{"gene":"MAPRE2","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2015,"finding":"Mutations in MAPRE2 cause Circumferential Skin Creases Kunze Type (CSC-KT) syndrome. Disease-associated MAPRE2 mutations result in enhanced binding of MAPRE2 to microtubules, implying an increased dwell time at microtubule plus ends. In vivo zebrafish analysis showed MAPRE2 variants perturb branchial arch patterning, either through excessive activity (recessive paradigm) or haploinsufficiency (dominant de novo paradigm).","method":"Patient mutation identification, functional microtubule-binding assay of mutant MAPRE2 proteins, zebrafish craniofacial developmental model (in vivo loss-of-function and gain-of-function)","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (biochemical binding assay + in vivo zebrafish model + patient genetics), moderate-to-strong evidence","pmids":["26637975"],"is_preprint":false},{"year":2016,"finding":"Aurora B and CDK1 phosphorylate MAPRE2 (EB2) at multiple sites within the amino terminus and a serine/threonine cluster in the linker domain connecting the calponin homology and end-binding homology domains. This phosphorylation is strictly associated with mitotic entry and progression and reduces MAPRE2 binding affinity for microtubules. Expression of non-phosphorylatable MAPRE2 induces stable kinetochore microtubule dynamics, delays bipolar metaphase plate formation in a microtubule binding-dependent manner, and leads to aneuploidy in unperturbed mitosis.","method":"In vitro kinase assays with purified Aurora B and CDK1, phospho-site mapping by mass spectrometry, non-phosphorylatable mutant expression, live-cell imaging of mitotic progression, aneuploidy quantification","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro kinase assay with mutagenesis, functional cellular phenotype with multiple orthogonal readouts in a single rigorous study","pmids":["27030108"],"is_preprint":false},{"year":2013,"finding":"MAPRE2 (EB2), but not EB1, is essential for initial microtubule reorganization during apico-basal epithelial differentiation. EB2 siRNA knockdown during early differentiation prevented microtubule reorganization, while knockdown at later stages promoted microtubule stability and bundle formation. Depletion of EB2 in undifferentiated epithelial cells induced formation of straight, less dynamic microtubules with EB1 and ACF7 lattice association and co-alignment with actin filaments, a phenotype rescued by formin inhibition. In situ tissue analysis revealed inverse correlation between EB2 expression level and presence of apico-basal microtubule bundles.","method":"siRNA knockdown, live-cell microtubule dynamics imaging, immunofluorescence, in situ tissue analysis (inner ear and intestinal crypt epithelium), formin inhibitor rescue","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KD + live imaging + in situ tissue correlation + pharmacological rescue), strong evidence for EB2-specific function","pmids":["23813963"],"is_preprint":false},{"year":2015,"finding":"MAPRE2 (EB2) interacts specifically with HAX1 (HCLS1-associated protein X-1) as identified by quantitative proteomics. Knockdown of either HAX1 or EB2 in skin epidermal cells stabilizes focal adhesions and impairs epidermal cell migration in vitro and in vivo. The EB2-Hax1 interaction is required for focal adhesion turnover and cell motility.","method":"Quantitative proteomics (EB2-specific interactor identification), co-immunoprecipitation validation, siRNA knockdown of EB2 and HAX1, focal adhesion dynamics assay, in vitro and in vivo migration assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction validation + KD with defined cellular phenotype (focal adhesion turnover, migration) in vitro and in vivo","pmids":["26527684"],"is_preprint":false},{"year":2009,"finding":"MAPRE2 expression is significantly increased in highly nerve-invasive pancreatic cancer cells compared to less invasive cells. Changes in MAPRE2 expression result in altered actin distribution in pancreatic cancer cells. MAPRE2 is predominantly expressed in normal pancreatic acinar cells but absent in ductal cells, while pancreatic cancer shows strong cytoplasmic and occasional nuclear MAPRE2 expression.","method":"Comparative gene expression analysis between high and low nerve-invasive cell lines, MAPRE2 overexpression/knockdown with actin distribution readout by immunofluorescence, immunohistochemistry of patient tissues","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, functional follow-up (actin redistribution upon MAPRE2 modulation) but limited mechanistic depth","pmids":["19787265"],"is_preprint":false},{"year":2020,"finding":"The ubiquitin ligase WDHD1 interacts with MAPRE2 in the nucleus and promotes MAPRE2 ubiquitination, leading to its degradation. WDHD1 knockout upregulates MAPRE2, while MAPRE2 knockout in A549 lung adenocarcinoma cells increases cell viability and decreases apoptosis upon cisplatin exposure. Thus WDHD1 induces cisplatin resistance partly by promoting MAPRE2 ubiquitination and reducing MAPRE2 protein levels.","method":"Co-immunoprecipitation (WDHD1-MAPRE2 interaction in nucleus), protein stability assay, ubiquitination assay, MAPRE2 knockout (cisplatin sensitivity readout), animal xenograft experiments","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP interaction validated, ubiquitination assay performed, functional KO phenotype in cells and animals, but single lab","pmids":["32426268"],"is_preprint":false},{"year":2019,"finding":"MAPRE2 (EB2) is required for anterograde trafficking of the TRPM4 channel to the plasma membrane. EB2 interacts with TRPM4 via a SxIP-like motif in TRPM4; mutations of this motif abolish the TRPM4-EB2 interaction, reduce plasma membrane TRPM4 expression, and cause ER retention. EB2 depletion impairs TRPM4-dependent focal adhesion disassembly and cell invasion.","method":"Bioinformatics motif identification, co-immunoprecipitation, site-directed mutagenesis of TRPM4 EB-binding motif, immunofluorescence subcellular localization, EB2 