":"HOMER2","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1999,"finding":"Cupidin/Homer2a N-terminal domain (highly conserved EVH1 domain) binds F-actin in vitro and associates with mGluR1; a Cupidin-mGluR1-actin complex was immunoprecipitated from cerebellar lysates. The C-terminal coiled-coil domain binds activated Cdc42 (GTP-dependent) in vitro and functionally interacts with activated Cdc42 in a heterologous expression system.","method":"In vitro F-actin binding assay, co-immunoprecipitation from cerebellar lysates, yeast two-hybrid and heterologous overexpression with activated Cdc42","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal in vitro and in vivo binding assays, domain mapping, and functional heterologous expression all in one study","pmids":["10493740"],"is_preprint":false},{"year":2003,"finding":"Homer2 tunes GPCR signal intensity by: (1) preferentially binding PLCβ in pancreatic acini and brain extracts; (2) stimulating GAP activity of RGS4 and PLCβ in an in vitro reconstitution system (with minimal effect on PLCβ-mediated PIP2 hydrolysis); (3) deletion of Homer2 (but not Homer3) increased agonist potency for PLCβ activation and Ca²⁺ oscillation frequency without altering IP3R localization or channel activity.","method":"Homer2−/− mouse acinar cells, in vitro reconstitution of RGS/PLCβ GAP activity, co-immunoprecipitation (Homer2–PLCβ), Ca²⁺ imaging","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution assay plus genetic knockout plus co-IP, multiple orthogonal methods in one rigorous study","pmids":["12860966"],"is_preprint":false},{"year":2003,"finding":"Cupidin/Homer2 clusters dissociate rapidly upon glutamate stimulation in cerebellar and hippocampal neurons via NMDA receptor-mediated Ca²⁺ influx, followed by MAPK/ERK and protein tyrosine kinase signaling; Ca²⁺-dependent protein phosphatase activity reduces specific Homer2 isoforms post-translationally. Declustering precedes that of F-actin and Drebrin.","method":"Live-cell immunofluorescence in cultured cerebellar and hippocampal neurons, pharmacological dissection (NMDA antagonists, MAPK/ERK inhibitors, phosphatase inhibitors)","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional/pharmacological follow-up in primary neurons, single lab","pmids":["14511114"],"is_preprint":false},{"year":2005,"finding":"Homer2 knock-out mice fail to develop ethanol-induced locomotor sensitization, place preference, or augmented extracellular dopamine/glutamate in nucleus accumbens after repeated EtOH; AAV-mediated re-expression of Homer2b in accumbens fully rescues these phenotypes, demonstrating a necessary and active role for accumbens Homer2 in EtOH-induced neuroplasticity.","method":"Constitutive Homer2 knockout mouse, AAV-mediated Homer2b rescue in nucleus accumbens, in vivo microdialysis, behavioral tests","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus viral rescue with clear mechanistic phenotypic readouts, replicated behavioral and neurochemical endpoints","pmids":["16049182"],"is_preprint":false},{"year":2005,"finding":"A novel Homer2-specific binding partner, 2B28 (containing UBA, coiled-coil, and UBX domains), was identified by yeast two-hybrid using Homer2b C-terminal half as bait. 2B28 co-localizes with ubiquitin and enhances proteasomal degradation of IκB and Homer1a when expressed in HEK293T cells; 2B28 specifically binds Homer2 but not Homer1.","method":"Yeast two-hybrid, co-localization in HEK293T cells, western blot for ubiquitin-pathway substrates","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus heterologous co-localization, single lab, two methods","pmids":["15944415"],"is_preprint":false},{"year":2007,"finding":"HOMER2 was identified as a direct binding partner of MYO18B (class XVIII myosin/tumor suppressor) by yeast two-hybrid; the two proteins co-localize at membrane protrusions and stress fibers (F-actin-rich regions), and HOMER2 expression enhances MYO18B's ability to suppress anchorage-independent growth.","method":"Yeast two-hybrid, co-localization by immunofluorescence, anchorage-independent growth assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus functional assay in cells, single lab","pmids":["17386922"],"is_preprint":false},{"year":2007,"finding":"Chronic alcohol consumption increases Homer2 protein levels in nucleus accumbens; AAV-mediated overexpression of Homer2b in NAC of C57BL/6J mice augments alcohol reinforcement, preference, conditioned place preference, motor tolerance, and NAC glutamate/dopamine sensitization without affecting GABA levels, indicating Homer2 upregulation is sufficient to promote alcohol neuroplasticity.","method":"AAV-mediated overexpression in vivo, in vivo microdialysis, behavioral tests (CPP, operant self-administration, tolerance)","journal":"Neuropsychopharmacology","confidence":"High","confidence_rationale":"Tier 2 / Strong — viral gain-of-function with multiple orthogonal behavioral and neurochemical readouts, extends KO findings from prior study","pmids":["17568396"],"is_preprint":false},{"year":2008,"finding":"Homer2 (and Homer3, but not Homer1) specifically interacts with Amyloid Precursor Protein (APP); their expression inhibits APP processing, reduces Aβ secretion, decreases cell-surface APP, and inhibits maturation of APP and BACE1.","method":"Co-immunoprecipitation, western blot for APP processing products, Aβ ELISA, cell-surface biotinylation","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal binding and functional readouts in transfected cells, single lab, multiple endpoints","pmids":["18387811"],"is_preprint":false},{"year":2009,"finding":"Cupidin/Homer2 interacts with activated Cdc42 via its C-terminal coiled-coil domain (residues ~191–283). A deletion mutant (Δ191–230) with reduced Cdc42 binding fails to suppress Cdc42-induced filopodia in HeLa cells, is mislocalized to dendritic shafts (not spines), reduces synapse number, decreases mEPSC amplitudes, and decreases Drebrin clustering. The N-terminal EVH1 domain mediates interaction with Drebrin (via Drebrin's Homer ligand motifs).","method":"Domain deletion mutagenesis, co-immunoprecipitation, HeLa filopodia assay, immunofluorescence in hippocampal neurons, whole-cell electrophysiology (mEPSCs)","journal":"BMC neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis-coupled functional rescue experiments in multiple systems, electrophysiology, single lab but multiple orthogonal readouts","pmids":["19309525"],"is_preprint":false},{"year":2009,"finding":"Binge alcohol drinking upregulates NAC mGluR5-Homer2-PI3K signaling; mGluR5 with F1128R point mutation (markedly reduced Homer binding) reduces basal NAC PI3K activity and decreases binge drinking by 50%; virus-mediated Homer2b knockdown in NAC attenuates binge alcohol intake.","method":"Transgenic mGluR5-F1128R knock-in mice, AAV Homer2b knockdown, intra-NAC pharmacology, PI3K activity assay","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — transgenic point mutation disrupting Homer binding plus viral knockdown plus biochemical PI3K assay, multiple orthogonal approaches","pmids":["19587272"],"is_preprint":false},{"year":2012,"finding":"Homer2a/b is characteristic of slow-twitch skeletal muscle and is downregulated early during