{"gene":"ERBIN","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2000,"finding":"ERBIN (ERBB2 interacting protein) was identified as a PDZ domain-containing protein that directly and specifically interacts with the C-terminus of ERBB2/HER2 via its PDZ domain, and colocalizes with ERBB2/HER2 at the lateral membrane of epithelial cells; mutation of the ERBIN-binding site in ERBB2/HER2 leads to mislocalization of the receptor away from the basolateral membrane.","method":"Co-immunoprecipitation, in vitro binding, immunofluorescence co-localization, mutagenesis of binding site","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (pulldown, Co-IP, localization, mutagenesis) in original discovery paper","pmids":["10878805"],"is_preprint":false},{"year":2001,"finding":"The Erbin PDZ domain interacts with ARVCF and delta-catenin at their C-terminal PDZ-binding motifs (DSWV-COOH), and Erbin associates with the cadherin-catenin complex through these interactions in vivo; endogenous delta-catenin and Erbin co-immunoprecipitate from neurons.","method":"C-terminal phage peptide library display, in vitro peptide binding assays, Co-IP, co-localization, mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — phage display, in vitro binding, Co-IP and mutagenesis; multiple orthogonal methods","pmids":["11821434"],"is_preprint":false},{"year":2001,"finding":"Erbin is concentrated at postsynaptic membranes at the neuromuscular junction and in the CNS, interacts specifically with ErbB2 (not ErbB3 or ErbB4), increases ErbB2 surface expression, and interacts with PSD-95 in transfected cells and synaptosomes.","method":"Co-immunoprecipitation, biotin labeling of surface proteins, immunostaining of postsynaptic membranes","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP and surface labeling from a single lab","pmids":["11279080"],"is_preprint":false},{"year":2001,"finding":"Erbin interacts with p0071 (plakophilin-4) in a PDZ domain-dependent manner, and both proteins colocalize in desmosomes of epithelial cells; disruption of this interaction by a dominant-negative approach impairs epithelial cell monolayer integrity.","method":"Yeast two-hybrid, in vitro binding, Co-IP, immunofluorescence co-localization, dominant-negative disruption","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Y2H, in vitro binding, Co-IP, functional disruption), replicated in two independent papers","pmids":["11711544","12047349"],"is_preprint":false},{"year":2001,"finding":"ERBIN interacts with eBPAG1 (bullous pemphigoid antigen 1) via its N-terminus and with the cytoplasmic domain of integrin β4 subunit, linking it to hemidesmosome components.","method":"Yeast two-hybrid, in vitro binding","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — yeast two-hybrid and in vitro binding, single lab","pmids":["11375975"],"is_preprint":false},{"year":2002,"finding":"Crystal structure of the human Erbin PDZ domain bound to the ErbB2 C-terminal peptide (EYLGLDVPV) at 1.25 Å resolution revealed a novel mode of class II ligand recognition by a class I PDZ domain; phosphorylation of tyrosine at position -7 of ErbB2 abolishes its interaction with the Erbin PDZ domain.","method":"X-ray crystallography at 1.25 Å resolution, binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure with mutagenesis/phosphorylation functional validation","pmids":["12444095"],"is_preprint":false},{"year":2002,"finding":"NMR structure of the Erbin PDZ domain in complex with a high-affinity peptide ligand; alanine and homolog scanning mutagenesis identified that the β2-β3 loop provides a binding pocket for residue at position -4 that is specific to Erbin's unusually long loop, determining ligand specificity.","method":"NMR structure determination, phage display, binding affinity measurements, alanine scanning mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — NMR structure + comprehensive mutagenesis + phage display energetic analysis","pmids":["12446668"],"is_preprint":false},{"year":2002,"finding":"Erbin is a negative regulator of the Ras-Raf-ERK signaling pathway: it associates with active (but not inactive) Ras and disrupts the Ras-Raf interaction in vitro and in vivo, thereby inhibiting ERK (but not Akt) activation; siRNA knockdown of Erbin enhances ERK activation and NGF-induced neuronal differentiation.","method":"Reporter assays, co-immunoprecipitation, in vitro interaction assay, siRNA knockdown, PC12 differentiation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, in vitro binding, gain/loss of function), replicated across multiple subsequent papers","pmids":["12379659"],"is_preprint":false},{"year":2005,"finding":"Erbin inhibits Raf activation by disrupting the Sur-8 (Shoc2)-Ras-Raf scaffold complex via its N-terminal LRR domain; expression of Erbin attenuated Sur-8 interactions with active Ras and Raf, while Erbin-shRNA increased these interactions and ERK activation.","method":"Co-immunoprecipitation, shRNA knockdown, reporter assays, LRR domain mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, domain mapping, shRNA/OE with functional readout, replicated in cardiac hypertrophy paper","pmids":["16301319"],"is_preprint":false},{"year":2005,"finding":"Erbin interacts directly with Nod2 (specifically requiring the LRR domain of Erbin and the CARD domains of Nod2), inhibits Nod2-dependent NF-κB activation and cytokine secretion; Erbin-/- mouse embryo fibroblasts show increased sensitivity to muramyl dipeptide.","method":"Biochemical screen, in vitro binding, Co-IP, overexpression and Erbin-/- MEF knockout studies, NF-κB reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — in vitro and in vivo interaction, knockout MEF functional data, replicated by independent lab","pmids":["16203728"],"is_preprint":false},{"year":2006,"finding":"Erbin interacts with Nod2 via yeast two-hybrid and Co-IP; Erbin's LRR domain and Nod2's CARD domains are necessary; no significant interaction with inactive or Crohn's disease-associated frameshift mutants of Nod2; bacterial (Shigella) infection alters Erbin/Nod2 complex dynamics; shRNA knockdown of Erbin negatively influences Nod2/MDP-mediated NF-κB activation.","method":"Yeast two-hybrid, Co-IP, immunofluorescence, shRNA knockdown, NF-κB reporter","journal":"Infection and immunity","confidence":"High","confidence_rationale":"Tier 2 — independent lab replication of Erbin-Nod2 interaction with domain mapping and functional validation","pmids":["16714539"],"is_preprint":false},{"year":2007,"finding":"Erbin interacts specifically with Smad3 (and to lesser extent Smad2) through a novel Smad-interacting domain (SID) adjacent to its PDZ domain; Erbin sequesters phospho-Smad2/3 away from Smad4 to negatively modulate TGF-β transcriptional responses; an alternatively spliced isoform lacking the SID fails to inhibit TGF-β responses.","method":"Co-IP, shRNA knockdown, reporter assays, Xenopus embryo gain/loss-of-function, splice isoform analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including Co-IP, knockdown, OE, splice variant analysis, and Xenopus epistasis","pmids":["17591701"],"is_preprint":false},{"year":2007,"finding":"Erbin forms a specific complex with Cav1.3 (L-type) but not Cav1.2 Ca2+ channels via PDZ domain interaction with the C-terminus of the long variant of Cav1.3 α1 subunit; Erbin enhances voltage-dependent facilitation (VDF) of Cav1.3 currents by relieving autoinhibition imposed by the α1.3 C-terminal domain.","method":"Co-IP from brain lysates, co-localization in cortical neurons, electrophysiology (whole-cell patch clamp), domain deletion mutagenesis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 — electrophysiology + Co-IP + mutagenesis with mechanistic explanation","pmids":["17287512"],"is_preprint":false},{"year":2008,"finding":"Palmitoylation of ERBIN at cysteines 14 and 16 in its N-terminal region is required for its plasma membrane localization; mutants with C14S and/or C16S substitutions localize to the cytoplasm rather than the plasma membrane, and both palmitoylation and LRR domain are required for membrane targeting.","method":"Mutagenesis of palmitoylation sites, in vivo palmitoylation detection, localization studies in transfected cells","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 1–2 — direct mutagenesis of palmitoylation sites with clear localization readout","pmids":["18498353"],"is_preprint":false},{"year":2008,"finding":"Erbin controls dendritic morphogenesis in hippocampal neurons by maintaining appropriate localization of delta-catenin; Erbin knockdown causes severe dendritic morphogenesis defects that are rescued by delta-catenin overexpression (but not vice versa), placing Erbin upstream of delta-catenin.","method":"shRNA knockdown, genetic knockout, rescue experiments, epistasis (Erbin upstream of delta-catenin), live imaging","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis established, clean KO with specific morphological phenotype, multiple rescue experiments","pmids":["18614673"],"is_preprint":false},{"year":2009,"finding":"Erbin is necessary for NRG1 signaling and PNS myelination; Erbin null mice display hypomyelination and reduced ErbB2 protein levels in sciatic nerves; Erbin with PDZ domain deletion (erbin ΔC/ΔC mice) phenocopies this, indicating that Erbin stabilizes ErbB2 protein via PDZ domain interaction.","method":"Erbin null mouse, erbin ΔC/ΔC knock-in mouse, electrophysiology, electron microscopy, protein level analysis, siRNA knockdown in cultured cells","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 — multiple mouse models, in vivo and in vitro mechanistic validation","pmids":["19458253"],"is_preprint":false},{"year":2009,"finding":"Erbin controls the functional output of Merlin (NF2 tumor suppressor) by determining whether Merlin inhibits or is inhibited by active PAK2; in epithelial cells, Erbin/Merlin complexes bind and inactivate GTPase-bound PAK2, preventing TGF-β-induced PAK2 activation.","method":"Co-IP, siRNA knockdown, kinase activity assays, epistasis in epithelial vs. mesenchymal cells","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, kinase assays, and cell-type epistasis with clear mechanistic model","pmids":["19289088"],"is_preprint":false},{"year":2011,"finding":"ERBIN is a new SARA-interacting protein recruited by SARA to early endosomes; SARA binds ERBIN via an ERBID domain on SARA, and ERBIN binds SARA via a SSID domain (aa 1208-1265) that also interacts with SMAD2/3; SARA competes with SMAD2/3 for binding to ERBIN and overexpression of SARA or ERBID peptide reverses ERBIN's inhibitory effect on SMAD2/3-dependent transcription.","method":"Co-IP, domain mapping, competition assays, reporter assays, confocal microscopy","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods with defined binding domains and functional competition assays","pmids":["21878490"],"is_preprint":false},{"year":2012,"finding":"Erbin is required for remyelination of regenerated axons after injury; Erbin expression increases