siRNA knockdown, focal adhesion and invasion assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct interaction validated by co-IP + mutagenesis, functional KD phenotype, but single lab","pmids":["31112396"],"is_preprint":false},{"year":2010,"finding":"A human cytomegalovirus microRNA (miR-US25-1) targets the 5'UTR of MAPRE2 mRNA to mediate repression of MAPRE2 expression, as part of a coordinated suppression of multiple cell cycle-related genes.","method":"RISC immunoprecipitation, reporter assays with MAPRE2 5'UTR, miRNA deletion from HCMV genome","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 — RISC-IP and functional reporter assay, but MAPRE2 is one of several targets identified in a large-scale study","pmids":["20585629"],"is_preprint":false},{"year":2006,"finding":"MAPRE2 was identified as a phosphoprotein in a global mass spectrometric phosphoproteomics screen of HeLa cells stimulated with EGF, detecting specific phosphorylation sites on MAPRE2 and their temporal dynamics.","method":"Global phosphoproteomic mass spectrometry (SILAC-based quantitative MS after EGF stimulation)","journal":"Cell","confidence":"Low","confidence_rationale":"Tier 4 — large-scale proteomics detection, no functional validation of specific MAPRE2 phosphorylation sites in this study","pmids":["17081983"],"is_preprint":false}],"current_model":"MAPRE2 (EB2) is a microtubule plus-end binding protein whose microtubule association is regulated by mitotic phosphorylation by Aurora B and CDK1 (reducing its microtubule affinity to ensure proper kinetochore dynamics), whose gain-of-function mutations cause enhanced microtubule dwell time leading to the CSC-KT tubulinopathy syndrome, and which promotes cell migration and focal adhesion turnover through a specific interaction with HAX1, controls epithelial microtubule reorganization during apico-basal differentiation, and is subject to ubiquitination by WDHD1 that modulates cisplatin sensitivity in lung cancer cells."},"narrative":{"teleology":[{"year":2006,"claim":"Detection of MAPRE2 as a phosphoprotein with EGF-responsive phosphosites established it as a signaling-responsive cytoskeletal regulator, though the functional relevance of individual sites was unknown.","evidence":"SILAC-based quantitative phosphoproteomics in EGF-stimulated HeLa cells","pmids":["17081983"],"confidence":"Low","gaps":["No functional validation of any specific MAPRE2 phosphorylation site","No kinase assignment","Single large-scale screen without targeted follow-up"]},{"year":2013,"claim":"Demonstration that EB2, but not EB1, is essential for initial microtubule reorganization during apico-basal epithelial differentiation revealed a non-redundant, tissue-specific function for MAPRE2 in controlling microtubule architecture.","evidence":"siRNA knockdown in differentiating epithelial cells, live-cell microtubule dynamics imaging, in situ tissue analysis, formin inhibitor rescue","pmids":["23813963"],"confidence":"High","gaps":["Direct binding partners mediating the EB2-specific reorganization signal not identified","Whether EB2 acts through suppressing formin-dependent bundling or via an independent route remains unclear"]},{"year":2015,"claim":"Identification of MAPRE2 mutations as the cause of CSC-KT syndrome, combined with evidence that mutant proteins display enhanced microtubule binding, established that aberrant plus-end dwell time is pathogenic and linked MAPRE2 to a developmental tubulinopathy.","evidence":"Patient mutation identification, biochemical microtubule-binding assays of mutant proteins, zebrafish craniofacial developmental model","pmids":["26637975"],"confidence":"High","gaps":["Precise downstream signaling pathways disrupted by enhanced EB2–microtubule binding in affected tissues not defined","Structural basis for altered dwell time of mutant proteins not resolved"]},{"year":2015,"claim":"Discovery of the EB2–HAX1 interaction and its requirement for focal adhesion turnover and cell migration provided the first defined molecular partnership explaining how EB2 regulates adhesion-coupled motility.","evidence":"Quantitative proteomics interactor screen, reciprocal co-immunoprecipitation, siRNA knockdown with focal adhesion dynamics and migration readouts in vitro and in vivo","pmids":["26527684"],"confidence":"High","gaps":["Structural basis of the EB2–HAX1 interface not determined","Whether HAX1 mediates EB2's role in all motility contexts or only in epidermal cells is unknown"]},{"year":2016,"claim":"Mapping of Aurora B and CDK1 phosphosites on MAPRE2 and demonstration that phosphorylation reduces microtubule affinity during mitosis resolved how cells temporally control EB2 activity to enable proper chromosome segregation.","evidence":"In vitro kinase assays, phospho-site mass spectrometry, non-phosphorylatable mutant expression, live-cell imaging of mitotic progression, aneuploidy quantification","pmids":["27030108"],"confidence":"High","gaps":["Phosphatases responsible for MAPRE2 dephosphorylation at mitotic exit not identified","Relative contributions of Aurora B versus CDK1 to in vivo MAPRE2 regulation not deconvolved"]},{"year":2019,"claim":"Demonstration that EB2 mediates anterograde trafficking of TRPM4 to the plasma membrane via a SxIP-like motif expanded EB2's functional repertoire beyond cytoskeletal regulation to cargo-specific vesicular transport.","evidence":"Co-immunoprecipitation, SxIP motif mutagenesis of TRPM4, EB2 siRNA knockdown with subcellular localization, focal adhesion and invasion assays","pmids":["31112396"],"confidence":"Medium","gaps":["Whether EB2 delivers other SxIP-containing cargoes to the plasma membrane not tested","Single-lab finding without independent replication"]},{"year":2020,"claim":"Identification of WDHD1-mediated ubiquitination and degradation of MAPRE2 in the nucleus, with consequences for cisplatin sensitivity, revealed a post-translational mechanism controlling MAPRE2 protein levels in cancer cells.","evidence":"Co-immunoprecipitation, ubiquitination assay, MAPRE2 knockout cisplatin sensitivity readout, xenograft experiments in A549 lung adenocarcinoma cells","pmids":["32426268"],"confidence":"Medium","gaps":["Specific ubiquitin chain linkage type on MAPRE2 not characterized","Nuclear function of MAPRE2 that would explain cisplatin sensitivity phenotype is undefined","Single-lab finding"]},{"year":null,"claim":"A unified structural and biophysical model explaining how MAPRE2 phosphorylation, disease mutations, and partner interactions (HAX1, TRPM4) converge on microtubule dwell-time control is still lacking.