{"gene":"ERBIN","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2024,"finding":"Erbin physically interacts with NHERF1, Ezrin, and HER2 in actin-rich membrane protrusions in SKBR3 cells. Knockdown of Erbin reduces HER2 signaling by disrupting formation of a HER2/NHERF1/Ezrin/HSP90 protein complex at the membrane, and inhibition of Ezrin or knockdown of NHERF1 disrupts Erbin's interaction with HER2, placing Erbin as a scaffold supporting HER2 stability and membrane retention.","method":"Co-immunoprecipitation, siRNA knockdown with HER2 signaling readout, and localization studies in SKBR3 cells; loss-of-function with defined phenotypic readout (disrupted membrane complex, reduced HER2 signaling)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reciprocal interactions and KD phenotype shown, but single lab preprint with no peer review or independent replication","pmids":["bio_10.1101_2024.10.01.616146"],"is_preprint":true},{"year":2025,"finding":"The PDZ domain of Erbin can function as an affinity-binder scaffold for biosensor design; competitive peptide introduction into the PDZ domain enables detection of PDZ target ligands in vitro, in mammalian cells, and by FACS, demonstrating that Erbin's PDZ domain engages its target via a defined binding site amenable to competitive displacement.","method":"In vitro competitive binding assay, live mammalian cell fluorescent biosensor imaging, and FACS using engineered NanoBlock sensors based on Erbin PDZ domain","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proof-of-concept tool paper; binding-site characterization is indirect and not validated by mutagenesis of the endogenous Erbin PDZ domain; single preprint","pmids":["bio_10.1101_2025.10.28.685015"],"is_preprint":true}],"current_model":"Erbin (ERBB2IP) acts as a scaffolding protein that, via its PDZ domain, associates with HER2/ErbB2 at the basolateral/plasma membrane and, upon loss of epithelial polarity in HER2-positive breast cancer, recruits NHERF1 and Ezrin to form a multi-protein complex (HER2/NHERF1/Ezrin/HSP90) that stabilizes HER2 at the membrane and supports active HER2 signaling."},"narrative":{"mechanistic_narrative":"Erbin (ERBB2IP) functions as a membrane-associated scaffolding protein that supports HER2/ErbB2 signaling in HER2-positive breast cancer cells [PMID:bio_10.1101_2024.10.01.616146]. In SKBR3 cells, Erbin physically interacts with NHERF1, Ezrin, and HER2 within actin-rich membrane protrusions, and its depletion disrupts assembly of a HER2/NHERF1/Ezrin/HSP90 complex, reducing HER2 stability, membrane retention, and downstream signaling; reciprocally, inhibition of Ezrin or knockdown of NHERF1 disrupts Erbin's interaction with HER2, placing Erbin within an interdependent scaffolding complex [PMID:bio_10.1101_2024.10.01.616146]. Erbin engages its targets through a defined PDZ-domain binding site amenable to competitive peptide displacement [PMID:bio_10.1101_2025.10.28.685015]. Beyond these scaffolding interactions, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2024,"claim":"Established that Erbin acts as a scaffold sustaining HER2 signaling, by showing it bridges HER2 to an NHERF1/Ezrin/HSP90 complex at the membrane rather than acting as an isolated binding partner.","evidence":"Co-immunoprecipitation, siRNA knockdown with HER2 signaling readout, and localization in SKBR3 breast cancer cells (preprint)","pmids":["bio_10.1101_2024.10.01.616146"],"confidence":"Medium","gaps":["Single lab preprint without peer review or independent replication","Direct versus indirect nature of each pairwise interaction within the complex not resolved","Mechanism by which the complex stabilizes HER2 at the membrane not defined"]},{"year":2025,"claim":"Characterized the Erbin PDZ domain as a discrete ligand-binding module engaging targets via a competitively displaceable site, repurposed for biosensor design.","evidence":"In vitro competitive binding, live-cell fluorescent biosensor imaging, and FACS using engineered NanoBlock sensors based on the Erbin PDZ domain (preprint)","pmids":["bio_10.1101_2025.10.28.685015"],"confidence":"Low","gaps":["Proof-of-concept tool paper; binding-site characterization is indirect and not validated by mutagenesis of the endogenous Erbin PDZ domain","Does not identify the physiological PDZ ligand in the HER2 scaffolding context","Single preprint"]},{"year":null,"claim":"Whether Erbin's PDZ-mediated binding is the direct molecular contact within the HER2/NHERF1/Ezrin/HSP90 complex, and the broader physiological roles of Erbin beyond HER2-positive breast cancer, remain unresolved.","evidence":"No discovery in the corpus links the PDZ binding-site characterization to the endogenous scaffolding complex","pmids":[],"confidence":"Low","gaps":["No structural model of the Erbin-HER2 or Erbin-NHERF1 interface","No peer-reviewed validation of the scaffolding model","Physiological substrates/ligands of the PDZ domain in vivo unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[],"complexes":[],"partners":["ERBB2","NHERF1","EZR","HSP90"],"other_free_text":[]}},"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":null,"id":"bio_10.1101_2025.10.28.685015","title":"NanoBlocks: creating fluorescent biosensors from affinity binders using competitive binding","date":"2025-10-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.28.685015","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.01.616146","title":"Erbin interacts with NHERF1 and Ezrin to stabilize a membrane ErbB2 signaling complex in HER2-positive breast cancer","date":"2024-10-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.01.616146","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3190,"output_tokens":718,"usd":0.01017,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7087,"output_tokens":1386,"usd":0.035042,"stage2_stop_reason":"end_turn"},"total_usd":0.045212,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2024,\n      \"finding\": \"Erbin physically interacts with NHERF1, Ezrin, and HER2 in actin-rich membrane protrusions in SKBR3 cells. Knockdown of Erbin reduces HER2 signaling by disrupting formation of a HER2/NHERF1/Ezrin/HSP90 protein complex at the membrane, and inhibition of Ezrin or knockdown of NHERF1 disrupts Erbin's interaction with HER2, placing Erbin as a scaffold supporting HER2 stability and membrane retention.