dramatically in injured nerves; Erbin null mice show fewer myelinated axons, impaired functional recovery, and reduced ErbB2 and NRG1 levels in axons after nerve injury.","method":"Erbin null mouse with sciatic nerve crush, electron microscopy, electrophysiology, Western blot for ErbB2 and NRG1","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — clean KO with specific molecular and functional phenotype","pmids":["23100438"],"is_preprint":false},{"year":2013,"finding":"Erbin is specifically expressed in cortical inhibitory (PV-positive) interneurons, localizes at excitatory synapses, and regulates AMPA receptor (AMPAR) surface expression by interacting with and stabilizing TARP γ-2; deletion of the γ-2-interacting domain in Erbin attenuates surface AMPAR and excitatory transmission specifically in PV interneurons.","method":"Conditional mouse knockouts, electrophysiology (mEPSC recordings), Co-IP, protein stability assays, behavioral analysis","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 — genetic KO, electrophysiology, Co-IP, and domain deletion with specific cell-type phenotype","pmids":["23354328"],"is_preprint":false},{"year":2013,"finding":"Desmoglein-1 (DSG1) promotes keratinocyte differentiation by binding Erbin (identified via yeast 2-hybrid screen); DSG1 requires Erbin to suppress ERK signaling; Erbin blocks ERK by interacting with and disrupting Ras-Raf scaffolds mediated by SHOC2; DSG1 overexpression enhances Erbin-SHOC2 interactions and decreases Ras-SHOC2 interactions.","method":"Yeast two-hybrid, Co-IP, siRNA knockdown, ERK activity assays, differentiation marker induction, patient biopsy analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — Y2H + Co-IP + functional epistasis + patient tissue validation","pmids":["23524970"],"is_preprint":false},{"year":2014,"finding":"Erbin forms a complex with ErbB2 and HSP90, promoting ErbB2 stability by preventing its degradation; deletion of the Erbin PDZ domain hinders ErbB2-dependent tumor development in MMTV-neu mice; disruption of Erbin-ErbB2 interaction decreases ErbB2-dependent proliferation.","method":"Co-IP (Erbin-ErbB2-HSP90 complex), MMTV-neu mouse model with Erbin PDZ deletion (erbin ΔC/ΔC), proliferation assays","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 — Co-IP of ternary complex, in vivo mouse model, and mechanistic domain deletion","pmids":["25288731"],"is_preprint":false},{"year":2014,"finding":"Erbin is a novel substrate of the SAG-βTrCP E3 ubiquitin ligase; SAG degrades Erbin to activate the Ras-Raf pathway; Erbin accumulation upon Sag deletion blocks Ras activation of Raf, and simultaneous one-allele deletion of Erbb2ip partially rescues SAG deletion phenotypes in keratinocytes.","method":"E3 ligase substrate identification, Co-IP, ubiquitination assay, Sag knockout mouse, Erbin genetic rescue","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — biochemical E3 ligase assay, genetic epistasis in vivo","pmids":["26056141"],"is_preprint":false},{"year":2015,"finding":"Erbin inhibits EGFR ubiquitination and stabilizes EGFR by interacting with c-Cbl (an E3 ubiquitin ligase for EGFR); the PDZ domain of Erbin is critical for interaction with c-Cbl and EGFR ubiquitination; deletion of Erbin PDZ domain (ErbinΔC/ΔC mice) demonstrates this regulation is necessary for CRC tumorigenesis.","method":"Co-IP, ubiquitination assay, PDZ domain deletion mice (ErbinΔC/ΔC), AOM-induced colon carcinogenesis, xenograft model","journal":"The Journal of pathology","confidence":"High","confidence_rationale":"Tier 2 — biochemical ubiquitination assay + in vivo genetic model + mechanistic domain mapping","pmids":["25521828"],"is_preprint":false},{"year":2017,"finding":"ERBIN acts as a SMAD anchor for receptor activation (SARA) and SMAD2/3 binding protein; STAT3 negatively regulates TGF-β signaling via ERBIN by forming a STAT3-ERBIN-SMAD2/3 complex; loss-of-function ERBB2IP mutations impair STAT3-ERBIN-SMAD2/3 complex formation, fail to constrain nuclear pSMAD2/3, leading to increased IL-4Rα expression and enhanced Th2 responses.","method":"Co-IP of STAT3-ERBIN-SMAD2/3 complex, patient-derived cells with ERBB2IP loss-of-function mutation, in vitro reconstitution, nuclear fractionation","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — human genetics combined with in vitro mechanistic validation and Co-IP complex characterization","pmids":["28126831"],"is_preprint":false},{"year":2017,"finding":"Erbin inactivates ERα signaling in HCC by interacting with ERα and enhancing binding of CHIP (an E3 ligase) to ERα, thereby promoting ubiquitination and degradation of ERα; deletion of Erbin PDZ domain disrupts Erbin-CHIP-ERα interaction, stabilizes ERα protein.","method":"Co-IP, ubiquitination assay, ErbinΔC/ΔC mice, DEN-induced HCC model, cell proliferation assays","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 — biochemical Co-IP of ternary complex, ubiquitination assay, in vivo mouse model","pmids":["28192186"],"is_preprint":false},{"year":2018,"finding":"Erbin interacts with KSR1 and displaces it from the RAF/MEK/ERK complex to prevent signal propagation; genetic deletion of Erbin in Apc knockout mice promotes colorectal tumorigenesis and significantly reduces survival.","method":"Co-IP, siRNA knockdown, Erbin/Apc double knockout mice, 3D organoid cultures, gene set enrichment analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — Co-IP of Erbin-KSR1 interaction with functional displacement assay and in vivo genetic model","pmids":["29980571"],"is_preprint":false},{"year":2019,"finding":"Erbin in amygdala parvalbumin (PV)-positive neurons is critical for maintaining excitatory postsynaptic responses on PV neurons and for excitation-inhibition balance in the amygdala; Erbin knockout or PV-specific Erbin knockdown reduces excitatory postsynaptic responses on PV neurons and increases anxiety-like behaviors; chemogenetic activation of amygdala PV neurons rescues anxiety in Erbin knockdown mice.","method":"Conditional knockdown in amygdala PV neurons, electrophysiology, chemogenetics (DREADD), behavioral assays","journal":"Biological psychiatry","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific KD with electrophysiology and chemogenetic rescue","pmids":["31889536"],"is_preprint":false},{"year":2019,"finding":"Scribble, Erbin, and Lano (three LAP proteins) redundantly regulate epithelial apicobasal polarity; triple Scrib/Erbin/Lano knockout disorganizes cell junctions, cytoskeleton, and mislocalizes apical and basolateral identity proteins; the conserved LAPSDa domain of these proteins is essential for basolateral identity and Llgl binding.","method":"Triple knockout in epithelial cells, rescue with LAP protein domains, immunofluorescence, structure-function analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — clean triple KO genetic epistasis with domain-level functional rescue","pmids":["31147384"],"is_preprint":false},{"year":2010,"finding":"Erbin interacts with MuSK and forms a complex with both MuSK and ErbB2 simultaneously; knockdown of Erbin reduces the density of agrin-dependent AChR aggregates on primary skeletal myotubes, demonstrating a role for Erbin at the NMJ in linking agrin and neuregulin signaling pathways.","method":"Co-IP, domain mapping of Erbin-MuSK interaction, siRNA knockdown, AChR aggregate density assay in primary myotubes","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, domain mapping, loss-of-function with specific synaptic phenotype","pmids":["20463225"],"is_preprint":false},{"year":2023,"finding":"The C-terminal region of Erbin (aa 391-964) interacts with the N-terminal region of transcription factor EB (TFEB) (aa 1-247), affects TFEB-14-3-3 and TFEB-PPP3CB complex stability and TFEB phosphorylation status, thereby promoting nuclear translocation of TFEB and lysosome biogenesis to support autophagy.","method":"Co-IP with domain mapping, TFEB nuclear translocation assays, autophagy flux assays, sepsis mouse model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP with domain mapping and functional TFEB translocation assays from single lab","pmids":["38105228"],"is_preprint":false},{"year":2024,"finding":"Erbin-deficient platelets/megakaryocytes show increased mitochondrial oxidative phosphorylation and secrete lipid metabolites (acyl-carnitine) by abolishing interaction with the prothrombotic protein ESAM; acyl-carnitine then promotes B cell-mediated antitumor immunity.","method":"Platelet/MK-specific Erbin knockout mice, Co-IP (Erbin-ESAM interaction), metabolomics, mitochondrial function assays, in vivo metastasis models","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 — specific KO with metabolomics, Co-IP, and in vivo functional data","pmids":["38232736"],"is_preprint":false},{"year":2024,"finding":"VCPIP1 is a deubiquitinase that interacts with Erbin and stabilizes it through deubiquitination; VCPIP1 deficiency reduces Erbin expression, increases NF-κB phosphorylation, and promotes release of inflammatory cytokines in macrophages.","method":"Deubiquitinase plasmid library screen, Co-IP, ubiquitination assay, siRNA knockdown, inflammatory cytokine measurement","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP and ubiquitination assay from single lab","pmids":["39550842"],"is_preprint":false},{"year":2024,"finding":"NoxO1 interacts with Erbin (identified by BioID proximity labeling) and co-localizes with EGFR; NoxO1 overexpression delays EGF-mediated kinase activation while NoxO1 KO has the opposite effect, suggesting NoxO1 modulates EGFR signaling through interaction with Erbin.","method":"BioID proximity labeling, co-localization microscopy, EGFR signaling assays in NoxO1 KO and OE cells","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — BioID identification with functional validation in KO/OE cells, single lab","pmids":["39426288"],"is_preprint":false},{"year":2012,"finding":"Erbin mediates catecholamine-induced β2-adrenergic receptor/Her2 complex formation via its PDZ domain (but not LRR domain); silencing of Erbin abrogates isoproterenol-induced ERK activation and causes severe cardiomyocyte apoptosis upon ISO treatment.","method":"Co-IP (β2-AR, Her2, Erbin complex), Erbin deletion mutants, siRNA knockdown, ERK activation assays, apoptosis assay in cardiomyocytes","journal":"International journal of cardiology","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP of ternary complex with domain deletion, functional knockdown from single lab","pmids":["22564389"],"is_preprint":false},{"year":2014,"finding":"Erbin expression is regulated by the transcription factor MITF; under basal conditions MITF activates Erbin expression via direct promoter binding; under β-adrenergic stimulation, FHL2 forms a complex with MITF (confirmed by Co-IP) and switches MITF from an activator to a repressor of Erbin promoter activity, contributing to cardiac hypertrophy.","method":"Yeast two-hybrid, Co-IP, chromatin immunoprecipitation (ChIP), promoter