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of MAPRE2 bound to microtubule plus ends or partner proteins","In vivo tissue-specific functions beyond epithelium and craniofacial development largely unexplored","The nuclear pool of MAPRE2 and its functional significance remain poorly defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,2,3,6]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1,2,3,6]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,2]}],"complexes":[],"partners":["HAX1","TRPM4","WDHD1","AURKB","CDK1"],"other_free_text":[]},"mechanistic_narrative":"MAPRE2 (EB2) is a microtubule plus-end tracking protein that governs microtubule dynamics in both interphase and mitosis, with specialized roles in epithelial differentiation, cell migration, and intracellular trafficking. During mitosis, Aurora B and CDK1 phosphorylate MAPRE2 to reduce its microtubule affinity, ensuring proper kinetochore–microtubule dynamics and faithful chromosome segregation; non-phosphorylatable MAPRE2 stabilizes kinetochore microtubules and causes aneuploidy [PMID:27030108]. In interphase, MAPRE2 promotes focal adhesion turnover and cell migration through a specific interaction with HAX1 [PMID:26527684] and facilitates anterograde trafficking of the TRPM4 channel to the plasma membrane via a SxIP-like motif [PMID:31112396]; it also uniquely drives initial microtubule reorganization during apico-basal epithelial differentiation, where its depletion leads to aberrantly stable, bundled microtubules [PMID:23813963]. Gain-of-function mutations in MAPRE2 that enhance microtubule dwell time cause Circumferential Skin Creases Kunze Type (CSC-KT) syndrome [PMID:26637975]."},"prefetch_data":{"uniprot":{"accession":"Q15555","full_name":"Microtubule-associated protein RP/EB family member 2","aliases":["APC-binding protein EB2","End-binding protein 2","EB2"],"length_aa":327,"mass_kda":37.0,"function":"Adapter protein that is involved in microtubule polymerization, and spindle function by stabilizing microtubules and anchoring them at centrosomes. Therefore, ensures mitotic progression and genome stability (PubMed:27030108). Acts as a central regulator of microtubule reorganization in apico-basal epithelial differentiation (By similarity). Plays a role during oocyte meiosis by regulating microtubule dynamics (By similarity). Participates in neurite growth by interacting with plexin B3/PLXNB3 and microtubule reorganization during apico-basal epithelial differentiation (PubMed:22373814). Also plays an essential role for cell migration and focal adhesion dynamics. Mechanistically, recruits HAX1 to microtubules in order to regulate focal adhesion dynamics (PubMed:26527684)","subcellular_location":"Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q15555/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAPRE2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MAPRE2","total_profiled":1310},"omim":[{"mim_id":"616734","title":"SKIN CREASES, CONGENITAL SYMMETRIC CIRCUMFERENTIAL, 2; CSCSC2","url":"https://www.omim.org/entry/616734"},{"mim_id":"605789","title":"MICROTUBULE-ASSOCIATED PROTEIN, RP/EB FAMILY, MEMBER 2; MAPRE2","url":"https://www.omim.org/entry/605789"},{"mim_id":"605788","title":"MICROTUBULE-ASSOCIATED PROTEIN, RP/EB FAMILY, MEMBER 3; MAPRE3","url":"https://www.omim.org/entry/605788"},{"mim_id":"604754","title":"ZINC FINGER PROTEIN 271, PSEUDOGENE; ZNF271P","url":"https://www.omim.org/entry/604754"},{"mim_id":"603108","title":"MICROTUBULE-ASSOCIATED PROTEIN, RP/EB FAMILY, MEMBER 1; MAPRE1","url":"https://www.omim.org/entry/603108"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":130.8}],"url":"https://www.proteinatlas.org/search/MAPRE2"},"hgnc":{"alias_symbol":["RP1","EB1","EB2"],"prev_symbol":[]},"alphafold":{"accession":"Q15555","domains":[{"cath_id":"1.10.418.10","chopping":"59-172","consensus_level":"high","plddt":95.1887,"start":59,"end":172},{"cath_id":"1.20.5.1430","chopping":"240-297","consensus_level":"high","plddt":88.6502,"start":240,"end":297}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15555","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15555-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15555-F1-predicted_aligned_error_v6.png","plddt_mean":74.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAPRE2","jax_strain_url":"https://www.jax.org/strain/search?query=MAPRE2"},"sequence":{"accession":"Q15555","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15555.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15555/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15555"}},"corpus_meta":[{"pmid":"10030671","id":"PMC_10030671","title":"EB1, 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binding assays, in vivo zebrafish model) with disease-causing mutations in a single rigorous study\",\n      \"pmids\": [\"26637975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Aurora B and CDK1 phosphorylate EB2 (MAPRE2) at multiple sites within the amino terminus and a linker cluster of serine/threonine residues upon mitotic entry, reducing EB2 binding affinity for microtubules; expression of non-phosphorylatable EB2 stabilizes kinetochore microtubule dynamics, delays bipolar metaphase plate formation, and causes aneuploidy.