denervation atrophy. In vivo reconstitution of Homer2 in denervated soleus partially rescues muscle mass, fiber size, and ubiquitination by transcriptionally downregulating MuRF1, Atrogin, and Myogenin.","method":"In vivo electroporation/transfection of denervated soleus, muscle mass and fiber morphometry, western blot, RT-PCR for atrophy markers","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo reconstitution with functional phenotypic rescue and transcriptional mechanism, single lab","pmids":["23076792"],"is_preprint":false},{"year":2014,"finding":"Homer2 co-immunoprecipitates with plasma membrane Ca²⁺-ATPase (PMCA) in parotid acinar cells and transfected HEK293 cells via a PPXXF-like motif in PMCA's N-terminus; mutation of this motif specifically abolishes PMCA-Homer2 interaction (but not PMCA-Homer1 interaction) and increases Ca²⁺ clearance. Homer2 deletion markedly increases PMCA4 expression at the apical pole and increases Ca²⁺ extrusion.","method":"Homer2−/− mouse parotid acinar cells, co-immunoprecipitation, site-directed mutagenesis of PMCA PPXXF motif, Ca²⁺ imaging, western blot/localization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis of binding motif plus knockout mice plus co-IP plus functional Ca²⁺ assay, multiple orthogonal methods","pmids":["25049230"],"is_preprint":false},{"year":2015,"finding":"Homer2 deletion reduces NMDA receptor current density in cultured hippocampal neurons at 14 DIV (but not 7 DIV) without affecting kainate receptor currents or GluN2B subunit sensitivity to ifenprodil, and does not alter acute ethanol inhibition of NMDA receptors.","method":"Whole-cell voltage-clamp electrophysiology in primary hippocampal neurons from Homer2 KO mice","journal":"Synapse","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct electrophysiological measurement in KO neurons with pharmacological dissection, single lab","pmids":["26426435"],"is_preprint":false},{"year":2015,"finding":"Homer2 is expressed in stereocilia of hair cells in the murine inner ear; Homer2 knockout mice develop early-onset rapidly progressive hearing loss. A dominant-negative p.Arg185Pro mutation (in the coiled-coil domain essential for multimerization and HOMER2-CDC42 interaction) causes autosomal dominant non-syndromic hearing loss (DFNA68) in humans.","method":"Homer2 KO mouse auditory phenotyping (ABR), immunofluorescence in inner ear, human genetics (whole exome sequencing + segregation), zebrafish mRNA overexpression of mutant","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse phenotype plus human genetic segregation plus zebrafish functional validation, replicated across species and methods","pmids":["25816005"],"is_preprint":false},{"year":2019,"finding":"Homer2 and Homer3 interact with NFATc1 and calcineurin; RANKL treatment disrupts Homer-NFATc1 interaction (restored by calcineurin inhibitor cyclosporine A). Deletion of Homer2/Homer3 markedly decreases bone density and facilitates RANKL-induced osteoclast differentiation through increased NFATc1 nuclear translocation, without altering RANKL-induced Ca²⁺ oscillations.","method":"Homer2/3 double knockout mice, RANKL-treated bone marrow-derived monocytes, co-immunoprecipitation, NFATc1 nuclear translocation assay, bone density measurement (micro-CT), osteoclast differentiation assay","journal":"The Journal of endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic double KO plus co-IP plus cyclosporine rescue plus nuclear translocation assay, multiple orthogonal methods","pmids":["31319381"],"is_preprint":false},{"year":2023,"finding":"CaMKIIα phosphorylates Homer2 at S117/S216; alanine substitution at these sites (Homer2-AA knock-in) prevents activity-dependent phosphorylation of S216 in cortical neurons. Acute cocaine injection causes dissociation of mGluR5-Homer2 scaffolds in striatal lysates in WT but not Homer2-AA mice. Homer2-AA mice are less sensitive to the aversive properties of high-dose cocaine under place-conditioning and taste-conditioning, indicating CaMKIIα-dependent Homer2 phosphorylation gates mGluR5 coupling and cocaine aversion.","method":"Homer2-AA knock-in mice (S117A/S216A), cortical neuron activity-dependent phosphorylation assay, co-immunoprecipitation of mGluR5-Homer2 from striatum, conditioned place aversion, taste conditioning","journal":"eNeuro","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — phosphorylation-site knock-in mutagenesis plus direct biochemical mGluR5 dissociation assay plus behavioral phenotyping, multiple orthogonal methods","pmids":["36973011"],"is_preprint":false},{"year":2025,"finding":"Homer2 ablation (Homer2−/− mice) causes: (1) slower insertion of nAChRs into the motor endplate and reduced nAChR activity; (2) reduced subsynaptic IP3R1 content and diminished IP3-releasable Ca²⁺; (3) impaired co-localization of CaMKIIβ with nAChRs at the endplate—demonstrating Homer2 organizes the subsynaptic microdomain coupling IP3R1 and CaMKIIβ to regulate nAChR dynamics.","method":"Homer2−/− transgenic mice, single-channel electrophysiology, immunofluorescence co-localization, Ca²⁺ imaging of IP3-releasable stores in isolated muscle fibers","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with electrophysiology and imaging readouts, single lab, preliminary dataset","pmids":["41259107"],"is_preprint":false},{"year":2026,"finding":"Homer2 directly binds NFATc1 in skeletal muscle, with co-immunoprecipitation showing markedly increased Homer2-NFATc1 interaction at 4 days post-injury during muscle regeneration. Homer2-positive mononuclear cells co-express myogenin, and Homer2/NFATc1 co-positive cells increase at days 4 and 6 post-injury, placing Homer2 in the calcineurin-NFAT pathway during muscle differentiation.","method":"Co-immunoprecipitation from regenerating tibialis anterior muscle, immunofluorescence co-localization with satellite cell (Pax7) and differentiation (myogenin) markers","journal":"Cells, tissues, organs","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single co-IP in vivo with correlative immunofluorescence, single lab, no functional rescue","pmids":["42258588"],"is_preprint":false}],"current_model":"HOMER2 is a postsynaptic scaffolding protein whose N-terminal EVH1 domain binds mGluR1/5, F-actin, Drebrin, PMCA, and APP, while its C-terminal coiled-coil domain mediates homo/hetero-multimerization and GTP-dependent interaction with Cdc42; it tunes GPCR-evoked Ca²⁺ signaling by stimulating RGS and PLCβ GAP activities, regulates NMDA receptor surface expression and mGluR5–Homer2 scaffold dynamics via CaMKIIα-dependent phosphorylation at S117/S216, organizes the subsynaptic IP3R1/CaMKIIβ microdomain at the neuromuscular junction, modulates NFATc1-calcineurin signaling in osteoclasts and muscle, and is essential for auditory hair-cell function—with dominant-negative mutations in its coiled-coil domain causing progressive sensorineural hearing loss (DFNA68)."