reporter assay, MITF mutant mice","journal":"International journal of cardiology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP + Co-IP + reporter assay + genetic mouse model from single lab","pmids":["26025865"],"is_preprint":false},{"year":2013,"finding":"Erbin interacts with Sema4C via Co-IP in HK2 renal tubular epithelial cells; overexpression of Erbin blocks Sema4C-induced epithelial-mesenchymal transition, and Erbin siRNA promotes EMT induced by Sema4C.","method":"Co-IP, Western blot for EMT markers, siRNA knockdown, overexpression","journal":"Journal of Huazhong University","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP with functional OE/KD, single lab, limited mechanistic depth","pmids":["24142719"],"is_preprint":false}],"current_model":"ERBIN (ERBB2IP) is a scaffolding protein containing N-terminal leucine-rich repeats (LRRs) and a C-terminal PDZ domain that localizes to basolateral membranes via palmitoylation at Cys14/16 and LRR-mediated targeting; it stabilizes ErbB2/HER2 (via PDZ-mediated interaction and HSP90 recruitment), suppresses the RAS-RAF-ERK pathway by disrupting the Ras-Raf-Shoc2 scaffold complex (through its LRR domain), inhibits TGF-β/Smad2/3 signaling by sequestering phospho-Smad2/3 away from Smad4 (via a Smad-interacting domain adjacent to the PDZ domain), negatively regulates Nod2-dependent NF-κB signaling (by direct LRR-CARD interaction), and acts as a node linking desmosomal cadherins (DSG1), cadherin-catenin complexes (via delta-catenin/ARVCF), and at synapses (stabilizing TARP γ-2 for AMPAR surface expression in PV interneurons and linking MuSK-ErbB2 signaling at the neuromuscular junction)."},"narrative":{"teleology":[{"year":2000,"claim":"The identification of ERBIN as a specific PDZ-domain partner of ErbB2 that directs its basolateral localization established ERBIN as a receptor-targeting scaffold rather than a generic adaptor.","evidence":"Co-IP, in vitro binding, mutagenesis of ErbB2 C-terminal PDZ-binding motif, immunofluorescence in epithelial cells","pmids":["10878805"],"confidence":"High","gaps":["Whether ERBIN interacts with other ErbB family members was unresolved","Mechanism by which ERBIN itself reaches the basolateral membrane was unknown"]},{"year":2001,"claim":"Discovery that ERBIN's PDZ domain engages p120-catenin relatives (delta-catenin, ARVCF, p0071) and hemidesmosomal components revealed it as a broad junction-associated scaffold linking receptor and adhesion complexes.","evidence":"Phage display, Co-IP from neurons, yeast two-hybrid, dominant-negative disruption of monolayer integrity","pmids":["11821434","11711544","11375975"],"confidence":"High","gaps":["Functional hierarchy between ERBIN's receptor-binding and adhesion-binding roles was unresolved","Whether ERBIN loss disrupts junctions in vivo was untested"]},{"year":2002,"claim":"Structural determination of the ERBIN PDZ domain at atomic resolution revealed an unusual β2-β3 loop that confers dual class I/II ligand recognition, explaining its broad but selective binding repertoire.","evidence":"X-ray crystallography at 1.25 Å (ErbB2 peptide complex) and NMR with alanine scanning mutagenesis","pmids":["12444095","12446668"],"confidence":"High","gaps":["Structure of the full-length protein or the LRR domain was not determined","How phosphorylation dynamically regulates ligand switching in vivo was untested"]},{"year":2002,"claim":"The discovery that ERBIN binds activated Ras and disrupts the Ras–Raf interaction established a signaling-suppressive function independent of its receptor-scaffolding role.","evidence":"Co-IP with active Ras, reporter assays, siRNA knockdown enhancing ERK activation in PC12 cells","pmids":["12379659"],"confidence":"High","gaps":["Which domain mediates Ras binding was unresolved","Physiological context for this ERK-suppressive role was unclear"]},{"year":2005,"claim":"Mapping the ERK-suppressive mechanism to the LRR domain's disruption of the Shoc2–Ras–Raf scaffold, and simultaneously discovering LRR-mediated inhibition of Nod2/NF-κB signaling, revealed the LRR as a multi-pathway signaling suppressor.","evidence":"LRR domain mapping, shRNA, Erbin-null MEFs with MDP stimulation, NF-κB reporters","pmids":["16301319","16203728"],"confidence":"High","gaps":["Whether LRR simultaneously engages Ras and Nod2 or uses distinct surfaces was unknown","In vivo inflammatory phenotypes of Erbin-null animals were incompletely characterized"]},{"year":2007,"claim":"Identification of a Smad-interacting domain (SID) adjacent to the PDZ domain that sequesters phospho-Smad2/3 from Smad4 established ERBIN as a negative regulator of TGF-β signaling through a third, mechanistically distinct domain.","evidence":"Co-IP, shRNA, Xenopus gain/loss-of-function, splice isoform lacking SID fails to inhibit TGF-β","pmids":["17591701"],"confidence":"High","gaps":["How ERBIN is recruited to the TGF-β receptor complex was unknown","Whether SID and PDZ domain functions are coordinated was unresolved"]},{"year":2008,"claim":"Demonstration that palmitoylation at Cys14/16 is required for plasma membrane targeting resolved how ERBIN itself reaches the membrane, complementing its LRR-dependent basolateral sorting.","evidence":"C14S/C16S mutagenesis with localization readout in transfected cells","pmids":["18498353"],"confidence":"High","gaps":["Identity of the palmitoyltransferase(s) responsible was unknown","Whether palmitoylation is dynamically regulated was untested"]},{"year":2008,"claim":"Erbin was placed upstream of delta-catenin in dendritic morphogenesis through genetic epistasis, demonstrating a neuronal developmental function beyond synapse-specific roles.","evidence":"shRNA/KO in hippocampal neurons, rescue experiments showing delta-catenin OE rescues Erbin loss but not vice versa","pmids":["18614673"],"confidence":"High","gaps":["Molecular mechanism by which ERBIN controls delta-catenin localization was unresolved","Whether this extends to in vivo dendritic architecture was unknown"]},{"year":2009,"claim":"Erbin-null and PDZ-deletion mice established that ERBIN stabilizes ErbB2 protein in Schwann cells and is required for NRG1-dependent peripheral myelination, providing the first in vivo physiological requirement.","evidence":"Erbin-null and erbin-ΔC/ΔC knock-in mice, electron microscopy, electrophysiology of sciatic nerves","pmids":["19458253"],"confidence":"High","gaps":["Whether ERBIN stabilizes ErbB2 through direct chaperone recruitment or prevention of degradation was unresolved"]},{"year":2010,"claim":"Discovery that ERBIN simultaneously complexes with MuSK and ErbB2 at the neuromuscular junction linked agrin and neuregulin signaling through a single scaffold.","evidence":"Co-IP of MuSK-ERBIN-ErbB2 ternary complex, siRNA reducing AChR aggregate density in primary myotubes","pmids":["20463225"],"confidence":"High","gaps":["Whether ERBIN is required for NMJ formation in vivo was untested","Stoichiometry of the MuSK-ERBIN-ErbB2 complex was unknown"]},{"year":2011,"claim":"Identification of SARA as a competitor for ERBIN's Smad-binding surface provided a mechanism for dynamic regulation of TGF-β signal attenuation at endosomes.","evidence":"Co-IP, domain mapping of SARA-ERBID and ERBIN-SSID, competition assays reversing ERBIN's inhibition of Smad-dependent transcription","pmids":["21878490"],"confidence":"High","gaps":["Whether SARA-ERBIN competition operates in specific tissue contexts was unresolved","Kinetic parameters of competitive binding were not determined"]},{"year":2013,"claim":"Cell-type-specific studies in PV interneurons revealed that ERBIN stabilizes TARP γ-2 to maintain surface AMPAR expression, establishing a distinct synaptic mechanism in inhibitory circuits.","evidence":"PV-specific conditional KO, mEPSC recordings, Co-IP, domain deletion attenuating surface AMPAR","pmids":["23354328"],"confidence":"High","gaps":["Whether ERBIN stabilizes TARP γ-2 through preventing ubiquitination or other degradation pathways was unknown","Role in other interneuron subtypes was untested"]},{"year":2013,"claim":"Linking desmoglein-1 to ERBIN-mediated suppression of Ras-Shoc2-Raf signaling in keratinocyte differentiation unified adhesion and ERK-suppressive functions in a single physiological axis.","evidence":"Y2H, Co-IP showing DSG1 enhances ERBIN-SHOC2 interaction, siRNA epistasis, patient biopsy analysis","pmids":["23524970"],"confidence":"High","gaps":["Whether other desmosomal cadherins similarly engage ERBIN was unknown","Structural basis for DSG1-dependent modulation of ERBIN-SHOC2 was unresolved"]},{"year":2014,"claim":"Co-immunoprecipitation of an ERBIN-ErbB2-HSP90 ternary complex and impaired ErbB2-driven tumorigenesis in erbin-ΔC/ΔC MMTV-neu mice resolved that ERBIN stabilizes ErbB2 by recruiting HSP90, with direct oncogenic consequences.","evidence":"Co-IP of ternary complex, MMTV-neu × erbin-ΔC/ΔC genetic cross, proliferation assays","pmids":["25288731"],"confidence":"High","gaps":["Whether ERBIN-HSP90 interaction is direct or bridged by ErbB2 was unclear","How ubiquitin-dependent turnover of ERBIN itself (by SAG-βTrCP) feeds back on ErbB2 stability in vivo was incompletely explored"]},{"year":2017,"claim":"Human loss-of-function ERBB2IP mutations causing impaired STAT3-ERBIN-Smad2/3 complex formation and dysregulated Th2 responses linked ERBIN's TGF-β-suppressive mechanism to human immune disease.","evidence":"Patient-derived cells with ERBB2IP mutations, Co-IP of STAT3-ERBIN-SMAD2/3, nuclear fractionation showing unconstrained pSmad2/3","pmids":["28126831"],"confidence":"High","gaps":["Full clinical spectrum of ERBB2IP deficiency was not delineated","Whether other LAP family members compensate in immune cells was unknown"]},{"year":2018,"claim":"Discovery that ERBIN displaces KSR1 from the RAF-MEK-ERK complex added a second, mechanistically distinct node of ERK pathway suppression beyond Shoc2 disruption.","evidence":"Co-IP of ERBIN-KSR1, Erbin/Apc double-KO mice with accelerated colorectal tumorigenesis and reduced survival","pmids":["29980571"],"confidence":"High","gaps":["Whether ERBIN engages KSR1 and Shoc2 simultaneously or competitively was unresolved","Domain on ERBIN mediating KSR1 interaction was not mapped"]},{"year":2019,"claim":"Triple knockout of Scribble, Erbin, and Lano demonstrated that LAP proteins redundantly maintain epithelial polarity through a conserved LAPSDa domain that binds Llgl, contextualizing ERBIN within a polarity module.","evidence":"Triple KO in epithelial cells, domain rescue, junction disorganization and polarity marker mislocalization","pmids":["31147384"],"confidence":"High","gaps":["Relative individual contributions of each LAP protein in different tissues were incompletely defined","Structural basis of LAPSDa-Llgl interaction was lacking"]},{"year":2024,"claim":"Platelet/megakaryocyte-specific ERBIN deletion revealed a metabolic role: loss of ERBIN-ESAM interaction increases mitochondrial oxidative phosphorylation and acyl-carnitine