\",\n      \"method\": \"In vitro kinase assays, phospho-mutant expression, live-cell imaging, flow cytometry for chromosome content\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with mutagenesis plus cellular phenotypic readouts, published in high-impact journal\",\n      \"pmids\": [\"27030108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MAPRE2 (EB2) does not directly regulate microtubule dynamic instability, but associates with HAX1 (HCLS1-associated protein X-1) as an EB2-specific interacting partner identified by quantitative proteomics; knockdown of HAX1 and EB2 stabilizes focal adhesions and impairs epidermal cell migration in vitro and in vivo, demonstrating that EB2-HAX1 interaction is required for focal adhesion turnover and cell motility.\",\n      \"method\": \"Quantitative proteomics, Co-IP, siRNA knockdown, in vitro and in vivo migration assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with quantitative proteomics identification plus clean KD with defined cellular phenotype\",\n      \"pmids\": [\"26527684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EB2 (MAPRE2) siRNA knockdown during early stages of apico-basal epithelial differentiation prevents microtubule reorganisation; EB2 downregulation at later stages promotes microtubule stability and bundle formation and induces EB1 and ACF7 lattice association and co-alignment with actin, a phenotype rescued by formin inhibition. EB2 is established as a central regulator of microtubule reorganisation during epithelial polarisation.\",\n      \"method\": \"siRNA knockdown, live-cell imaging, immunofluorescence, in situ tissue analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with specific cellular phenotype, rescue experiment, and in situ tissue validation\",\n      \"pmids\": [\"23813963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MAPRE2 (EB2) is highly expressed in pancreatic cancer cells with high nerve-invasive capacity; altered MAPRE2 expression results in changes in actin distribution, implicating MAPRE2 in perineural invasion through cytoskeletal reorganisation.\",\n      \"method\": \"MAPRE2 expression modulation, actin distribution imaging, comparative analysis of nerve-invasive cell lines\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab with expression manipulation and actin phenotype but limited mechanistic depth\",\n      \"pmids\": [\"19787265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EB1 and EB2 (MAPRE2) proteins are required for TRPM4 anterograde trafficking to the plasma membrane; mutations of the EB-binding SxIP-like motif in TRPM4 abolish the TRPM4-EB interaction, leading to ER retention of TRPM4 and impaired focal adhesion disassembly and cell invasion.\",\n      \"method\": \"Co-IP, mutagenesis of SxIP motif, live-cell imaging, siRNA knockdown, functional channel assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis-validated interaction plus functional trafficking readout, but EB1 and EB2 not fully separated mechanistically\",\n      \"pmids\": [\"31112396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WDHD1 ubiquitin ligase interacts with MAPRE2 in the nucleus and promotes ubiquitination of MAPRE2, leading to its degradation; MAPRE2 knockout increases cisplatin resistance in lung adenocarcinoma cells, demonstrating that MAPRE2 ubiquitination by WDHD1 regulates cisplatin sensitivity.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, protein stability assay, MAPRE2 knockout functional experiments, animal tumor experiments\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with ubiquitination assay and clean KO phenotype, but single lab\",\n      \"pmids\": [\"32426268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"RP1 (MAPRE2 family member) protein directly binds to wild-type APC protein but not to mutated APC; RP1 is differentially expressed in T cells activated by CD3/CD28 co-stimulation, placing RP1 as an APC-binding EB1-family protein induced in proliferating cells.\",\n      \"method\": \"Bacterially expressed RP1 protein binding assay, differential mRNA display, Northern blot\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct in vitro binding assay validated but limited mechanistic follow-up on MAPRE2 specifically\",\n      \"pmids\": [\"9233623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The CH domain (amino acids 1–133) of EB1 family members including RP1 (MAPRE2) is necessary and sufficient for microtubule binding; EB1-like C-terminal motif mediates interactions with APC and p150glued via overlapping but distinct regions; microtubule bundling activity requires amino acids 1–181 of EB1 and is independent of APC or p150glued binding domains.\",\n      \"method\": \"In vitro binding assays, deletion mutagenesis, co-sedimentation, transfection/overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted domain mapping with deletion mutagenesis across multiple interactions\",\n      \"pmids\": [\"14514668\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAPRE2 (EB2) is a microtubule plus-end binding protein whose dwell time at growing microtubule ends is tuned by phosphorylation (notably by Aurora B and CDK1 during mitosis), whose interaction with HAX1 drives focal adhesion turnover and cell migration, and whose ubiquitination by WDHD1 controls its stability and cisplatin sensitivity; disease-causing mutations in MAPRE2 enhance its microtubule binding affinity and disrupt craniofacial patterning in vivo, while its unique property of not directly stabilizing microtubule dynamics (unlike EB1/EB3) allows it to regulate epithelial microtubule reorganisation and cargo trafficking (e.g., TRPM4) through partner-dependent mechanisms.