},"narrative":{"mechanistic_narrative":"HOMER2 (Cupidin) is a multidomain scaffolding protein that organizes Ca²⁺ signaling and cytoskeletal architecture at postsynaptic and other specialized membrane microdomains [PMID:10493740, PMID:12860966]. Its N-terminal EVH1 domain binds F-actin, the metabotropic glutamate receptor mGluR1, and the actin-regulator Drebrin, while its C-terminal coiled-coil domain mediates GTP-dependent interaction with activated Cdc42 and self-multimerization [PMID:10493740, PMID:19309525]; through these contacts HOMER2 couples filopodial/spine actin dynamics to glutamate receptor scaffolds, and a Cdc42-binding-deficient mutant mislocalizes from spines, reduces synapse number, and lowers mEPSC amplitude [PMID:19309525]. HOMER2 tunes GPCR-evoked Ca²⁺ signaling by binding PLCβ and stimulating the GAP activities of RGS4 and PLCβ, so that its loss raises agonist potency and Ca²⁺-oscillation frequency [PMID:12860966], and it constrains Ca²⁺ clearance by binding the plasma-membrane Ca²⁺-ATPase (PMCA) via a PPXXF-like motif [PMID:25049230]. CaMKIIα-dependent phosphorylation of HOMER2 at S117/S216 gates dissociation of mGluR5–HOMER2 scaffolds, linking activity-dependent signaling to behavioral plasticity [PMID:36973011], and accumbens HOMER2 within the mGluR5–HOMER2–PI3K axis is both necessary and sufficient for alcohol-induced neuroplasticity [PMID:16049182, PMID:17568396, PMID:19587272]. Beyond neurons, HOMER2 binds NFATc1 and calcineurin to restrain NFATc1 nuclear translocation in osteoclasts and acts in the calcineurin–NFAT pathway during muscle regeneration and denervation atrophy [PMID:31319381, PMID:23076792, PMID:42258588], and it organizes the subsynaptic IP3R1/CaMKIIβ microdomain controlling nAChR dynamics at the neuromuscular junction [PMID:41259107]. HOMER2 is expressed in hair-cell stereocilia and is required for hearing; a dominant-negative coiled-coil mutation (p.Arg185Pro) causes autosomal dominant non-syndromic hearing loss DFNA68 [PMID:25816005].","teleology":[{"year":1999,"claim":"Established the domain architecture and core interactions of HOMER2/Cupidin, defining it as a bridge between glutamate receptors, the actin cytoskeleton, and a Rho-family GTPase.","evidence":"In vitro F-actin binding, co-IP from cerebellar lysates, and yeast two-hybrid/heterologous assays with activated Cdc42","pmids":["10493740"],"confidence":"High","gaps":["Functional consequence of Cdc42 binding in neurons not resolved","No structural model of EVH1–ligand or coiled-coil–Cdc42 interfaces"]},{"year":2003,"claim":"Showed HOMER2 actively tunes GPCR Ca²⁺ signal intensity rather than serving as a passive scaffold, by promoting RGS/PLCβ GAP activity.","evidence":"Homer2−/− acinar cells, in vitro reconstitution of RGS/PLCβ GAP activity, co-IP, and Ca²⁺ imaging","pmids":["12860966"],"confidence":"High","gaps":["Whether this GAP-stimulating role operates in neurons not tested","Structural basis of HOMER2–PLCβ contact unknown"]},{"year":2003,"claim":"Demonstrated that HOMER2 scaffold clusters are dynamically regulated, dissociating upon NMDAR-mediated Ca²⁺ influx via downstream kinase/phosphatase signaling.","evidence":"Live-cell immunofluorescence in cultured neurons with pharmacological dissection","pmids":["14511114"],"confidence":"Medium","gaps":["Direct phosphorylation/dephosphorylation sites not identified in this study","Single lab, correlative pharmacology"]},{"year":2005,"claim":"Defined accumbens HOMER2 as necessary for alcohol-induced neuroplasticity, establishing an in vivo behavioral function.","evidence":"Constitutive Homer2 KO with AAV-mediated accumbens rescue, microdialysis, and behavioral tests","pmids":["16049182"],"confidence":"High","gaps":["Molecular partners mediating the accumbens effect not pinpointed here"]},{"year":2005,"claim":"Identified a HOMER2-specific partner (2B28) linking HOMER2 to the ubiquitin–proteasome pathway.","evidence":"Yeast two-hybrid with HOMER2b bait, heterologous co-localization, and degradation assays in HEK293T","pmids":["15944415"],"confidence":"Medium","gaps":["No in vivo validation of 2B28–HOMER2 function","Physiological relevance of HOMER2 in protein degradation unclear"]},{"year":2007,"claim":"Extended HOMER2's cytoskeletal role to tumor-suppressor signaling and to APP processing, broadening its interactome beyond synaptic scaffolding.","evidence":"Yeast two-hybrid/co-localization with MYO18B and anchorage-independent growth; reciprocal co-IP with APP plus Aβ and surface-APP assays","pmids":["17386922","18387811"],"confidence":"Medium","gaps":["Both interactions characterized largely in transfected cells","No endogenous/in vivo confirmation"]},{"year":2009,"claim":"Mapped the Cdc42-binding region of the coiled-coil domain and showed it is required for spine targeting, synapse number, synaptic transmission, and Drebrin clustering.","evidence":"Domain-deletion mutagenesis, HeLa filopodia assay, neuronal immunofluorescence, and mEPSC electrophysiology","pmids":["19309525"],"confidence":"High","gaps":["How Cdc42 binding mechanistically positions HOMER2 in spines not fully resolved"]},{"year":2009,"claim":"Demonstrated that the mGluR5–HOMER2 interaction drives the mGluR5–PI3K axis governing binge alcohol intake, identifying a specific signaling pathway downstream of the scaffold.","evidence":"mGluR5-F1128R knock-in (reduced Homer binding), AAV Homer2b knockdown, intra-NAC pharmacology, and PI3K activity assay","pmids":["19587272"],"confidence":"High","gaps":["Direct biochemical link from HOMER2 to PI3K not fully mapped"]},{"year":2012,"claim":"Revealed a muscle role for HOMER2 as a transcriptional restraint on atrophy programs during denervation.","evidence":"In vivo reconstitution in denervated soleus, morphometry, and atrophy-marker RT-PCR/western blot","pmids":["23076792"],"confidence":"Medium","gaps":["Mechanism linking HOMER2 to MuRF1/Atrogin transcription unresolved","Single lab"]},{"year":2014,"claim":"Showed HOMER2 binds PMCA via a PPXXF-like motif to limit Ca²⁺ extrusion, defining a direct mechanism for HOMER2 control of cytosolic Ca²⁺ clearance.","evidence":"Homer2−/− parotid acinar cells, co-IP, site-directed mutagenesis of the PMCA motif, and Ca²⁺ imaging","pmids":["25049230"],"confidence":"High","gaps":["Whether HOMER2–PMCA regulation operates in neurons or muscle not addressed"]},{"year":2015,"claim":"Established HOMER2 as essential for hearing and identified a dominant coiled-coil mutation as the cause of human DFNA68.","evidence":"Homer2 KO mouse ABR, inner-ear immunofluorescence, human exome/segregation, and zebrafish mutant overexpression","pmids":["25816005"],"confidence":"High","gaps":["Molecular function of HOMER2 within stereocilia not mechanistically defined"]},{"year":2015,"claim":"Showed HOMER2 supports NMDA receptor current density in a developmentally timed, receptor-selective manner.","evidence":"Whole-cell voltage-clamp in Homer2 KO hippocampal neurons with pharmacological dissection","pmids":["26426435"],"confidence":"Medium","gaps":["Mechanism of NMDAR surface/current regulation not identified","Single lab"]},{"year":2019,"claim":"Identified HOMER2 (with HOMER3) as a restraint on calcineurin–NFATc1 signaling in osteoclasts, linking the scaffold to bone homeostasis independent of Ca²⁺ oscillations.","evidence":"Homer2/3 double KO mice, co-IP, cyclosporine A rescue, NFATc1 translocation assay, micro-CT, and osteoclast differentiation","pmids":["31319381"],"confidence":"High","gaps":["Structural basis of HOMER2–NFATc1/calcineurin binding unknown"]},{"year":2023,"claim":"Defined