secretion, promoting B cell antitumor immunity.","evidence":"MK-specific Erbin KO mice, Co-IP of ERBIN-ESAM, metabolomics, mitochondrial assays, in vivo metastasis models","pmids":["38232736"],"confidence":"High","gaps":["Mechanism linking ERBIN-ESAM to mitochondrial activity was not molecularly defined","Whether this metabolic function operates in non-hematopoietic cells was unknown"]},{"year":null,"claim":"A full-length structural model of ERBIN and the basis for simultaneous engagement of its LRR, SID, and PDZ domains with distinct partners remain unresolved; how tissue-specific isoforms and post-translational turnover (palmitoylation, SAG/βTrCP-mediated ubiquitination, VCPIP1-mediated deubiquitination) are dynamically coordinated in vivo is unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length structure or cryo-EM model exists","Dynamic regulation of multi-domain engagement is unexplored","In vivo consequences of ERBIN post-translational modifications beyond palmitoylation are poorly characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,7,8,11,16,20,26,29]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,8,9,11,20,22,26]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,13,28]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[13]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,7,8,11,15,20,21,23,24,26]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,10,24,32]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[1,3,28]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2,12,14,19,27,29]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[15,18,20]}],"complexes":["ErbB2-ERBIN-HSP90 complex","LAP polarity module (Scribble/Erbin/Lano)","MuSK-ERBIN-ErbB2 complex","STAT3-ERBIN-SMAD2/3 complex"],"partners":["ERBB2","SHOC2","NOD2","SMAD3","CTNND2","KSR1","CACNA1D","ESAM"],"other_free_text":[]},"mechanistic_narrative":"ERBIN is a multidomain scaffolding protein of the LAP (LRR and PDZ) family that orchestrates epithelial polarity, receptor tyrosine kinase stability, and suppression of multiple mitogenic and inflammatory signaling cascades. Its PDZ domain directly binds the C-terminus of ErbB2/HER2, recruiting HSP90 to stabilize ErbB2 and directing the receptor to basolateral membranes—functions essential for peripheral nerve myelination and ErbB2-dependent tumorigenesis [PMID:10878805, PMID:19458253, PMID:25288731]. The N-terminal leucine-rich repeat (LRR) domain binds activated Ras and displaces Raf from the Ras–Shoc2–Raf and KSR1 scaffold complexes, thereby suppressing ERK signaling downstream of desmoglein-1 and in colorectal epithelium, while the same domain interacts with Nod2 CARD domains to inhibit NF-κB activation [PMID:12379659, PMID:16301319, PMID:29980571, PMID:16203728]. A Smad-interacting domain adjacent to the PDZ domain sequesters phospho-Smad2/3 from Smad4 to attenuate TGF-β transcriptional responses—a mechanism further modulated by SARA competition and STAT3 complex formation, whose disruption by loss-of-function ERBB2IP mutations causes dysregulated Th2 immune responses [PMID:17591701, PMID:21878490, PMID:28126831]."},"prefetch_data":{"uniprot":{"accession":"Q96RT1","full_name":"Erbin","aliases":["Densin-180-like protein","Erbb2-interacting protein","Protein LAP2"],"length_aa":1412,"mass_kda":158.3,"function":"Acts as an adapter for the receptor ERBB2, in epithelia. By binding the unphosphorylated 'Tyr-1248' of receptor ERBB2, it may contribute to stabilize this unphosphorylated state (PubMed:16203728). Inhibits NOD2-dependent NF-kappa-B signaling and pro-inflammatory cytokine secretion (PubMed:16203728)","subcellular_location":"Cell junction, hemidesmosome; Nucleus membrane; Basolateral cell membrane","url":"https://www.uniprot.org/uniprotkb/Q96RT1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ERBIN","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ERBIN","total_profiled":1310},"omim":[{"mim_id":"614453","title":"LEUCINE-RICH REPEAT-CONTAINING PROTEIN 7; LRRC7","url":"https://www.omim.org/entry/614453"},{"mim_id":"608195","title":"LEUCINE-RICH REPEAT-CONTAINING PROTEIN 1; LRRC1","url":"https://www.omim.org/entry/608195"},{"mim_id":"606944","title":"ERBB2 INTERACTING PROTEIN; ERBIN","url":"https://www.omim.org/entry/606944"},{"mim_id":"147060","title":"HYPER-IgE SYNDROME 1, AUTOSOMAL DOMINANT, WITH RECURRENT INFECTIONS; HIES1","url":"https://www.omim.org/entry/147060"},{"mim_id":"102582","title":"SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3; STAT3","url":"https://www.omim.org/entry/102582"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cell Junctions","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ERBIN"},"hgnc":{"alias_symbol":["LAP2"],"prev_symbol":["ERBB2IP"]},"alphafold":{"accession":"Q96RT1","domains":[{"cath_id":"3.80.10.10","chopping":"21-181","consensus_level":"medium","plddt":95.4175,"start":21,"end":181},{"cath_id":"2.30.42.10","chopping":"1319-1411","consensus_level":"high","plddt":86.8357,"start":1319,"end":1411}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96RT1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96RT1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96RT1-F1-predicted_aligned_error_v6.png","plddt_mean":55.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ERBIN","jax_strain_url":"https://www.jax.org/strain/search?query=ERBIN"},"sequence":{"accession":"Q96RT1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96RT1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96RT1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96RT1"}},"corpus_meta":[{"pmid":"10878805","id":"PMC_10878805","title":"ERBIN: a basolateral PDZ protein that interacts with the mammalian ERBB2/HER2 receptor.","date":"2000","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10878805","citation_count":264,"is_preprint":false},{"pmid":"10393804","id":"PMC_10393804","title":"LAP2 binding protein 1 (L2BP1/BAF) is a candidate mediator of LAP2-chromatin interaction.","date":"1999","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/10393804","citation_count":195,"is_preprint":false},{"pmid":"11500367","id":"PMC_11500367","title":"Solution structure of the constant region of nuclear envelope protein LAP2 reveals two LEM-domain structures: one binds BAF and the other binds DNA.","date":"2001","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11500367","citation_count":187,"is_preprint":false},{"pmid":"11285238","id":"PMC_11285238","title":"LAP2 binds to BAF.DNA complexes: requirement for the LEM domain and modulation by variable regions.","date":"2001","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11285238","citation_count":179,"is_preprint":false},{"pmid":"7737115","id":"PMC_7737115","title":"Cloning of a cDNA for lamina-associated polypeptide 2 (LAP2) and identification of regions that specify targeting to the nuclear envelope.","date":"1995","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/7737115","citation_count":167,"is_preprint":false},{"pmid":"33225938","id":"PMC_33225938","title":"The circular RNA circ-ERBIN promotes growth and metastasis of colorectal cancer by miR-125a-5p and miR-138-5p/4EBP-1 mediated cap-independent HIF-1α translation.","date":"2020","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33225938","citation_count":158,"is_preprint":false},{"pmid":"16203728","id":"PMC_16203728","title":"A role for Erbin in the regulation of Nod2-dependent NF-kappaB signaling.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16203728","citation_count":156,"is_preprint":false},{"pmid":"16714539","id":"PMC_16714539","title":"Role for erbin in bacterial activation of Nod2.","date":"2006","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/16714539","citation_count":133,"is_preprint":false},{"pmid":"10087255","id":"PMC_10087255","title":"Roles of LAP2 proteins in nuclear assembly and DNA replication: truncated LAP2beta proteins alter lamina assembly, envelope formation, nuclear size, and DNA replication efficiency in Xenopus laevis extracts.","date":"1999","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10087255","citation_count":133,"is_preprint":false},{"pmid":"11821434","id":"PMC_11821434","title":"The Erbin PDZ domain binds with high affinity and specificity to the carboxyl termini of delta-catenin and ARVCF.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11821434","citation_count":130,"is_preprint":false},{"pmid":"12446668","id":"PMC_12446668","title":"Origins of PDZ domain ligand specificity. Structure determination and mutagenesis of the Erbin PDZ domain.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12446668","citation_count":127,"is_preprint":false},{"pmid":"23524970","id":"PMC_23524970","title":"Desmoglein-1/Erbin interaction suppresses ERK activation to support epidermal differentiation.","date":"2013","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/23524970","citation_count":115,"is_preprint":false},{"pmid":"12379659","id":"PMC_12379659","title":"Erbin suppresses the MAP kinase pathway.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12379659","citation_count":103,"is_preprint":false},{"pmid":"9461618","id":"PMC_9461618","title":"The major nuclear envelope targeting domain of LAP2 coincides with its lamin binding region but is distinct from its chromatin interaction domain.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9461618","citation_count":100,"is_preprint":false},{"pmid":"9382857","id":"PMC_9382857","title":"Lamin-binding fragment of LAP2 inhibits increase in nuclear volume during the cell cycle and progression into S phase.","date":"1997","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9382857","citation_count":98,"is_preprint":false},{"pmid":"12444095","id":"PMC_12444095","title":"Novel mode of ligand recognition by the Erbin PDZ domain.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12444095","citation_count":91,"is_preprint":false},{"pmid":"16301319","id":"PMC_16301319","title":"Erbin inhibits RAF activation by disrupting the sur-8-Ras-Raf complex.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16301319","citation_count":88,"is_preprint":false},{"pmid":"11711544","id":"PMC_11711544","title":"Interaction between Erbin and a Catenin-related protein in epithelial cells.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11711544","citation_count":84,"is_preprint":false},{"pmid":"11279080","id":"PMC_11279080","title":"Erbin is a protein concentrated at postsynaptic membranes that interacts with PSD-95.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11279080","citation_count":84,"is_preprint":false},{"pmid":"11278603","id":"PMC_11278603","title":"The ERBB2/HER2 receptor differentially interacts with ERBIN and PICK1 PSD-95/DLG/ZO-1 domain proteins.