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nPapers about MAPRE2 (EB2, microtubule end-binding protein 2, the canonical MAPRE2 protein):\n- PMID:26637975 — KEEP (directly about MAPRE2 mutations causing CSC-KT syndrome)\n- PMID:19787265 — KEEP (directly about MAPRE2 in pancreatic cancer perineural invasion)\n- PMID:32426268 — KEEP (directly about MAPRE2 ubiquitination by WDHD1)\n- PMID:27030108 — KEEP (about EB2/MAPRE2 phosphorylation in mitosis)\n- PMID:23813963 — KEEP (about EB2/MAPRE2 role in epithelial differentiation)\n- PMID:26527684 — KEEP (about EB2/MAPRE2 and Hax1 in focal adhesion/cell migration)\n- PMID:31112396 — KEEP (EB1- and EB2-dependent TRPM4 trafficking)\n- PMID:17081983 — KEEP (mass spec phosphoproteomics, MAPRE2 phosphorylation sites detected)\n- PMID:20585629 — KEEP (viral miRNA targets MAPRE2 5'UTR)\n\nPapers primarily about EB1 (MAPRE1), not MAPRE2:\n- PMID:10030671, 12388761, 24508171, 12388762, 9724749, 16247021, 28204846, 12842007, 22764224, 21737685, 14514668, 18477699, 12403791, 11950877, 36536176, 27617931, 17968321, 29379139, 25225338, 25297623, 12789661, 19701929, 17709426, 23236459, 26323690, 24492008, 24421324, 29162697, 19528074 (EBV EB2), 12208942 (EBV EB2), etc. — EXCLUDE (EB1/MAPRE1 or EBV EB2 protein, not MAPRE2)\n\nEBV EB2 (BMLF1/SM/Mta) papers — EXCLUDE (alias collision, viral protein not MAPRE2):\n- PMID:16129689, 12403791, 10846090, 12208942, 12857728, 16254345, 19793817, 17699575, 19528074, 22505578 — EXCLUDE\n\nRP1 (retinitis pigmentosa gene) papers — EXCLUDE (different gene):\n- PMID:10845615, 10484783, 11527933, 19657028, 11095597, 9233623 (RP1 as EB1 family member — this one mentions MAPRE2 family but is about RP1), etc. — EXCLUDE\n\nPlant Rp1 disease resistance gene — EXCLUDE (symbol collision, plant NLR gene)\n\nlncRNA RP1 papers — EXCLUDE (alt-locus product)\n\nInteractome/proteome papers from gene2pubmed that detected MAPRE2 in large-scale datasets:\n- PMID:16189514, 25416956, 32296183, 26186194, 28514442, 33961781, 22939629, 17081983, 15592455 — these are large-scale studies; MAPRE2 phosphorylation detected in PMID:17081983 is relevant\n\nPapers about EB2 (MAPRE2) specifically:\n- PMID:27030108: \"Phosphorylation of EB2 by Aurora B and CDK1 ensures mitotic progression and genome stability\" — KEEP\n- PMID:23813963: \"The microtubule end-binding protein EB2 is a central regulator...\" — KEEP\n- PMID:26527684: \"Regulation of Focal Adhesion Dynamics and Cell Motility by the EB2 and Hax1 Protein Complex\" — KEEP\n- PMID:31112396: \"EB1- and EB2-dependent anterograde trafficking of TRPM4\" — KEEP (mentions EB2)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"Mutations in MAPRE2 cause Circumferential Skin Creases Kunze Type (CSC-KT) syndrome. Disease-associated MAPRE2 mutations result in enhanced binding of MAPRE2 to microtubules, implying an increased dwell time at microtubule plus ends. In vivo zebrafish analysis showed MAPRE2 variants perturb branchial arch patterning, either through excessive activity (recessive paradigm) or haploinsufficiency (dominant de novo paradigm).\",\n      \"method\": \"Patient mutation identification, functional microtubule-binding assay of mutant MAPRE2 proteins, zebrafish craniofacial developmental model (in vivo loss-of-function and gain-of-function)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (biochemical binding assay + in vivo zebrafish model + patient genetics), moderate-to-strong evidence\",\n      \"pmids\": [\"26637975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Aurora B and CDK1 phosphorylate MAPRE2 (EB2) at multiple sites within the amino terminus and a serine/threonine cluster in the linker domain connecting the calponin homology and end-binding homology domains. This phosphorylation is strictly associated with mitotic entry and progression and reduces MAPRE2 binding affinity for microtubules. Expression of non-phosphorylatable MAPRE2 induces stable kinetochore microtubule dynamics, delays bipolar metaphase plate formation in a microtubule binding-dependent manner, and leads to aneuploidy in unperturbed mitosis.\",\n      \"method\": \"In vitro kinase assays with purified Aurora B and CDK1, phospho-site mapping by mass spectrometry, non-phosphorylatable mutant expression, live-cell imaging of mitotic progression, aneuploidy quantification\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinase assay with mutagenesis, functional cellular phenotype with multiple orthogonal readouts in a single rigorous study\",\n      \"pmids\": [\"27030108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MAPRE2 (EB2), but not EB1, is essential for initial microtubule reorganization during apico-basal epithelial differentiation. EB2 siRNA knockdown during early differentiation prevented microtubule reorganization, while knockdown at later stages promoted microtubule stability and bundle formation. Depletion of EB2 in undifferentiated epithelial cells induced formation of straight, less dynamic microtubules with EB1 and ACF7 lattice association and co-alignment with actin filaments, a phenotype rescued by formin inhibition. In situ tissue analysis revealed inverse correlation between EB2 expression level and presence of apico-basal microtubule bundles.\",\n      \"method\": \"siRNA knockdown, live-cell microtubule dynamics imaging, immunofluorescence, in situ tissue analysis (inner ear and intestinal crypt epithelium), formin inhibitor rescue\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KD + live imaging + in situ tissue correlation + pharmacological rescue), strong evidence for EB2-specific function\",\n      \"pmids\": [\"23813963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MAPRE2 (EB2) interacts specifically with HAX1 (HCLS1-associated protein X-1) as identified by quantitative proteomics. Knockdown of either HAX1 or EB2 in skin epidermal cells stabilizes focal adhesions and impairs epidermal cell migration in vitro and in vivo. The EB2-Hax1 interaction is required for focal adhesion turnover and cell motility.\",\n      \"method\": \"Quantitative proteomics (EB2-specific interactor identification), co-immunoprecipitation validation, siRNA knockdown of EB2 and HAX1, focal adhesion dynamics assay, in vitro and in vivo migration assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction validation + KD with defined cellular phenotype (focal adhesion turnover, migration) in vitro and in vivo\",\n      \"pmids\": [\"26527684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MAPRE2 expression is significantly increased in highly nerve-invasive pancreatic cancer cells compared to less invasive cells. Changes in MAPRE2 expression result in altered actin distribution in pancreatic cancer cells. MAPRE2 is predominantly expressed in normal pancreatic acinar cells but absent in ductal cells, while pancreatic cancer shows strong cytoplasmic and occasional nuclear MAPRE2 expression.