CaMKIIα phosphorylation of HOMER2 at S117/S216 as the switch controlling activity-dependent mGluR5–HOMER2 scaffold dissociation and cocaine aversion.","evidence":"Homer2-AA (S117A/S216A) knock-in mice, neuronal phosphorylation assay, striatal mGluR5–HOMER2 co-IP, and conditioned aversion behavior","pmids":["36973011"],"confidence":"High","gaps":["How phosphorylation alters scaffold structure mechanistically not resolved"]},{"year":2025,"claim":"Showed HOMER2 organizes a subsynaptic IP3R1/CaMKIIβ microdomain at the neuromuscular junction to control nAChR insertion and activity.","evidence":"Homer2−/− mice, single-channel electrophysiology, co-localization imaging, and Ca²⁺ imaging of IP3-releasable stores","pmids":["41259107"],"confidence":"Medium","gaps":["Direct HOMER2–IP3R1 binding at the NMJ not biochemically demonstrated here","Single lab, preliminary dataset"]},{"year":2026,"claim":"Placed HOMER2–NFATc1 binding within the muscle regeneration/differentiation program, extending the calcineurin–NFAT role to satellite-cell-derived myogenesis.","evidence":"Co-IP from regenerating muscle and immunofluorescence with Pax7/myogenin markers","pmids":["42258588"],"confidence":"Medium","gaps":["Correlative, no functional rescue","Single in vivo co-IP without reciprocal validation"]},{"year":null,"claim":"How HOMER2's distinct interaction modules are coordinated to specify tissue-specific outputs, and the structural basis of its key binding interfaces, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of EVH1- or coiled-coil-ligand complexes","Mechanism integrating Ca²⁺-handling, cytoskeletal, and NFAT roles across tissues unresolved","Molecular function of HOMER2 in stereocilia undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,8,11,15]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[11,16]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,5,8]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,9,14]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,8,12]}],"complexes":[],"partners":["GRM1","GRM5","CDC42","PLCB","ATP2B4","DBN1","NFATC1","MYO18B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NSB8","full_name":"Homer protein homolog 2","aliases":["Cupidin"],"length_aa":354,"mass_kda":40.6,"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. May also couple GRM1 to PI3 kinase through its interaction with AGAP2. Isoforms can be differently regulated and may play an important role in maintaining the plasticity at glutamatergic synapses (PubMed:9808459). Required for normal hearing (PubMed:25816005). 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; Cell membrane; Postsynaptic density; Synapse; Cell projection, stereocilium","url":"https://www.uniprot.org/uniprotkb/Q9NSB8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HOMER2","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":[{"gene":"HOMER1","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/HOMER2","total_profiled":1310},"omim":[{"mim_id":"616707","title":"DEAFNESS, AUTOSOMAL DOMINANT 68; DFNA68","url":"https://www.omim.org/entry/616707"},{"mim_id":"614294","title":"CHROMOSOME 15q25 DELETION SYNDROME","url":"https://www.omim.org/entry/614294"},{"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"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"pancreas","ntpm":213.3}],"url":"https://www.proteinatlas.org/search/HOMER2"},"hgnc":{"alias_symbol":["CPD","Cupidin","Vesl-2","HOMER-2B","HOMER-2","HOMER-2A","DFNA68"],"prev_symbol":[]},"alphafold":{"accession":"Q9NSB8","domains":[{"cath_id":"2.30.29.30","chopping":"6-117","consensus_level":"medium","plddt":94.5032,"start":6,"end":117}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NSB8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NSB8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NSB8-F1-predicted_aligned_error_v6.png","plddt_mean":88.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HOMER2","jax_strain_url":"https://www.jax.org/strain/search?query=HOMER2"},"sequence":{"accession":"Q9NSB8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NSB8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NSB8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NSB8"}},"corpus_meta":[{"pmid":"16049182","id":"PMC_16049182","title":"Homer2 is necessary for EtOH-induced neuroplasticity.","date":"2005","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/16049182","citation_count":139,"is_preprint":false},{"pmid":"19587272","id":"PMC_19587272","title":"Binge drinking upregulates accumbens mGluR5-Homer2-PI3K signaling: functional implications for alcoholism.","date":"2009","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/19587272","citation_count":134,"is_preprint":false},{"pmid":"10493740","id":"PMC_10493740","title":"Cupidin, an isoform of Homer/Vesl, interacts with the actin cytoskeleton and activated rho family small GTPases and is expressed in developing mouse cerebellar granule cells.","date":"1999","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/10493740","citation_count":91,"is_preprint":false},{"pmid":"17568396","id":"PMC_17568396","title":"Accumbens Homer2 overexpression facilitates alcohol-induced neuroplasticity in C57BL/6J mice.","date":"2007","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/17568396","citation_count":91,"is_preprint":false},{"pmid":"12860966","id":"PMC_12860966","title":"Homer 2 tunes G protein-coupled receptors stimulus intensity by regulating RGS proteins and PLCbeta GAP activities.","date":"2003","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12860966","citation_count":81,"is_preprint":false},{"pmid":"19309525","id":"PMC_19309525","title":"Interaction of Cupidin/Homer2 with two actin cytoskeletal regulators, Cdc42 small GTPase and Drebrin, in dendritic spines.","date":"2009","source":"BMC 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variant in HOMER2 for autosomal dominant non-syndromic deafness.","date":"2018","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30047143","citation_count":11,"is_preprint":false},{"pmid":"28728878","id":"PMC_28728878","title":"A mass spectrometry-based proteomic analysis of Homer2-interacting proteins in the mouse brain.","date":"2017","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/28728878","citation_count":11,"is_preprint":false},{"pmid":"30268522","id":"PMC_30268522","title":"Prolonged-access to cocaine induces distinct Homer2 DNA methylation, hydroxymethylation, and transcriptional profiles in the dorsomedial prefrontal cortex of Male Sprague-Dawley rats.","date":"2018","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30268522","citation_count":10,"is_preprint":false},{"pmid":"23076792","id":"PMC_23076792","title":"Homer 2 antagonizes protein degradation in slow-twitch skeletal muscles.","date":"2012","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/23076792","citation_count":10,"is_preprint":false},{"pmid":"33809266","id":"PMC_33809266","title":"A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/33809266","citation_count":8,"is_preprint":false},{"pmid":"35008503","id":"PMC_35008503","title":"Reciprocal Homer1a and Homer2 Isoform Expression Is a Key Mechanism for Muscle Soleus Atrophy in Spaceflown Mice.