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11278603","citation_count":82,"is_preprint":false},{"pmid":"28126831","id":"PMC_28126831","title":"ERBIN deficiency links STAT3 and TGF-β pathway defects with atopy in humans.","date":"2017","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28126831","citation_count":80,"is_preprint":false},{"pmid":"11375975","id":"PMC_11375975","title":"The hemidesmosomal protein bullous pemphigoid antigen 1 and the integrin beta 4 subunit bind to ERBIN. Molecular cloning of multiple alternative splice variants of ERBIN and analysis of their tissue expression.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11375975","citation_count":69,"is_preprint":false},{"pmid":"12047349","id":"PMC_12047349","title":"ERBIN associates with p0071, an armadillo protein, at cell-cell junctions of epithelial cells.","date":"2002","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/12047349","citation_count":67,"is_preprint":false},{"pmid":"30551364","id":"PMC_30551364","title":"LncRNA KTN1-AS1 promotes tumor growth of hepatocellular carcinoma by targeting miR-23c/ERBB2IP axis.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/30551364","citation_count":64,"is_preprint":false},{"pmid":"19458253","id":"PMC_19458253","title":"Erbin regulates NRG1 signaling and myelination.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19458253","citation_count":63,"is_preprint":false},{"pmid":"9664044","id":"PMC_9664044","title":"Nuclear envelope remodelling during rat spermiogenesis: distribution and expression pattern of LAP2/thymopoietins.","date":"1998","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/9664044","citation_count":61,"is_preprint":false},{"pmid":"12538639","id":"PMC_12538639","title":"HA95 and LAP2 beta mediate a novel chromatin-nuclear envelope interaction implicated in initiation of DNA replication.","date":"2003","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12538639","citation_count":60,"is_preprint":false},{"pmid":"15659388","id":"PMC_15659388","title":"Erbin regulates mitogen-activated protein (MAP) kinase activation and MAP kinase-dependent interactions between Merlin and adherens junction protein complexes in Schwann cells.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15659388","citation_count":59,"is_preprint":false},{"pmid":"36171629","id":"PMC_36171629","title":"Erbin protects against sepsis-associated encephalopathy by attenuating microglia pyroptosis via IRE1α/Xbp1s-Ca2+ axis.","date":"2022","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/36171629","citation_count":58,"is_preprint":false},{"pmid":"17591701","id":"PMC_17591701","title":"Erbin inhibits transforming growth factor beta signaling through a novel Smad-interacting domain.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17591701","citation_count":56,"is_preprint":false},{"pmid":"30503211","id":"PMC_30503211","title":"LAP2 Proteins Chaperone GLI1 Movement between the Lamina and Chromatin to Regulate Transcription.","date":"2018","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/30503211","citation_count":53,"is_preprint":false},{"pmid":"31889536","id":"PMC_31889536","title":"Erbin in Amygdala Parvalbumin-Positive Neurons Modulates Anxiety-like Behaviors.","date":"2019","source":"Biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/31889536","citation_count":53,"is_preprint":false},{"pmid":"23354328","id":"PMC_23354328","title":"Erbin interacts with TARP γ-2 for surface expression of AMPA receptors in cortical interneurons.","date":"2013","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23354328","citation_count":46,"is_preprint":false},{"pmid":"31147384","id":"PMC_31147384","title":"Scribble, Erbin, and Lano redundantly regulate epithelial polarity and apical adhesion complex.","date":"2019","source":"The Journal of cell 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Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/17287512","citation_count":42,"is_preprint":false},{"pmid":"19289088","id":"PMC_19289088","title":"Erbin and the NF2 tumor suppressor Merlin cooperatively regulate cell-type-specific activation of PAK2 by TGF-beta.","date":"2009","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/19289088","citation_count":41,"is_preprint":false},{"pmid":"18614673","id":"PMC_18614673","title":"Erbin controls dendritic morphogenesis by regulating localization of delta-catenin.","date":"2008","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/18614673","citation_count":40,"is_preprint":false},{"pmid":"23100438","id":"PMC_23100438","title":"Erbin is required for myelination in regenerated axons after injury.","date":"2012","source":"The Journal of neuroscience : the official journal of the Society for 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Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban","url":"https://pubmed.ncbi.nlm.nih.gov/24142719","citation_count":9,"is_preprint":false},{"pmid":"11934151","id":"PMC_11934151","title":"Lamina-associated polypeptide 2 (LAP2) expression in fish and amphibians.","date":"2002","source":"The International journal of developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/11934151","citation_count":9,"is_preprint":false},{"pmid":"39216682","id":"PMC_39216682","title":"Erbin alleviates sepsis-induced cardiomyopathy by inhibiting RIPK1-dependent necroptosis through activating PKA/CREB pathway.","date":"2024","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/39216682","citation_count":8,"is_preprint":false},{"pmid":"19013433","id":"PMC_19013433","title":"Biochemical studies and molecular dynamics simulations of Smad3-Erbin interaction identify a non-classical Erbin PDZ binding.","date":"2008","source":"Biochemical and biophysical research 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preparation of its polyclonal antibody.","date":"2008","source":"Preparative biochemistry & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/18569875","citation_count":4,"is_preprint":false},{"pmid":"39550842","id":"PMC_39550842","title":"VCPIP1 negatively regulates NF-κB signaling pathways by deubiquitinating and stabilizing Erbin in MDP-stimulated macrophages.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39550842","citation_count":3,"is_preprint":false},{"pmid":"39426288","id":"PMC_39426288","title":"NoxO1 regulates EGFR signaling by its interaction with Erbin.","date":"2024","source":"Redox 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vitro binding, immunofluorescence co-localization, mutagenesis of binding site\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (pulldown, Co-IP, localization, mutagenesis) in original discovery paper\",\n      \"pmids\": [\"10878805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The Erbin PDZ domain interacts with ARVCF and delta-catenin at their C-terminal PDZ-binding motifs (DSWV-COOH), and Erbin associates with the cadherin-catenin complex through these interactions in vivo; endogenous delta-catenin and Erbin co-immunoprecipitate from neurons.\",\n      \"method\": \"C-terminal phage peptide library display, in vitro peptide binding assays, Co-IP, co-localization, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — phage display, in vitro binding, Co-IP and mutagenesis; multiple orthogonal methods\",\n      \"pmids\": [\"11821434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Erbin is concentrated at postsynaptic membranes at the neuromuscular junction and in the CNS, interacts specifically with ErbB2 (not ErbB3 or ErbB4), increases ErbB2 surface expression, and interacts with PSD-95 in transfected cells and synaptosomes.\",\n      \"method\": \"Co-immunoprecipitation, biotin labeling of surface proteins, immunostaining of postsynaptic membranes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP and surface labeling from a single lab\",\n      \"pmids\": [\"11279080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Erbin interacts with p0071 (plakophilin-4) in a PDZ domain-dependent manner, and both proteins colocalize in desmosomes of epithelial cells; disruption of this interaction by a dominant-negative approach impairs epithelial cell monolayer integrity.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding, Co-IP, immunofluorescence co-localization, dominant-negative disruption\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Y2H, in vitro binding, Co-IP, functional disruption), replicated in two independent papers\",\n      \"pmids\": [\"11711544\", \"12047349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"ERBIN interacts with eBPAG1 (bullous pemphigoid antigen 1) via its N-terminus and with the cytoplasmic domain of integrin β4 subunit, linking it to hemidesmosome components.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid and in vitro binding, single lab\",\n      \"pmids\": [\"11375975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Crystal structure of the human Erbin PDZ domain bound to the ErbB2 C-terminal peptide (EYLGLDVPV) at 1.25 Å resolution revealed a novel mode of class II ligand recognition by a class I PDZ domain; phosphorylation of tyrosine at position -7 of ErbB2 abolishes its interaction with the Erbin PDZ domain.\",\n      \"method\": \"X-ray crystallography at 1.25 Å resolution, binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure with mutagenesis/phosphorylation functional validation\",\n      \"pmids\": [\"12444095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"NMR structure of the Erbin PDZ domain in complex with a high-affinity peptide ligand; alanine and homolog scanning mutagenesis identified that the β2-β3 loop provides a binding pocket for residue at position -4 that is specific to Erbin's unusually long loop, determining ligand specificity.\",\n      \"method\": \"NMR structure determination, phage display, binding affinity measurements, alanine scanning mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure + comprehensive mutagenesis + phage display energetic analysis\",\n      \"pmids\": [\"12446668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Erbin is a negative regulator of the Ras-Raf-ERK signaling pathway: it associates with active (but not inactive) Ras and disrupts the Ras-Raf interaction in vitro and in vivo, thereby inhibiting ERK (but not Akt) activation; siRNA knockdown of Erbin enhances ERK activation and NGF-induced neuronal differentiation.\",\n      \"method\": \"Reporter assays, co-immunoprecipitation, in vitro interaction assay, siRNA knockdown, PC12 differentiation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, in vitro binding, gain/loss of function), replicated across multiple subsequent papers\",\n      \"pmids\": [\"12379659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Erbin inhibits Raf activation by disrupting the Sur-8 (Shoc2)-Ras-Raf scaffold complex via its N-terminal LRR domain; expression of Erbin attenuated Sur-8 interactions with active Ras and Raf, while Erbin-shRNA increased these interactions and ERK activation.