\",\n      \"method\": \"Comparative gene expression analysis between high and low nerve-invasive cell lines, MAPRE2 overexpression/knockdown with actin distribution readout by immunofluorescence, immunohistochemistry of patient tissues\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, functional follow-up (actin redistribution upon MAPRE2 modulation) but limited mechanistic depth\",\n      \"pmids\": [\"19787265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The ubiquitin ligase WDHD1 interacts with MAPRE2 in the nucleus and promotes MAPRE2 ubiquitination, leading to its degradation. WDHD1 knockout upregulates MAPRE2, while MAPRE2 knockout in A549 lung adenocarcinoma cells increases cell viability and decreases apoptosis upon cisplatin exposure. Thus WDHD1 induces cisplatin resistance partly by promoting MAPRE2 ubiquitination and reducing MAPRE2 protein levels.\",\n      \"method\": \"Co-immunoprecipitation (WDHD1-MAPRE2 interaction in nucleus), protein stability assay, ubiquitination assay, MAPRE2 knockout (cisplatin sensitivity readout), animal xenograft experiments\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP interaction validated, ubiquitination assay performed, functional KO phenotype in cells and animals, but single lab\",\n      \"pmids\": [\"32426268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAPRE2 (EB2) is required for anterograde trafficking of the TRPM4 channel to the plasma membrane. EB2 interacts with TRPM4 via a SxIP-like motif in TRPM4; mutations of this motif abolish the TRPM4-EB2 interaction, reduce plasma membrane TRPM4 expression, and cause ER retention. EB2 depletion impairs TRPM4-dependent focal adhesion disassembly and cell invasion.\",\n      \"method\": \"Bioinformatics motif identification, co-immunoprecipitation, site-directed mutagenesis of TRPM4 EB-binding motif, immunofluorescence subcellular localization, EB2 siRNA knockdown, focal adhesion and invasion assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct interaction validated by co-IP + mutagenesis, functional KD phenotype, but single lab\",\n      \"pmids\": [\"31112396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A human cytomegalovirus microRNA (miR-US25-1) targets the 5'UTR of MAPRE2 mRNA to mediate repression of MAPRE2 expression, as part of a coordinated suppression of multiple cell cycle-related genes.\",\n      \"method\": \"RISC immunoprecipitation, reporter assays with MAPRE2 5'UTR, miRNA deletion from HCMV genome\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RISC-IP and functional reporter assay, but MAPRE2 is one of several targets identified in a large-scale study\",\n      \"pmids\": [\"20585629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MAPRE2 was identified as a phosphoprotein in a global mass spectrometric phosphoproteomics screen of HeLa cells stimulated with EGF, detecting specific phosphorylation sites on MAPRE2 and their temporal dynamics.\",\n      \"method\": \"Global phosphoproteomic mass spectrometry (SILAC-based quantitative MS after EGF stimulation)\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — large-scale proteomics detection, no functional validation of specific MAPRE2 phosphorylation sites in this study\",\n      \"pmids\": [\"17081983\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAPRE2 (EB2) is a microtubule plus-end binding protein whose microtubule association is regulated by mitotic phosphorylation by Aurora B and CDK1 (reducing its microtubule affinity to ensure proper kinetochore dynamics), whose gain-of-function mutations cause enhanced microtubule dwell time leading to the CSC-KT tubulinopathy syndrome, and which promotes cell migration and focal adhesion turnover through a specific interaction with HAX1, controls epithelial microtubule reorganization during apico-basal differentiation, and is subject to ubiquitination by WDHD1 that modulates cisplatin sensitivity in lung cancer cells.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MAPRE2 (EB2) is a microtubule plus-end tracking protein that regulates microtubule dynamics, epithelial polarity, cell migration, and mitotic fidelity through partner-dependent mechanisms rather than direct stabilization of microtubule dynamic instability. Its N-terminal CH domain mediates microtubule binding while its C-terminal EB1-like motif interacts with APC and p150glued; during mitosis, Aurora B and CDK1 phosphorylate EB2 to reduce its microtubule binding affinity, and expression of non-phosphorylatable EB2 stabilizes kinetochore–microtubule attachments, delays metaphase plate formation, and causes aneuploidy [PMID:27030108, PMID:14514668]. EB2 uniquely partners with HAX1 to drive focal adhesion turnover and epidermal cell migration, and facilitates TRPM4 channel trafficking to the plasma membrane via an SxIP-dependent interaction [PMID:26527684, PMID:31112396]. Mutations in MAPRE2 that enhance microtubule binding cause circumferential skin creases Kunze type through disrupted branchial arch patterning, as demonstrated by patient genetics and zebrafish models [PMID:26637975].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"The initial identification of RP1 (MAPRE2) as an EB1-family protein that directly binds wild-type APC established MAPRE2 as a component of the APC–microtubule regulatory axis.\",\n      \"evidence\": \"In vitro binding assay with bacterially expressed RP1 and APC fragments; differential mRNA display in activated T cells\",\n      \"pmids\": [\"9233623\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding was shown for RP1–APC but functional consequences of this interaction for MAPRE2 specifically were not explored\", \"No cellular phenotype reported for MAPRE2 loss or overexpression\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Domain mapping revealed that the CH domain (aa 1–133) of EB1-family proteins including MAPRE2 is necessary and sufficient for microtubule binding, while the C-terminal EB1-like motif mediates APC and p150glued interactions through overlapping but distinct sites, defining the modular architecture of EB2.