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35008503","citation_count":7,"is_preprint":false},{"pmid":"33587295","id":"PMC_33587295","title":"MPEP Lowers Binge Drinking in Male and Female C57BL/6 Mice: Relationship with mGlu5/Homer2/Erk2 Signaling.","date":"2021","source":"Alcoholism, clinical and experimental research","url":"https://pubmed.ncbi.nlm.nih.gov/33587295","citation_count":6,"is_preprint":false},{"pmid":"37173411","id":"PMC_37173411","title":"Identification and in vivo functional investigation of a HOMER2 nonstop variant causing hearing loss.","date":"2023","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/37173411","citation_count":6,"is_preprint":false},{"pmid":"27832625","id":"PMC_27832625","title":"Diagnostic Potential of Differentially Expressed Homer1 and Homer2 in Ischemic Stroke.","date":"2016","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/27832625","citation_count":6,"is_preprint":false},{"pmid":"12378015","id":"PMC_12378015","title":"Potential role of Homer-2a on cutaneous vascular anomaly.","date":"2002","source":"Journal of Korean medical science","url":"https://pubmed.ncbi.nlm.nih.gov/12378015","citation_count":6,"is_preprint":false},{"pmid":"34564458","id":"PMC_34564458","title":"Preliminary Observations on Skeletal Muscle Adaptation and Plasticity in Homer 2-/- Mice.","date":"2021","source":"Metabolites","url":"https://pubmed.ncbi.nlm.nih.gov/34564458","citation_count":5,"is_preprint":false},{"pmid":"29891190","id":"PMC_29891190","title":"Overexpression of HOMER2 predicts better outcome in low-grade endometrioid endometrial adenocarcinoma.","date":"2018","source":"Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/29891190","citation_count":4,"is_preprint":false},{"pmid":"33995622","id":"PMC_33995622","title":"Homer2 and Homer3 Act as Novel Biomarkers in Diagnosis of hepatitis B virus-induced Hepatocellular Carcinoma.","date":"2021","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33995622","citation_count":3,"is_preprint":false},{"pmid":"36973011","id":"PMC_36973011","title":"Evidence for Phosphorylation-Dependent, Dynamic, Regulation of mGlu5 and Homer2 in Expression of Cocaine Aversion in Mice.","date":"2023","source":"eNeuro","url":"https://pubmed.ncbi.nlm.nih.gov/36973011","citation_count":1,"is_preprint":false},{"pmid":"40515814","id":"PMC_40515814","title":"Impact of HOMER2 frameshift extension variant on auditory function and development.","date":"2025","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40515814","citation_count":0,"is_preprint":false},{"pmid":"42258588","id":"PMC_42258588","title":"Homer 2 regulates muscle differentiation with NFATc1.","date":"2026","source":"Cells, tissues, organs","url":"https://pubmed.ncbi.nlm.nih.gov/42258588","citation_count":0,"is_preprint":false},{"pmid":"41259107","id":"PMC_41259107","title":"Adaptation of the endplate in skeletal muscle of Homer 2-/- mice.","date":"2025","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/41259107","citation_count":0,"is_preprint":false},{"pmid":"41351289","id":"PMC_41351289","title":"A Novel Frameshift Variant c.1023_1029del (p.Asp342ArgfsTer54) Leading to Extended Incorrect Protein C Termini in HOMER2 Causing Autosomal Dominant Nonsyndromic Hearing Loss.","date":"2025","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/41351289","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.08.20.24312225","title":"Heterogeneous group of genetically determined auditory neuropathy spectrum disorders","date":"2024-08-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.20.24312225","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":24887,"output_tokens":4942,"usd":0.074396,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13399,"output_tokens":4837,"usd":0.09396,"stage2_stop_reason":"end_turn"},"total_usd":0.168356,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"Cupidin/Homer2a N-terminal domain (highly conserved EVH1 domain) binds F-actin in vitro and associates with mGluR1; a Cupidin-mGluR1-actin complex was immunoprecipitated from cerebellar lysates. The C-terminal coiled-coil domain binds activated Cdc42 (GTP-dependent) in vitro and functionally interacts with activated Cdc42 in a heterologous expression system.\",\n      \"method\": \"In vitro F-actin binding assay, co-immunoprecipitation from cerebellar lysates, yeast two-hybrid and heterologous overexpression with activated Cdc42\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal in vitro and in vivo binding assays, domain mapping, and functional heterologous expression all in one study\",\n      \"pmids\": [\"10493740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Homer2 tunes GPCR signal intensity by: (1) preferentially binding PLCβ in pancreatic acini and brain extracts; (2) stimulating GAP activity of RGS4 and PLCβ in an in vitro reconstitution system (with minimal effect on PLCβ-mediated PIP2 hydrolysis); (3) deletion of Homer2 (but not Homer3) increased agonist potency for PLCβ activation and Ca²⁺ oscillation frequency without altering IP3R localization or channel activity.\",\n      \"method\": \"Homer2−/− mouse acinar cells, in vitro reconstitution of RGS/PLCβ GAP activity, co-immunoprecipitation (Homer2–PLCβ), Ca²⁺ imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution assay plus genetic knockout plus co-IP, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"12860966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Cupidin/Homer2 clusters dissociate rapidly upon glutamate stimulation in cerebellar and hippocampal neurons via NMDA receptor-mediated Ca²⁺ influx, followed by MAPK/ERK and protein tyrosine kinase signaling; Ca²⁺-dependent protein phosphatase activity reduces specific Homer2 isoforms post-translationally. Declustering precedes that of F-actin and Drebrin.\",\n      \"method\": \"Live-cell immunofluorescence in cultured cerebellar and hippocampal neurons, pharmacological dissection (NMDA antagonists, MAPK/ERK inhibitors, phosphatase inhibitors)\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional/pharmacological follow-up in primary neurons, single lab\",\n      \"pmids\": [\"14511114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Homer2 knock-out mice fail to develop ethanol-induced locomotor sensitization, place preference, or augmented extracellular dopamine/glutamate in nucleus accumbens after repeated EtOH; AAV-mediated re-expression of Homer2b in accumbens fully rescues these phenotypes, demonstrating a necessary and active role for accumbens Homer2 in EtOH-induced neuroplasticity.\",\n      \"method\": \"Constitutive Homer2 knockout mouse, AAV-mediated Homer2b rescue in nucleus accumbens, in vivo microdialysis, behavioral tests\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus viral rescue with clear mechanistic phenotypic readouts, replicated behavioral and neurochemical endpoints\",\n      \"pmids\": [\"16049182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A novel Homer2-specific binding partner, 2B28 (containing UBA, coiled-coil, and UBX domains), was identified by yeast two-hybrid using Homer2b C-terminal half as bait. 2B28 co-localizes with ubiquitin and enhances proteasomal degradation of IκB and Homer1a when expressed in HEK293T cells; 2B28 specifically binds Homer2 but not Homer1.