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, reporter assays, LRR domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, domain mapping, shRNA/OE with functional readout, replicated in cardiac hypertrophy paper\",\n      \"pmids\": [\"16301319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Erbin interacts directly with Nod2 (specifically requiring the LRR domain of Erbin and the CARD domains of Nod2), inhibits Nod2-dependent NF-κB activation and cytokine secretion; Erbin-/- mouse embryo fibroblasts show increased sensitivity to muramyl dipeptide.\",\n      \"method\": \"Biochemical screen, in vitro binding, Co-IP, overexpression and Erbin-/- MEF knockout studies, NF-κB reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo interaction, knockout MEF functional data, replicated by independent lab\",\n      \"pmids\": [\"16203728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Erbin interacts with Nod2 via yeast two-hybrid and Co-IP; Erbin's LRR domain and Nod2's CARD domains are necessary; no significant interaction with inactive or Crohn's disease-associated frameshift mutants of Nod2; bacterial (Shigella) infection alters Erbin/Nod2 complex dynamics; shRNA knockdown of Erbin negatively influences Nod2/MDP-mediated NF-κB activation.\",\n      \"method\": \"Yeast two-hybrid, Co-IP, immunofluorescence, shRNA knockdown, NF-κB reporter\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — independent lab replication of Erbin-Nod2 interaction with domain mapping and functional validation\",\n      \"pmids\": [\"16714539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Erbin interacts specifically with Smad3 (and to lesser extent Smad2) through a novel Smad-interacting domain (SID) adjacent to its PDZ domain; Erbin sequesters phospho-Smad2/3 away from Smad4 to negatively modulate TGF-β transcriptional responses; an alternatively spliced isoform lacking the SID fails to inhibit TGF-β responses.\",\n      \"method\": \"Co-IP, shRNA knockdown, reporter assays, Xenopus embryo gain/loss-of-function, splice isoform analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including Co-IP, knockdown, OE, splice variant analysis, and Xenopus epistasis\",\n      \"pmids\": [\"17591701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Erbin forms a specific complex with Cav1.3 (L-type) but not Cav1.2 Ca2+ channels via PDZ domain interaction with the C-terminus of the long variant of Cav1.3 α1 subunit; Erbin enhances voltage-dependent facilitation (VDF) of Cav1.3 currents by relieving autoinhibition imposed by the α1.3 C-terminal domain.\",\n      \"method\": \"Co-IP from brain lysates, co-localization in cortical neurons, electrophysiology (whole-cell patch clamp), domain deletion mutagenesis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — electrophysiology + Co-IP + mutagenesis with mechanistic explanation\",\n      \"pmids\": [\"17287512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Palmitoylation of ERBIN at cysteines 14 and 16 in its N-terminal region is required for its plasma membrane localization; mutants with C14S and/or C16S substitutions localize to the cytoplasm rather than the plasma membrane, and both palmitoylation and LRR domain are required for membrane targeting.\",\n      \"method\": \"Mutagenesis of palmitoylation sites, in vivo palmitoylation detection, localization studies in transfected cells\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct mutagenesis of palmitoylation sites with clear localization readout\",\n      \"pmids\": [\"18498353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Erbin controls dendritic morphogenesis in hippocampal neurons by maintaining appropriate localization of delta-catenin; Erbin knockdown causes severe dendritic morphogenesis defects that are rescued by delta-catenin overexpression (but not vice versa), placing Erbin upstream of delta-catenin.\",\n      \"method\": \"shRNA knockdown, genetic knockout, rescue experiments, epistasis (Erbin upstream of delta-catenin), live imaging\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis established, clean KO with specific morphological phenotype, multiple rescue experiments\",\n      \"pmids\": [\"18614673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Erbin is necessary for NRG1 signaling and PNS myelination; Erbin null mice display hypomyelination and reduced ErbB2 protein levels in sciatic nerves; Erbin with PDZ domain deletion (erbin ΔC/ΔC mice) phenocopies this, indicating that Erbin stabilizes ErbB2 protein via PDZ domain interaction.\",\n      \"method\": \"Erbin null mouse, erbin ΔC/ΔC knock-in mouse, electrophysiology, electron microscopy, protein level analysis, siRNA knockdown in cultured cells\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple mouse models, in vivo and in vitro mechanistic validation\",\n      \"pmids\": [\"19458253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Erbin controls the functional output of Merlin (NF2 tumor suppressor) by determining whether Merlin inhibits or is inhibited by active PAK2; in epithelial cells, Erbin/Merlin complexes bind and inactivate GTPase-bound PAK2, preventing TGF-β-induced PAK2 activation.\",\n      \"method\": \"Co-IP, siRNA knockdown, kinase activity assays, epistasis in epithelial vs. mesenchymal cells\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, kinase assays, and cell-type epistasis with clear mechanistic model\",\n      \"pmids\": [\"19289088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ERBIN is a new SARA-interacting protein recruited by SARA to early endosomes; SARA binds ERBIN via an ERBID domain on SARA, and ERBIN binds SARA via a SSID domain (aa 1208-1265) that also interacts with SMAD2/3; SARA competes with SMAD2/3 for binding to ERBIN and overexpression of SARA or ERBID peptide reverses ERBIN's inhibitory effect on SMAD2/3-dependent transcription.\",\n      \"method\": \"Co-IP, domain mapping, competition assays, reporter assays, confocal microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods with defined binding domains and functional competition assays\",\n      \"pmids\": [\"21878490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Erbin is required for remyelination of regenerated axons after injury; Erbin expression increases dramatically in injured nerves; Erbin null mice show fewer myelinated axons, impaired functional recovery, and reduced ErbB2 and NRG1 levels in axons after nerve injury.\",\n      \"method\": \"Erbin null mouse with sciatic nerve crush, electron microscopy, electrophysiology, Western blot for ErbB2 and NRG1\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific molecular and functional phenotype\",\n      \"pmids\": [\"23100438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Erbin is specifically expressed in cortical inhibitory (PV-positive) interneurons, localizes at excitatory synapses, and regulates AMPA receptor (AMPAR) surface expression by interacting with and stabilizing TARP γ-2; deletion of the γ-2-interacting domain in Erbin attenuates surface AMPAR and excitatory transmission specifically in PV interneurons.\",\n      \"method\": \"Conditional mouse knockouts, electrophysiology (mEPSC recordings), Co-IP, protein stability assays, behavioral analysis\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO, electrophysiology, Co-IP, and domain deletion with specific cell-type phenotype\",\n      \"pmids\": [\"23354328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Desmoglein-1 (DSG1) promotes keratinocyte differentiation by binding Erbin (identified via yeast 2-hybrid screen); DSG1 requires Erbin to suppress ERK signaling; Erbin blocks ERK by interacting with and disrupting Ras-Raf scaffolds mediated by SHOC2; DSG1 overexpression enhances Erbin-SHOC2 interactions and decreases Ras-SHOC2 interactions.\",\n      \"method\": \"Yeast two-hybrid, Co-IP, siRNA knockdown, ERK activity assays, differentiation marker induction, patient biopsy analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Y2H + Co-IP + functional epistasis + patient tissue validation\",\n      \"pmids\": [\"23524970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Erbin forms a complex with ErbB2 and HSP90, promoting ErbB2 stability by preventing its degradation; deletion of the Erbin PDZ domain hinders ErbB2-dependent tumor development in MMTV-neu mice; disruption of Erbin-ErbB2 interaction decreases ErbB2-dependent proliferation.\",\n      \"method\": \"Co-IP (Erbin-ErbB2-HSP90 complex), MMTV-neu mouse model with Erbin PDZ deletion (erbin ΔC/ΔC), proliferation assays\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of ternary complex, in vivo mouse model, and mechanistic domain deletion\",\n      \"pmids\": [\"25288731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Erbin is a novel substrate of the SAG-βTrCP E3 ubiquitin ligase; SAG degrades Erbin to activate the Ras-Raf pathway; Erbin accumulation upon Sag deletion blocks Ras activation of Raf, and simultaneous one-allele deletion of Erbb2ip partially rescues SAG deletion phenotypes in keratinocytes.\",\n      \"method\": \"E3 ligase substrate identification, Co-IP, ubiquitination assay, Sag knockout mouse, Erbin genetic rescue\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — biochemical E3 ligase assay, genetic epistasis in vivo\",\n      \"pmids\": [\"26056141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Erbin inhibits EGFR ubiquitination and stabilizes EGFR by interacting with c-Cbl (an E3 ubiquitin ligase for EGFR); the PDZ domain of Erbin is critical for interaction with c-Cbl and EGFR ubiquitination; deletion of Erbin PDZ domain (ErbinΔC/ΔC mice) demonstrates this regulation is necessary for CRC tumorigenesis.\",\n      \"method\": \"Co-IP, ubiquitination assay, PDZ domain deletion mice (ErbinΔC/ΔC), AOM-induced colon carcinogenesis, xenograft model\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — biochemical ubiquitination assay + in vivo genetic model + mechanistic domain mapping\",\n      \"pmids\": [\"25521828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ERBIN acts as a SMAD anchor for receptor activation (SARA) and SMAD2/3 binding protein; STAT3 negatively regulates TGF-β signaling via ERBIN by forming a STAT3-ERBIN-SMAD2/3 complex; loss-of-function ERBB2IP mutations impair STAT3-ERBIN-SMAD2/3 complex formation, fail to constrain nuclear pSMAD2/3, leading to increased IL-4Rα expression and enhanced Th2 responses.\",\n      \"method\": \"Co-IP of STAT3-ERBIN-SMAD2/3 complex, patient-derived cells with ERBB2IP loss-of-function mutation, in vitro reconstitution, nuclear fractionation\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human genetics combined with in vitro mechanistic validation and Co-IP complex characterization\",\n      \"pmids\": [\"28126831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Erbin inactivates ERα signaling in HCC by interacting with ERα and enhancing binding of CHIP (an E3 ligase) to ERα, thereby promoting ubiquitination and degradation of ERα; deletion of Erbin PDZ domain disrupts Erbin-CHIP-ERα interaction, stabilizes ERα protein.