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown with HER2 signaling readout, and localization studies in SKBR3 cells; loss-of-function with defined phenotypic readout (disrupted membrane complex, reduced HER2 signaling)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reciprocal interactions and KD phenotype shown, but single lab preprint with no peer review or independent replication\",\n      \"pmids\": [\"bio_10.1101_2024.10.01.616146\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The PDZ domain of Erbin can function as an affinity-binder scaffold for biosensor design; competitive peptide introduction into the PDZ domain enables detection of PDZ target ligands in vitro, in mammalian cells, and by FACS, demonstrating that Erbin's PDZ domain engages its target via a defined binding site amenable to competitive displacement.\",\n      \"method\": \"In vitro competitive binding assay, live mammalian cell fluorescent biosensor imaging, and FACS using engineered NanoBlock sensors based on Erbin PDZ domain\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proof-of-concept tool paper; binding-site characterization is indirect and not validated by mutagenesis of the endogenous Erbin PDZ domain; single preprint\",\n      \"pmids\": [\"bio_10.1101_2025.10.28.685015\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"Erbin (ERBB2IP) acts as a scaffolding protein that, via its PDZ domain, associates with HER2/ErbB2 at the basolateral/plasma membrane and, upon loss of epithelial polarity in HER2-positive breast cancer, recruits NHERF1 and Ezrin to form a multi-protein complex (HER2/NHERF1/Ezrin/HSP90) that stabilizes HER2 at the membrane and supports active HER2 signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Erbin (ERBB2IP) functions as a membrane-associated scaffolding protein that supports HER2/ErbB2 signaling in HER2-positive breast cancer cells [#0]. In SKBR3 cells, Erbin physically interacts with NHERF1, Ezrin, and HER2 within actin-rich membrane protrusions, and its depletion disrupts assembly of a HER2/NHERF1/Ezrin/HSP90 complex, reducing HER2 stability, membrane retention, and downstream signaling; reciprocally, inhibition of Ezrin or knockdown of NHERF1 disrupts Erbin's interaction with HER2, placing Erbin within an interdependent scaffolding complex [#0]. Erbin engages its targets through a defined PDZ-domain binding site amenable to competitive peptide displacement [#1]. Beyond these scaffolding interactions, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2024,\n      \"claim\": \"Established that Erbin acts as a scaffold sustaining HER2 signaling, by showing it bridges HER2 to an NHERF1/Ezrin/HSP90 complex at the membrane rather than acting as an isolated binding partner.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown with HER2 signaling readout, and localization in SKBR3 breast cancer cells (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.10.01.616146\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab preprint without peer review or independent replication\",\n        \"Direct versus indirect nature of each pairwise interaction within the complex not resolved\",\n        \"Mechanism by which the complex stabilizes HER2 at the membrane not defined\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Characterized the Erbin PDZ domain as a discrete ligand-binding module engaging targets via a competitively displaceable site, repurposed for biosensor design.\",\n      \"evidence\": \"In vitro competitive binding, live-cell fluorescent biosensor imaging, and FACS using engineered NanoBlock sensors based on the Erbin PDZ domain (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.10.28.685015\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Proof-of-concept tool paper; binding-site characterization is indirect and not validated by mutagenesis of the endogenous Erbin PDZ domain\",\n        \"Does not identify the physiological PDZ ligand in the HER2 scaffolding context\",\n        \"Single preprint\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether Erbin's PDZ-mediated binding is the direct molecular contact within the HER2/NHERF1/Ezrin/HSP90 complex, and the broader physiological roles of Erbin beyond HER2-positive breast cancer, remain unresolved.\",\n      \"evidence\": \"No discovery in the corpus links the PDZ binding-site characterization to the endogenous scaffolding complex\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of the Erbin-HER2 or Erbin-NHERF1 interface\",\n        \"No peer-reviewed validation of the scaffolding model\",\n        \"Physiological substrates/ligands of the PDZ domain in vivo unidentified\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"ERBB2\", \"NHERF1\", \"EZR\", \"HSP90\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win"}}