\",\n      \"method\": \"Yeast two-hybrid, co-localization in HEK293T cells, western blot for ubiquitin-pathway substrates\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus heterologous co-localization, single lab, two methods\",\n      \"pmids\": [\"15944415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HOMER2 was identified as a direct binding partner of MYO18B (class XVIII myosin/tumor suppressor) by yeast two-hybrid; the two proteins co-localize at membrane protrusions and stress fibers (F-actin-rich regions), and HOMER2 expression enhances MYO18B's ability to suppress anchorage-independent growth.\",\n      \"method\": \"Yeast two-hybrid, co-localization by immunofluorescence, anchorage-independent growth assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus functional assay in cells, single lab\",\n      \"pmids\": [\"17386922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Chronic alcohol consumption increases Homer2 protein levels in nucleus accumbens; AAV-mediated overexpression of Homer2b in NAC of C57BL/6J mice augments alcohol reinforcement, preference, conditioned place preference, motor tolerance, and NAC glutamate/dopamine sensitization without affecting GABA levels, indicating Homer2 upregulation is sufficient to promote alcohol neuroplasticity.\",\n      \"method\": \"AAV-mediated overexpression in vivo, in vivo microdialysis, behavioral tests (CPP, operant self-administration, tolerance)\",\n      \"journal\": \"Neuropsychopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — viral gain-of-function with multiple orthogonal behavioral and neurochemical readouts, extends KO findings from prior study\",\n      \"pmids\": [\"17568396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Homer2 (and Homer3, but not Homer1) specifically interacts with Amyloid Precursor Protein (APP); their expression inhibits APP processing, reduces Aβ secretion, decreases cell-surface APP, and inhibits maturation of APP and BACE1.\",\n      \"method\": \"Co-immunoprecipitation, western blot for APP processing products, Aβ ELISA, cell-surface biotinylation\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal binding and functional readouts in transfected cells, single lab, multiple endpoints\",\n      \"pmids\": [\"18387811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cupidin/Homer2 interacts with activated Cdc42 via its C-terminal coiled-coil domain (residues ~191–283). A deletion mutant (Δ191–230) with reduced Cdc42 binding fails to suppress Cdc42-induced filopodia in HeLa cells, is mislocalized to dendritic shafts (not spines), reduces synapse number, decreases mEPSC amplitudes, and decreases Drebrin clustering. The N-terminal EVH1 domain mediates interaction with Drebrin (via Drebrin's Homer ligand motifs).\",\n      \"method\": \"Domain deletion mutagenesis, co-immunoprecipitation, HeLa filopodia assay, immunofluorescence in hippocampal neurons, whole-cell electrophysiology (mEPSCs)\",\n      \"journal\": \"BMC neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis-coupled functional rescue experiments in multiple systems, electrophysiology, single lab but multiple orthogonal readouts\",\n      \"pmids\": [\"19309525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Binge alcohol drinking upregulates NAC mGluR5-Homer2-PI3K signaling; mGluR5 with F1128R point mutation (markedly reduced Homer binding) reduces basal NAC PI3K activity and decreases binge drinking by 50%; virus-mediated Homer2b knockdown in NAC attenuates binge alcohol intake.\",\n      \"method\": \"Transgenic mGluR5-F1128R knock-in mice, AAV Homer2b knockdown, intra-NAC pharmacology, PI3K activity assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transgenic point mutation disrupting Homer binding plus viral knockdown plus biochemical PI3K assay, multiple orthogonal approaches\",\n      \"pmids\": [\"19587272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Homer2a/b is characteristic of slow-twitch skeletal muscle and is downregulated early during denervation atrophy. In vivo reconstitution of Homer2 in denervated soleus partially rescues muscle mass, fiber size, and ubiquitination by transcriptionally downregulating MuRF1, Atrogin, and Myogenin.\",\n      \"method\": \"In vivo electroporation/transfection of denervated soleus, muscle mass and fiber morphometry, western blot, RT-PCR for atrophy markers\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo reconstitution with functional phenotypic rescue and transcriptional mechanism, single lab\",\n      \"pmids\": [\"23076792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Homer2 co-immunoprecipitates with plasma membrane Ca²⁺-ATPase (PMCA) in parotid acinar cells and transfected HEK293 cells via a PPXXF-like motif in PMCA's N-terminus; mutation of this motif specifically abolishes PMCA-Homer2 interaction (but not PMCA-Homer1 interaction) and increases Ca²⁺ clearance. Homer2 deletion markedly increases PMCA4 expression at the apical pole and increases Ca²⁺ extrusion.\",\n      \"method\": \"Homer2−/− mouse parotid acinar cells, co-immunoprecipitation, site-directed mutagenesis of PMCA PPXXF motif, Ca²⁺ imaging, western blot/localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis of binding motif plus knockout mice plus co-IP plus functional Ca²⁺ assay, multiple orthogonal methods\",\n      \"pmids\": [\"25049230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Homer2 deletion reduces NMDA receptor current density in cultured hippocampal neurons at 14 DIV (but not 7 DIV) without affecting kainate receptor currents or GluN2B subunit sensitivity to ifenprodil, and does not alter acute ethanol inhibition of NMDA receptors.\",\n      \"method\": \"Whole-cell voltage-clamp electrophysiology in primary hippocampal neurons from Homer2 KO mice\",\n      \"journal\": \"Synapse\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct electrophysiological measurement in KO neurons with pharmacological dissection, single lab\",\n      \"pmids\": [\"26426435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Homer2 is expressed in stereocilia of hair cells in the murine inner ear; Homer2 knockout mice develop early-onset rapidly progressive hearing loss. A dominant-negative p.Arg185Pro mutation (in the coiled-coil domain essential for multimerization and HOMER2-CDC42 interaction) causes autosomal dominant non-syndromic hearing loss (DFNA68) in humans.\",\n      \"method\": \"Homer2 KO mouse auditory phenotyping (ABR), immunofluorescence in inner ear, human genetics (whole exome sequencing + segregation), zebrafish mRNA overexpression of mutant\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse phenotype plus human genetic segregation plus zebrafish functional validation, replicated across species and methods\",\n      \"pmids\": [\"25816005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Homer2 and Homer3 interact with NFATc1 and calcineurin; RANKL treatment disrupts Homer-NFATc1 interaction (restored by calcineurin inhibitor cyclosporine A). Deletion of Homer2/Homer3 markedly decreases bone density and facilitates RANKL-induced osteoclast differentiation through increased NFATc1 nuclear translocation, without altering RANKL-induced Ca²⁺ oscillations.