\",\n      \"method\": \"Co-IP, ubiquitination assay, ErbinΔC/ΔC mice, DEN-induced HCC model, cell proliferation assays\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — biochemical Co-IP of ternary complex, ubiquitination assay, in vivo mouse model\",\n      \"pmids\": [\"28192186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Erbin interacts with KSR1 and displaces it from the RAF/MEK/ERK complex to prevent signal propagation; genetic deletion of Erbin in Apc knockout mice promotes colorectal tumorigenesis and significantly reduces survival.\",\n      \"method\": \"Co-IP, siRNA knockdown, Erbin/Apc double knockout mice, 3D organoid cultures, gene set enrichment analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of Erbin-KSR1 interaction with functional displacement assay and in vivo genetic model\",\n      \"pmids\": [\"29980571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Erbin in amygdala parvalbumin (PV)-positive neurons is critical for maintaining excitatory postsynaptic responses on PV neurons and for excitation-inhibition balance in the amygdala; Erbin knockout or PV-specific Erbin knockdown reduces excitatory postsynaptic responses on PV neurons and increases anxiety-like behaviors; chemogenetic activation of amygdala PV neurons rescues anxiety in Erbin knockdown mice.\",\n      \"method\": \"Conditional knockdown in amygdala PV neurons, electrophysiology, chemogenetics (DREADD), behavioral assays\",\n      \"journal\": \"Biological psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific KD with electrophysiology and chemogenetic rescue\",\n      \"pmids\": [\"31889536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Scribble, Erbin, and Lano (three LAP proteins) redundantly regulate epithelial apicobasal polarity; triple Scrib/Erbin/Lano knockout disorganizes cell junctions, cytoskeleton, and mislocalizes apical and basolateral identity proteins; the conserved LAPSDa domain of these proteins is essential for basolateral identity and Llgl binding.\",\n      \"method\": \"Triple knockout in epithelial cells, rescue with LAP protein domains, immunofluorescence, structure-function analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean triple KO genetic epistasis with domain-level functional rescue\",\n      \"pmids\": [\"31147384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Erbin interacts with MuSK and forms a complex with both MuSK and ErbB2 simultaneously; knockdown of Erbin reduces the density of agrin-dependent AChR aggregates on primary skeletal myotubes, demonstrating a role for Erbin at the NMJ in linking agrin and neuregulin signaling pathways.\",\n      \"method\": \"Co-IP, domain mapping of Erbin-MuSK interaction, siRNA knockdown, AChR aggregate density assay in primary myotubes\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, domain mapping, loss-of-function with specific synaptic phenotype\",\n      \"pmids\": [\"20463225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The C-terminal region of Erbin (aa 391-964) interacts with the N-terminal region of transcription factor EB (TFEB) (aa 1-247), affects TFEB-14-3-3 and TFEB-PPP3CB complex stability and TFEB phosphorylation status, thereby promoting nuclear translocation of TFEB and lysosome biogenesis to support autophagy.\",\n      \"method\": \"Co-IP with domain mapping, TFEB nuclear translocation assays, autophagy flux assays, sepsis mouse model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP with domain mapping and functional TFEB translocation assays from single lab\",\n      \"pmids\": [\"38105228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Erbin-deficient platelets/megakaryocytes show increased mitochondrial oxidative phosphorylation and secrete lipid metabolites (acyl-carnitine) by abolishing interaction with the prothrombotic protein ESAM; acyl-carnitine then promotes B cell-mediated antitumor immunity.\",\n      \"method\": \"Platelet/MK-specific Erbin knockout mice, Co-IP (Erbin-ESAM interaction), metabolomics, mitochondrial function assays, in vivo metastasis models\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — specific KO with metabolomics, Co-IP, and in vivo functional data\",\n      \"pmids\": [\"38232736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VCPIP1 is a deubiquitinase that interacts with Erbin and stabilizes it through deubiquitination; VCPIP1 deficiency reduces Erbin expression, increases NF-κB phosphorylation, and promotes release of inflammatory cytokines in macrophages.\",\n      \"method\": \"Deubiquitinase plasmid library screen, Co-IP, ubiquitination assay, siRNA knockdown, inflammatory cytokine measurement\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP and ubiquitination assay from single lab\",\n      \"pmids\": [\"39550842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NoxO1 interacts with Erbin (identified by BioID proximity labeling) and co-localizes with EGFR; NoxO1 overexpression delays EGF-mediated kinase activation while NoxO1 KO has the opposite effect, suggesting NoxO1 modulates EGFR signaling through interaction with Erbin.\",\n      \"method\": \"BioID proximity labeling, co-localization microscopy, EGFR signaling assays in NoxO1 KO and OE cells\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — BioID identification with functional validation in KO/OE cells, single lab\",\n      \"pmids\": [\"39426288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Erbin mediates catecholamine-induced β2-adrenergic receptor/Her2 complex formation via its PDZ domain (but not LRR domain); silencing of Erbin abrogates isoproterenol-induced ERK activation and causes severe cardiomyocyte apoptosis upon ISO treatment.\",\n      \"method\": \"Co-IP (β2-AR, Her2, Erbin complex), Erbin deletion mutants, siRNA knockdown, ERK activation assays, apoptosis assay in cardiomyocytes\",\n      \"journal\": \"International journal of cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP of ternary complex with domain deletion, functional knockdown from single lab\",\n      \"pmids\": [\"22564389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Erbin expression is regulated by the transcription factor MITF; under basal conditions MITF activates Erbin expression via direct promoter binding; under β-adrenergic stimulation, FHL2 forms a complex with MITF (confirmed by Co-IP) and switches MITF from an activator to a repressor of Erbin promoter activity, contributing to cardiac hypertrophy.\",\n      \"method\": \"Yeast two-hybrid, Co-IP, chromatin immunoprecipitation (ChIP), promoter reporter assay, MITF mutant mice\",\n      \"journal\": \"International journal of cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP + Co-IP + reporter assay + genetic mouse model from single lab\",\n      \"pmids\": [\"26025865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Erbin interacts with Sema4C via Co-IP in HK2 renal tubular epithelial cells; overexpression of Erbin blocks Sema4C-induced epithelial-mesenchymal transition, and Erbin siRNA promotes EMT induced by Sema4C.\",\n      \"method\": \"Co-IP, Western blot for EMT markers, siRNA knockdown, overexpression\",\n      \"journal\": \"Journal of Huazhong University\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with functional OE/KD, single lab, limited mechanistic depth\",\n      \"pmids\": [\"24142719\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ERBIN (ERBB2IP) is a scaffolding protein containing N-terminal leucine-rich repeats (LRRs) and a C-terminal PDZ domain that localizes to basolateral membranes via palmitoylation at Cys14/16 and LRR-mediated targeting; it stabilizes ErbB2/HER2 (via PDZ-mediated interaction and HSP90 recruitment), suppresses the RAS-RAF-ERK pathway by disrupting the Ras-Raf-Shoc2 scaffold complex (through its LRR domain), inhibits TGF-β/Smad2/3 signaling by sequestering phospho-Smad2/3 away from Smad4 (via a Smad-interacting domain adjacent to the PDZ domain), negatively regulates Nod2-dependent NF-κB signaling (by direct LRR-CARD interaction), and acts as a node linking desmosomal cadherins (DSG1), cadherin-catenin complexes (via delta-catenin/ARVCF), and at synapses (stabilizing TARP γ-2 for AMPAR surface expression in PV interneurons and linking MuSK-ErbB2 signaling at the neuromuscular junction).\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ERBIN is a multidomain scaffolding protein of the LAP (LRR and PDZ) family that orchestrates epithelial polarity, receptor tyrosine kinase stability, and suppression of multiple mitogenic and inflammatory signaling cascades. Its PDZ domain directly binds the C-terminus of ErbB2/HER2, recruiting HSP90 to stabilize ErbB2 and directing the receptor to basolateral membranes—functions essential for peripheral nerve myelination and ErbB2-dependent tumorigenesis [PMID:10878805, PMID:19458253, PMID:25288731]. The N-terminal leucine-rich repeat (LRR) domain binds activated Ras and displaces Raf from the Ras–Shoc2–Raf and KSR1 scaffold complexes, thereby suppressing ERK signaling downstream of desmoglein-1 and in colorectal epithelium, while the same domain interacts with Nod2 CARD domains to inhibit NF-κB activation [PMID:12379659, PMID:16301319, PMID:29980571, PMID:16203728]. A Smad-interacting domain adjacent to the PDZ domain sequesters phospho-Smad2/3 from Smad4 to attenuate TGF-β transcriptional responses—a mechanism further modulated by SARA competition and STAT3 complex formation, whose disruption by loss-of-function ERBB2IP mutations causes dysregulated Th2 immune responses [PMID:17591701, PMID:21878490, PMID:28126831].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"The identification of ERBIN as a specific PDZ-domain partner of ErbB2 that directs its basolateral localization established ERBIN as a receptor-targeting scaffold rather than a generic adaptor.\",\n      \"evidence\": \"Co-IP, in vitro binding, mutagenesis of ErbB2 C-terminal PDZ-binding motif, immunofluorescence in epithelial cells\",\n      \"pmids\": [\"10878805\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ERBIN interacts with other ErbB family members was unresolved\", \"Mechanism by which ERBIN itself reaches the basolateral membrane was unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Discovery that ERBIN's PDZ domain engages p120-catenin relatives (delta-catenin, ARVCF, p0071) and hemidesmosomal components revealed it as a broad junction-associated scaffold linking receptor and adhesion complexes.\",\n      \"evidence\": \"Phage display, Co-IP from neurons, yeast two-hybrid, dominant-negative disruption of monolayer integrity\",\n      \"pmids\": [\"11821434\", \"11711544\", \"11375975\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional hierarchy between ERBIN's receptor-binding and adhesion-binding roles was unresolved\", \"Whether ERBIN loss disrupts junctions in vivo was untested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Structural determination of the ERBIN PDZ domain at atomic resolution revealed an unusual β2-β3 loop that confers dual class I/II ligand recognition, explaining its broad but selective binding repertoire.