\",\n      \"evidence\": \"Deletion mutagenesis, in vitro co-sedimentation, and transfection-based binding assays\",\n      \"pmids\": [\"14514668\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural data for EB2 CH domain–microtubule interface not resolved\", \"Microtubule bundling was mapped for EB1 but not specifically tested for EB2\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"EB2 was shown to be a central regulator of epithelial microtubule reorganisation during apico-basal polarisation, functioning distinctly from EB1/EB3 by not directly stabilizing microtubule dynamics but instead gating EB1/ACF7 lattice association and actin co-alignment.\",\n      \"evidence\": \"siRNA knockdown in epithelial cells, live-cell imaging, formin inhibition rescue, and in situ tissue analysis\",\n      \"pmids\": [\"23813963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which EB2 prevents EB1 lattice association is unknown\", \"Whether EB2 interacts directly with actin regulators was not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Two key advances defined EB2's unique partner network and disease relevance: quantitative proteomics identified HAX1 as an EB2-specific interactor required for focal adhesion turnover and cell migration, while patient mutation studies established that enhanced EB2–microtubule binding causes circumferential skin creases Kunze type through disrupted branchial arch patterning.\",\n      \"evidence\": \"Quantitative proteomics with reciprocal Co-IP, siRNA, in vivo migration assays (HAX1 study); patient mutation functional analysis, zebrafish craniofacial model, microtubule binding assays (disease study)\",\n      \"pmids\": [\"26527684\", \"26637975\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How enhanced EB2 dwell time at microtubule ends mechanistically disrupts neural crest cell behavior is unknown\", \"Whether HAX1 interaction is regulated by the same phosphorylation events that control EB2–microtubule binding is untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The discovery that Aurora B and CDK1 phosphorylate EB2 at mitotic entry to reduce its microtubule binding affinity resolved how EB2 dwell time is dynamically regulated during the cell cycle; non-phosphorylatable EB2 stabilized kinetochore–microtubule dynamics and caused aneuploidy, establishing EB2 phosphoregulation as essential for mitotic fidelity.\",\n      \"evidence\": \"In vitro kinase assays, phospho-mutant expression, live-cell imaging, flow cytometry for chromosome content\",\n      \"pmids\": [\"27030108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase(s) responsible for EB2 dephosphorylation at mitotic exit not identified\", \"Whether disease-causing MAPRE2 mutations alter phosphorylation sensitivity was not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"EB1 and EB2 were shown to mediate TRPM4 anterograde trafficking to the plasma membrane via an SxIP-like motif, extending EB2's functional repertoire to ion channel cargo transport and linking it to focal adhesion disassembly through TRPM4-dependent signaling.\",\n      \"evidence\": \"Co-IP, SxIP motif mutagenesis, live-cell imaging, siRNA knockdown, functional channel assays\",\n      \"pmids\": [\"31112396\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"EB1 and EB2 contributions to TRPM4 trafficking were not fully separated\", \"Whether EB2-specific partners like HAX1 participate in TRPM4 trafficking is unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"WDHD1 was identified as a ubiquitin ligase that interacts with and ubiquitinates MAPRE2 in the nucleus, promoting its degradation; MAPRE2 knockout increased cisplatin resistance, establishing post-translational control of EB2 protein levels as a determinant of chemosensitivity.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assay, protein stability assay, MAPRE2 knockout in lung adenocarcinoma cells, animal tumor experiments\",\n      \"pmids\": [\"32426268\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"WDHD1 is not a canonical E3 ligase; the ubiquitination mechanism needs independent confirmation\", \"How nuclear MAPRE2 degradation relates to its cytoplasmic microtubule-tracking function is unclear\", \"Single-lab finding not yet replicated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of EB2's distinct behavior from EB1/EB3, how disease-causing mutations mechanistically disrupt neural crest cell function, whether EB2 phosphorylation by Aurora B/CDK1 is coordinated with its partner interactions (HAX1, TRPM4), and the physiological significance of nuclear EB2 ubiquitination by WDHD1.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No atomic-resolution structure of EB2 on microtubules\", \"Phosphorylation–partner interaction crosstalk untested\", \"Nuclear function of MAPRE2 uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 3, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 3, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HAX1\", \"APC\", \"DLGAP5\", \"WDHD1\", \"TRPM4\", \"AURB\", \"CDK1\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"MAPRE2 (EB2) is a microtubule plus-end tracking protein that governs microtubule dynamics in both interphase and mitosis, with specialized roles in epithelial differentiation, cell migration, and intracellular trafficking. During mitosis, Aurora B and CDK1 phosphorylate MAPRE2 to reduce its microtubule affinity, ensuring proper kinetochore–microtubule dynamics and faithful chromosome segregation; non-phosphorylatable MAPRE2 stabilizes kinetochore microtubules and causes aneuploidy [PMID:27030108]. In interphase, MAPRE2 promotes focal adhesion turnover and cell migration through a specific interaction with HAX1 [PMID:26527684] and facilitates anterograde trafficking of the TRPM4 channel to the plasma membrane via a SxIP-like motif [PMID:31112396]; it also uniquely drives initial microtubule reorganization during apico-basal epithelial differentiation, where its depletion leads to aberrantly stable, bundled microtubules [PMID:23813963]. Gain-of-function mutations in MAPRE2 that enhance microtubule dwell time cause Circumferential Skin Creases Kunze Type (CSC-KT) syndrome [PMID:26637975].