\",\n      \"method\": \"Homer2/3 double knockout mice, RANKL-treated bone marrow-derived monocytes, co-immunoprecipitation, NFATc1 nuclear translocation assay, bone density measurement (micro-CT), osteoclast differentiation assay\",\n      \"journal\": \"The Journal of endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic double KO plus co-IP plus cyclosporine rescue plus nuclear translocation assay, multiple orthogonal methods\",\n      \"pmids\": [\"31319381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CaMKIIα phosphorylates Homer2 at S117/S216; alanine substitution at these sites (Homer2-AA knock-in) prevents activity-dependent phosphorylation of S216 in cortical neurons. Acute cocaine injection causes dissociation of mGluR5-Homer2 scaffolds in striatal lysates in WT but not Homer2-AA mice. Homer2-AA mice are less sensitive to the aversive properties of high-dose cocaine under place-conditioning and taste-conditioning, indicating CaMKIIα-dependent Homer2 phosphorylation gates mGluR5 coupling and cocaine aversion.\",\n      \"method\": \"Homer2-AA knock-in mice (S117A/S216A), cortical neuron activity-dependent phosphorylation assay, co-immunoprecipitation of mGluR5-Homer2 from striatum, conditioned place aversion, taste conditioning\",\n      \"journal\": \"eNeuro\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — phosphorylation-site knock-in mutagenesis plus direct biochemical mGluR5 dissociation assay plus behavioral phenotyping, multiple orthogonal methods\",\n      \"pmids\": [\"36973011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Homer2 ablation (Homer2−/− mice) causes: (1) slower insertion of nAChRs into the motor endplate and reduced nAChR activity; (2) reduced subsynaptic IP3R1 content and diminished IP3-releasable Ca²⁺; (3) impaired co-localization of CaMKIIβ with nAChRs at the endplate—demonstrating Homer2 organizes the subsynaptic microdomain coupling IP3R1 and CaMKIIβ to regulate nAChR dynamics.\",\n      \"method\": \"Homer2−/− transgenic mice, single-channel electrophysiology, immunofluorescence co-localization, Ca²⁺ imaging of IP3-releasable stores in isolated muscle fibers\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with electrophysiology and imaging readouts, single lab, preliminary dataset\",\n      \"pmids\": [\"41259107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Homer2 directly binds NFATc1 in skeletal muscle, with co-immunoprecipitation showing markedly increased Homer2-NFATc1 interaction at 4 days post-injury during muscle regeneration. Homer2-positive mononuclear cells co-express myogenin, and Homer2/NFATc1 co-positive cells increase at days 4 and 6 post-injury, placing Homer2 in the calcineurin-NFAT pathway during muscle differentiation.\",\n      \"method\": \"Co-immunoprecipitation from regenerating tibialis anterior muscle, immunofluorescence co-localization with satellite cell (Pax7) and differentiation (myogenin) markers\",\n      \"journal\": \"Cells, tissues, organs\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP in vivo with correlative immunofluorescence, single lab, no functional rescue\",\n      \"pmids\": [\"42258588\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HOMER2 is a postsynaptic scaffolding protein whose N-terminal EVH1 domain binds mGluR1/5, F-actin, Drebrin, PMCA, and APP, while its C-terminal coiled-coil domain mediates homo/hetero-multimerization and GTP-dependent interaction with Cdc42; it tunes GPCR-evoked Ca²⁺ signaling by stimulating RGS and PLCβ GAP activities, regulates NMDA receptor surface expression and mGluR5–Homer2 scaffold dynamics via CaMKIIα-dependent phosphorylation at S117/S216, organizes the subsynaptic IP3R1/CaMKIIβ microdomain at the neuromuscular junction, modulates NFATc1-calcineurin signaling in osteoclasts and muscle, and is essential for auditory hair-cell function—with dominant-negative mutations in its coiled-coil domain causing progressive sensorineural hearing loss (DFNA68).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HOMER2 (Cupidin) is a multidomain scaffolding protein that organizes Ca²⁺ signaling and cytoskeletal architecture at postsynaptic and other specialized membrane microdomains [#0, #1]. Its N-terminal EVH1 domain binds F-actin, the metabotropic glutamate receptor mGluR1, and the actin-regulator Drebrin, while its C-terminal coiled-coil domain mediates GTP-dependent interaction with activated Cdc42 and self-multimerization [#0, #8]; through these contacts HOMER2 couples filopodial/spine actin dynamics to glutamate receptor scaffolds, and a Cdc42-binding-deficient mutant mislocalizes from spines, reduces synapse number, and lowers mEPSC amplitude [#8]. HOMER2 tunes GPCR-evoked Ca²⁺ signaling by binding PLCβ and stimulating the GAP activities of RGS4 and PLCβ, so that its loss raises agonist potency and Ca²⁺-oscillation frequency [#1], and it constrains Ca²⁺ clearance by binding the plasma-membrane Ca²⁺-ATPase (PMCA) via a PPXXF-like motif [#11]. CaMKIIα-dependent phosphorylation of HOMER2 at S117/S216 gates dissociation of mGluR5–HOMER2 scaffolds, linking activity-dependent signaling to behavioral plasticity [#15], and accumbens HOMER2 within the mGluR5–HOMER2–PI3K axis is both necessary and sufficient for alcohol-induced neuroplasticity [#3, #6, #9]. Beyond neurons, HOMER2 binds NFATc1 and calcineurin to restrain NFATc1 nuclear translocation in osteoclasts and acts in the calcineurin–NFAT pathway during muscle regeneration and denervation atrophy [#14, #10, #17], and it organizes the subsynaptic IP3R1/CaMKIIβ microdomain controlling nAChR dynamics at the neuromuscular junction [#16]. HOMER2 is expressed in hair-cell stereocilia and is required for hearing; a dominant-negative coiled-coil mutation (p.Arg185Pro) causes autosomal dominant non-syndromic hearing loss DFNA68 [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the domain architecture and core interactions of HOMER2/Cupidin, defining it as a bridge between glutamate receptors, the actin cytoskeleton, and a Rho-family GTPase.\",\n      \"evidence\": \"In vitro F-actin binding, co-IP from cerebellar lysates, and yeast two-hybrid/heterologous assays with activated Cdc42\",\n      \"pmids\": [\"10493740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Cdc42 binding in neurons not resolved\", \"No structural model of EVH1–ligand or coiled-coil–Cdc42 interfaces\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed HOMER2 actively tunes GPCR Ca²⁺ signal intensity rather than serving as a passive scaffold, by promoting RGS/PLCβ GAP activity.\",\n      \"evidence\": \"Homer2−/− acinar cells, in vitro reconstitution of RGS/PLCβ GAP activity, co-IP, and Ca²⁺ imaging\",\n      \"pmids\": [\"12860966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this GAP-stimulating role operates in neurons not tested\", \"Structural basis of HOMER2–PLCβ contact unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated that HOMER2 scaffold clusters are dynamically regulated, dissociating upon NMDAR-mediated Ca²⁺ influx via downstream kinase/phosphatase signaling.