\",\n      \"evidence\": \"X-ray crystallography at 1.25 Å (ErbB2 peptide complex) and NMR with alanine scanning mutagenesis\",\n      \"pmids\": [\"12444095\", \"12446668\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the full-length protein or the LRR domain was not determined\", \"How phosphorylation dynamically regulates ligand switching in vivo was untested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"The discovery that ERBIN binds activated Ras and disrupts the Ras–Raf interaction established a signaling-suppressive function independent of its receptor-scaffolding role.\",\n      \"evidence\": \"Co-IP with active Ras, reporter assays, siRNA knockdown enhancing ERK activation in PC12 cells\",\n      \"pmids\": [\"12379659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which domain mediates Ras binding was unresolved\", \"Physiological context for this ERK-suppressive role was unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Mapping the ERK-suppressive mechanism to the LRR domain's disruption of the Shoc2–Ras–Raf scaffold, and simultaneously discovering LRR-mediated inhibition of Nod2/NF-κB signaling, revealed the LRR as a multi-pathway signaling suppressor.\",\n      \"evidence\": \"LRR domain mapping, shRNA, Erbin-null MEFs with MDP stimulation, NF-κB reporters\",\n      \"pmids\": [\"16301319\", \"16203728\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LRR simultaneously engages Ras and Nod2 or uses distinct surfaces was unknown\", \"In vivo inflammatory phenotypes of Erbin-null animals were incompletely characterized\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of a Smad-interacting domain (SID) adjacent to the PDZ domain that sequesters phospho-Smad2/3 from Smad4 established ERBIN as a negative regulator of TGF-β signaling through a third, mechanistically distinct domain.\",\n      \"evidence\": \"Co-IP, shRNA, Xenopus gain/loss-of-function, splice isoform lacking SID fails to inhibit TGF-β\",\n      \"pmids\": [\"17591701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ERBIN is recruited to the TGF-β receptor complex was unknown\", \"Whether SID and PDZ domain functions are coordinated was unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstration that palmitoylation at Cys14/16 is required for plasma membrane targeting resolved how ERBIN itself reaches the membrane, complementing its LRR-dependent basolateral sorting.\",\n      \"evidence\": \"C14S/C16S mutagenesis with localization readout in transfected cells\",\n      \"pmids\": [\"18498353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the palmitoyltransferase(s) responsible was unknown\", \"Whether palmitoylation is dynamically regulated was untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Erbin was placed upstream of delta-catenin in dendritic morphogenesis through genetic epistasis, demonstrating a neuronal developmental function beyond synapse-specific roles.\",\n      \"evidence\": \"shRNA/KO in hippocampal neurons, rescue experiments showing delta-catenin OE rescues Erbin loss but not vice versa\",\n      \"pmids\": [\"18614673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which ERBIN controls delta-catenin localization was unresolved\", \"Whether this extends to in vivo dendritic architecture was unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Erbin-null and PDZ-deletion mice established that ERBIN stabilizes ErbB2 protein in Schwann cells and is required for NRG1-dependent peripheral myelination, providing the first in vivo physiological requirement.\",\n      \"evidence\": \"Erbin-null and erbin-ΔC/ΔC knock-in mice, electron microscopy, electrophysiology of sciatic nerves\",\n      \"pmids\": [\"19458253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ERBIN stabilizes ErbB2 through direct chaperone recruitment or prevention of degradation was unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that ERBIN simultaneously complexes with MuSK and ErbB2 at the neuromuscular junction linked agrin and neuregulin signaling through a single scaffold.\",\n      \"evidence\": \"Co-IP of MuSK-ERBIN-ErbB2 ternary complex, siRNA reducing AChR aggregate density in primary myotubes\",\n      \"pmids\": [\"20463225\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ERBIN is required for NMJ formation in vivo was untested\", \"Stoichiometry of the MuSK-ERBIN-ErbB2 complex was unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of SARA as a competitor for ERBIN's Smad-binding surface provided a mechanism for dynamic regulation of TGF-β signal attenuation at endosomes.\",\n      \"evidence\": \"Co-IP, domain mapping of SARA-ERBID and ERBIN-SSID, competition assays reversing ERBIN's inhibition of Smad-dependent transcription\",\n      \"pmids\": [\"21878490\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SARA-ERBIN competition operates in specific tissue contexts was unresolved\", \"Kinetic parameters of competitive binding were not determined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Cell-type-specific studies in PV interneurons revealed that ERBIN stabilizes TARP γ-2 to maintain surface AMPAR expression, establishing a distinct synaptic mechanism in inhibitory circuits.\",\n      \"evidence\": \"PV-specific conditional KO, mEPSC recordings, Co-IP, domain deletion attenuating surface AMPAR\",\n      \"pmids\": [\"23354328\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ERBIN stabilizes TARP γ-2 through preventing ubiquitination or other degradation pathways was unknown\", \"Role in other interneuron subtypes was untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linking desmoglein-1 to ERBIN-mediated suppression of Ras-Shoc2-Raf signaling in keratinocyte differentiation unified adhesion and ERK-suppressive functions in a single physiological axis.\",\n      \"evidence\": \"Y2H, Co-IP showing DSG1 enhances ERBIN-SHOC2 interaction, siRNA epistasis, patient biopsy analysis\",\n      \"pmids\": [\"23524970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other desmosomal cadherins similarly engage ERBIN was unknown\", \"Structural basis for DSG1-dependent modulation of ERBIN-SHOC2 was unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Co-immunoprecipitation of an ERBIN-ErbB2-HSP90 ternary complex and impaired ErbB2-driven tumorigenesis in erbin-ΔC/ΔC MMTV-neu mice resolved that ERBIN stabilizes ErbB2 by recruiting HSP90, with direct oncogenic consequences.\",\n      \"evidence\": \"Co-IP of ternary complex, MMTV-neu × erbin-ΔC/ΔC genetic cross, proliferation assays\",\n      \"pmids\": [\"25288731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ERBIN-HSP90 interaction is direct or bridged by ErbB2 was unclear\", \"How ubiquitin-dependent turnover of ERBIN itself (by SAG-βTrCP) feeds back on ErbB2 stability in vivo was incompletely explored\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Human loss-of-function ERBB2IP mutations causing impaired STAT3-ERBIN-Smad2/3 complex formation and dysregulated Th2 responses linked ERBIN's TGF-β-suppressive mechanism to human immune disease.\",\n      \"evidence\": \"Patient-derived cells with ERBB2IP mutations, Co-IP of STAT3-ERBIN-SMAD2/3, nuclear fractionation showing unconstrained pSmad2/3\",\n      \"pmids\": [\"28126831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full clinical spectrum of ERBB2IP deficiency was not delineated\", \"Whether other LAP family members compensate in immune cells was unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that ERBIN displaces KSR1 from the RAF-MEK-ERK complex added a second, mechanistically distinct node of ERK pathway suppression beyond Shoc2 disruption.\",\n      \"evidence\": \"Co-IP of ERBIN-KSR1, Erbin/Apc double-KO mice with accelerated colorectal tumorigenesis and reduced survival\",\n      \"pmids\": [\"29980571\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ERBIN engages KSR1 and Shoc2 simultaneously or competitively was unresolved\", \"Domain on ERBIN mediating KSR1 interaction was not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Triple knockout of Scribble, Erbin, and Lano demonstrated that LAP proteins redundantly maintain epithelial polarity through a conserved LAPSDa domain that binds Llgl, contextualizing ERBIN within a polarity module.\",\n      \"evidence\": \"Triple KO in epithelial cells, domain rescue, junction disorganization and polarity marker mislocalization\",\n      \"pmids\": [\"31147384\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative individual contributions of each LAP protein in different tissues were incompletely defined\", \"Structural basis of LAPSDa-Llgl interaction was lacking\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Platelet/megakaryocyte-specific ERBIN deletion revealed a metabolic role: loss of ERBIN-ESAM interaction increases mitochondrial oxidative phosphorylation and acyl-carnitine secretion, promoting B cell antitumor immunity.\",\n      \"evidence\": \"MK-specific Erbin KO mice, Co-IP of ERBIN-ESAM, metabolomics, mitochondrial assays, in vivo metastasis models\",\n      \"pmids\": [\"38232736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking ERBIN-ESAM to mitochondrial activity was not molecularly defined\", \"Whether this metabolic function operates in non-hematopoietic cells was unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A full-length structural model of ERBIN and the basis for simultaneous engagement of its LRR, SID, and PDZ domains with distinct partners remain unresolved; how tissue-specific isoforms and post-translational turnover (palmitoylation, SAG/βTrCP-mediated ubiquitination, VCPIP1-mediated deubiquitination) are dynamically coordinated in vivo is unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length structure or cryo-EM model exists\", \"Dynamic regulation of multi-domain engagement is unexplored\", \"In vivo consequences of ERBIN post-translational modifications beyond palmitoylation are poorly characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 7, 8, 11, 16, 20, 26, 29]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 8, 9, 11, 20, 22, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 13, 28]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 7, 8, 11, 15, 20, 21, 23, 24, 26]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 10, 24, 32]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [1, 3, 28]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 12, 14, 19, 27, 29]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [15, 18, 20]}\n    ],\n    \"complexes\": [\n      \"ErbB2-ERBIN-HSP90 complex\",\n      \"LAP polarity module (Scribble/Erbin/Lano)\",\n      \"MuSK-ERBIN-ErbB2 complex\",\n      \"STAT3-ERBIN-SMAD2/3 complex\"\n    ],\n    \"partners\": [\n      \"ERBB2\",\n      \"SHOC2\",\n      \"NOD2\",\n      \"SMAD3\",\n      \"CTNND2\",\n      \"KSR1\",\n      \"CACNA1D\",\n      \"ESAM\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}