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Detection of MAPRE2 as a phosphoprotein with EGF-responsive phosphosites established it as a signaling-responsive cytoskeletal regulator, though the functional relevance of individual sites was unknown.\",\n      \"evidence\": \"SILAC-based quantitative phosphoproteomics in EGF-stimulated HeLa cells\",\n      \"pmids\": [\"17081983\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional validation of any specific MAPRE2 phosphorylation site\", \"No kinase assignment\", \"Single large-scale screen without targeted follow-up\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstration that EB2, but not EB1, is essential for initial microtubule reorganization during apico-basal epithelial differentiation revealed a non-redundant, tissue-specific function for MAPRE2 in controlling microtubule architecture.\",\n      \"evidence\": \"siRNA knockdown in differentiating epithelial cells, live-cell microtubule dynamics imaging, in situ tissue analysis, formin inhibitor rescue\",\n      \"pmids\": [\"23813963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding partners mediating the EB2-specific reorganization signal not identified\", \"Whether EB2 acts through suppressing formin-dependent bundling or via an independent route remains unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of MAPRE2 mutations as the cause of CSC-KT syndrome, combined with evidence that mutant proteins display enhanced microtubule binding, established that aberrant plus-end dwell time is pathogenic and linked MAPRE2 to a developmental tubulinopathy.\",\n      \"evidence\": \"Patient mutation identification, biochemical microtubule-binding assays of mutant proteins, zebrafish craniofacial developmental model\",\n      \"pmids\": [\"26637975\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise downstream signaling pathways disrupted by enhanced EB2–microtubule binding in affected tissues not defined\", \"Structural basis for altered dwell time of mutant proteins not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery of the EB2–HAX1 interaction and its requirement for focal adhesion turnover and cell migration provided the first defined molecular partnership explaining how EB2 regulates adhesion-coupled motility.\",\n      \"evidence\": \"Quantitative proteomics interactor screen, reciprocal co-immunoprecipitation, siRNA knockdown with focal adhesion dynamics and migration readouts in vitro and in vivo\",\n      \"pmids\": [\"26527684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the EB2–HAX1 interface not determined\", \"Whether HAX1 mediates EB2's role in all motility contexts or only in epidermal cells is unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapping of Aurora B and CDK1 phosphosites on MAPRE2 and demonstration that phosphorylation reduces microtubule affinity during mitosis resolved how cells temporally control EB2 activity to enable proper chromosome segregation.\",\n      \"evidence\": \"In vitro kinase assays, phospho-site mass spectrometry, non-phosphorylatable mutant expression, live-cell imaging of mitotic progression, aneuploidy quantification\",\n      \"pmids\": [\"27030108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatases responsible for MAPRE2 dephosphorylation at mitotic exit not identified\", \"Relative contributions of Aurora B versus CDK1 to in vivo MAPRE2 regulation not deconvolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstration that EB2 mediates anterograde trafficking of TRPM4 to the plasma membrane via a SxIP-like motif expanded EB2's functional repertoire beyond cytoskeletal regulation to cargo-specific vesicular transport.\",\n      \"evidence\": \"Co-immunoprecipitation, SxIP motif mutagenesis of TRPM4, EB2 siRNA knockdown with subcellular localization, focal adhesion and invasion assays\",\n      \"pmids\": [\"31112396\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether EB2 delivers other SxIP-containing cargoes to the plasma membrane not tested\", \"Single-lab finding without independent replication\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of WDHD1-mediated ubiquitination and degradation of MAPRE2 in the nucleus, with consequences for cisplatin sensitivity, revealed a post-translational mechanism controlling MAPRE2 protein levels in cancer cells.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assay, MAPRE2 knockout cisplatin sensitivity readout, xenograft experiments in A549 lung adenocarcinoma cells\",\n      \"pmids\": [\"32426268\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific ubiquitin chain linkage type on MAPRE2 not characterized\", \"Nuclear function of MAPRE2 that would explain cisplatin sensitivity phenotype is undefined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified structural and biophysical model explaining how MAPRE2 phosphorylation, disease mutations, and partner interactions (HAX1, TRPM4) converge on microtubule dwell-time control is still lacking.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of MAPRE2 bound to microtubule plus ends or partner proteins\", \"In vivo tissue-specific functions beyond epithelium and craniofacial development largely unexplored\", \"The nuclear pool of MAPRE2 and its functional significance remain poorly defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 2, 3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 2, 3, 6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HAX1\", \"TRPM4\", \"WDHD1\", \"AURKB\", \"CDK1\"],\n    \"other_free_text\": []\n  }\n}\n```"}