\",\n      \"evidence\": \"Live-cell immunofluorescence in cultured neurons with pharmacological dissection\",\n      \"pmids\": [\"14511114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphorylation/dephosphorylation sites not identified in this study\", \"Single lab, correlative pharmacology\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined accumbens HOMER2 as necessary for alcohol-induced neuroplasticity, establishing an in vivo behavioral function.\",\n      \"evidence\": \"Constitutive Homer2 KO with AAV-mediated accumbens rescue, microdialysis, and behavioral tests\",\n      \"pmids\": [\"16049182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partners mediating the accumbens effect not pinpointed here\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified a HOMER2-specific partner (2B28) linking HOMER2 to the ubiquitin–proteasome pathway.\",\n      \"evidence\": \"Yeast two-hybrid with HOMER2b bait, heterologous co-localization, and degradation assays in HEK293T\",\n      \"pmids\": [\"15944415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo validation of 2B28–HOMER2 function\", \"Physiological relevance of HOMER2 in protein degradation unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended HOMER2's cytoskeletal role to tumor-suppressor signaling and to APP processing, broadening its interactome beyond synaptic scaffolding.\",\n      \"evidence\": \"Yeast two-hybrid/co-localization with MYO18B and anchorage-independent growth; reciprocal co-IP with APP plus Aβ and surface-APP assays\",\n      \"pmids\": [\"17386922\", \"18387811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Both interactions characterized largely in transfected cells\", \"No endogenous/in vivo confirmation\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapped the Cdc42-binding region of the coiled-coil domain and showed it is required for spine targeting, synapse number, synaptic transmission, and Drebrin clustering.\",\n      \"evidence\": \"Domain-deletion mutagenesis, HeLa filopodia assay, neuronal immunofluorescence, and mEPSC electrophysiology\",\n      \"pmids\": [\"19309525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Cdc42 binding mechanistically positions HOMER2 in spines not fully resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated that the mGluR5–HOMER2 interaction drives the mGluR5–PI3K axis governing binge alcohol intake, identifying a specific signaling pathway downstream of the scaffold.\",\n      \"evidence\": \"mGluR5-F1128R knock-in (reduced Homer binding), AAV Homer2b knockdown, intra-NAC pharmacology, and PI3K activity assay\",\n      \"pmids\": [\"19587272\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link from HOMER2 to PI3K not fully mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed a muscle role for HOMER2 as a transcriptional restraint on atrophy programs during denervation.\",\n      \"evidence\": \"In vivo reconstitution in denervated soleus, morphometry, and atrophy-marker RT-PCR/western blot\",\n      \"pmids\": [\"23076792\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking HOMER2 to MuRF1/Atrogin transcription unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed HOMER2 binds PMCA via a PPXXF-like motif to limit Ca²⁺ extrusion, defining a direct mechanism for HOMER2 control of cytosolic Ca²⁺ clearance.\",\n      \"evidence\": \"Homer2−/− parotid acinar cells, co-IP, site-directed mutagenesis of the PMCA motif, and Ca²⁺ imaging\",\n      \"pmids\": [\"25049230\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HOMER2–PMCA regulation operates in neurons or muscle not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established HOMER2 as essential for hearing and identified a dominant coiled-coil mutation as the cause of human DFNA68.\",\n      \"evidence\": \"Homer2 KO mouse ABR, inner-ear immunofluorescence, human exome/segregation, and zebrafish mutant overexpression\",\n      \"pmids\": [\"25816005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular function of HOMER2 within stereocilia not mechanistically defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed HOMER2 supports NMDA receptor current density in a developmentally timed, receptor-selective manner.\",\n      \"evidence\": \"Whole-cell voltage-clamp in Homer2 KO hippocampal neurons with pharmacological dissection\",\n      \"pmids\": [\"26426435\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of NMDAR surface/current regulation not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified HOMER2 (with HOMER3) as a restraint on calcineurin–NFATc1 signaling in osteoclasts, linking the scaffold to bone homeostasis independent of Ca²⁺ oscillations.\",\n      \"evidence\": \"Homer2/3 double KO mice, co-IP, cyclosporine A rescue, NFATc1 translocation assay, micro-CT, and osteoclast differentiation\",\n      \"pmids\": [\"31319381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of HOMER2–NFATc1/calcineurin binding unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined CaMKIIα phosphorylation of HOMER2 at S117/S216 as the switch controlling activity-dependent mGluR5–HOMER2 scaffold dissociation and cocaine aversion.\",\n      \"evidence\": \"Homer2-AA (S117A/S216A) knock-in mice, neuronal phosphorylation assay, striatal mGluR5–HOMER2 co-IP, and conditioned aversion behavior\",\n      \"pmids\": [\"36973011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation alters scaffold structure mechanistically not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed HOMER2 organizes a subsynaptic IP3R1/CaMKIIβ microdomain at the neuromuscular junction to control nAChR insertion and activity.\",\n      \"evidence\": \"Homer2−/− mice, single-channel electrophysiology, co-localization imaging, and Ca²⁺ imaging of IP3-releasable stores\",\n      \"pmids\": [\"41259107\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct HOMER2–IP3R1 binding at the NMJ not biochemically demonstrated here\", \"Single lab, preliminary dataset\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Placed HOMER2–NFATc1 binding within the muscle regeneration/differentiation program, extending the calcineurin–NFAT role to satellite-cell-derived myogenesis.\",\n      \"evidence\": \"Co-IP from regenerating muscle and immunofluorescence with Pax7/myogenin markers\",\n      \"pmids\": [\"42258588\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative, no functional rescue\", \"Single in vivo co-IP without reciprocal validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HOMER2's distinct interaction modules are coordinated to specify tissue-specific outputs, and the structural basis of its key binding interfaces, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of EVH1- or coiled-coil-ligand complexes\", \"Mechanism integrating Ca²⁺-handling, cytoskeletal, and NFAT roles across tissues unresolved\", \"Molecular function of HOMER2 in stereocilia undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 8, 11, 15]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [11, 16]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 5, 8]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 9, 14]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 8, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GRM1\", \"GRM5\", \"CDC42\", \"PLCB\", \"ATP2B4\", \"DBN1\", \"NFATC1\", \"MYO18B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}