{"gene":"MAP7","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1993,"finding":"E-MAP-115 (MAP7) was identified as a novel microtubule-associated protein of 115 kDa with nucleotide-insensitive binding to microtubules. Its microtubule-binding site was localized to a basic alpha-helical region in the NH2-terminal domain using in vitro microtubule-binding assays and expression of mutant polypeptides. Overexpression of this domain in fibroblasts rendered microtubules stable to nocodazole, identifying it as a microtubule-stabilizing protein.","method":"In vitro microtubule-binding assays, mutant polypeptide expression, nocodazole resistance assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding assay with domain mutants plus in vivo functional readout (nocodazole resistance), foundational paper replicated by subsequent work","pmids":["8408219"],"is_preprint":false},{"year":1995,"finding":"Binding of E-MAP-115 (MAP7) to microtubules is regulated by cell cycle-dependent phosphorylation. In mitotic HeLa cells, E-MAP-115 is hyperphosphorylated (~15-fold increase in 32P incorporation) specifically on threonine residues, and this hyperphosphorylated form cannot stably bind microtubules in vitro. The protein dissociates from microtubules in early prophase and progressively reassociates after late prophase, suggesting phosphorylation drives mitotic spindle assembly by releasing MAP7 from interphase microtubules.","method":"32P metabolic labeling, SDS-PAGE mobility shift, in vitro microtubule-binding assay with mitotic vs. interphase protein, immunolabeling across cell cycle stages","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical methods (radiolabeling, in vitro binding, immunofluorescence at cell cycle stages) in a single rigorous study","pmids":["7490279"],"is_preprint":false},{"year":1999,"finding":"E-MAP-115 (ensconsin/MAP7) associates dynamically with microtubule lattices immediately upon polymerization and dissociates concomitant with depolymerization in vivo, as shown by dual-wavelength time-lapse fluorescence imaging with GFP-EMTB chimeras. Cells expressing four to ten times the physiological level of MAP7 showed microtubule dynamics indistinguishable from untransfected cells, establishing that MAP7 at physiological levels is NOT a microtubule stabilizer in vivo.","method":"Dual-wavelength time-lapse fluorescence live imaging, stable GFP-EMTB chimera cell lines, microinjection with labeled tubulin","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct live-cell imaging with quantitative dynamics analysis, functional negative result robustly supported by multiple expression levels","pmids":["10564643"],"is_preprint":false},{"year":2000,"finding":"Genetic knockout of E-MAP-115 (MAP7) in mice causes male sterility due to deformation of spermatid nuclei and gradual loss of germ cells. Microtubule associations in the manchette of spermatids and in Sertoli cells were morphologically abnormal in null mice, establishing an essential in vivo role for MAP7 in microtubule organization required for spermatogenesis.","method":"Gene trap mutagenesis generating null allele, histological and morphological analysis of testes, immunolabeling of microtubule structures","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null in mice with specific cellular and structural phenotype, replicated by subsequent localization studies","pmids":["10837026"],"is_preprint":false},{"year":2017,"finding":"MAP7 is expressed at the onset of axon collateral branch formation in dorsal root ganglion (DRG) neurons, localizes to branch points colocalizing with stable microtubules, and its loss or overexpression alters axon branching. Domain analysis of a gain-of-function truncated MAP7 mutant mouse showed the amino-terminal half is responsible for branch formation independently of kinesin-1 interaction, establishing MAP7 as a regulator of axon collateral branch morphogenesis.","method":"shRNA knockdown, overexpression, domain truncation analysis, time-lapse imaging, spontaneous mutant mouse analysis, in vitro DRG culture branching assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple loss- and gain-of-function approaches in vitro and in vivo with defined phenotypic readouts and domain dissection","pmids":["28069923"],"is_preprint":false},{"year":2018,"finding":"MAP7 recruits kinesin-1 to microtubules via direct interaction, using a kinesin-1-binding domain distinct from its two microtubule-binding sites. The kinesin-1-interacting domain is required for axon and branch growth but not branch formation, while both microtubule-binding sites are required for branch formation. MAP7 localizes to branch sites and dynamically recruits kinesin-1, altering organelle transport behaviors (pause/speed switching).","method":"Structure-function analysis with domain deletions, live-cell imaging of organelle transport, co-immunoprecipitation, sensory neuron culture knockdown/overexpression","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain dissection with multiple mutants, live transport imaging, reciprocal functional rescue, multiple orthogonal methods in one study","pmids":["30132755"],"is_preprint":false},{"year":2018,"finding":"MAP7 and its paralog MAP7D1 bind Disheveled (Dvl), direct its cortical localization, and facilitate cortical targeting of microtubule plus-ends in response to Wnt5a signaling. Wnt5a signaling also promotes MAP7/7D1 movement toward MT plus-ends, and depletion of KIF5B (Kinesin-1) abolishes this MAP7/7D1 dynamics and Disheveled localization. This MAP7-Disheveled feedback loop and its role in Wnt5a signaling is evolutionarily conserved (shown also in Drosophila Ensconsin/Disheveled).","method":"Co-IP (MAP7/Dvl interaction), shRNA knockdown, live imaging, cortical localization assay, Drosophila genetic analysis","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional imaging in HeLa cells and Drosophila, single lab but multiple methods and cross-species validation","pmids":["29880710"],"is_preprint":false},{"year":2019,"finding":"MAP7 shifts organelle (phagosome) transport toward the microtubule plus-end (~80% plus-end directed vs. ~50% without MAP7) by increasing the binding rate of kinesin-1 to microtubules without altering the force of individual motors. For ensembles of kinesin-1, MAP7 leads to more simultaneously engaged motors generating force, thereby biasing transport direction.","method":"In vitro phagosome motility reconstitution, single-molecule imaging of kinesin-1, optical trapping force measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified organelles and motors, single-molecule imaging and force measurements, multiple orthogonal biophysical methods","pmids":["31085585"],"is_preprint":false},{"year":2019,"finding":"MAP7 prevents axon branch retraction by binding to the acetylated/stable region of individual microtubules while avoiding the dynamic plus-end, creating a boundary that prevents microtubule depolymerization and rescues polymerization. This boundary function maintains stable microtubules at branch junctions and can prevent branch retraction caused by laser-induced severing or nocodazole treatment.","method":"Live-cell imaging, MAP7 depletion (shRNA), laser-induced microtubule severing, single-microtubule dynamics analysis, colocalization with acetylated tubulin","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct live imaging of single microtubule dynamics plus laser severing experiments with functional branch retraction readout, multiple orthogonal approaches","pmids":["31391261"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM and single-molecule imaging revealed that the MAP7 microtubule-binding domain (MTBD) binds as an extended alpha-helix between the protofilament ridge and lateral contact site, partially overlapping with the kinesin-1 binding site, thereby inhibiting kinesin-1 motility when MTs are saturated with MAP7. However, the projection domain of MAP7 tethers kinesin-1 to the MT, preventing dissociation and facilitating binding to available neighboring sites, resulting in biphasic (concentration-dependent) regulation of kinesin-1 by MAP7.","method":"Cryo-electron microscopy, single-molecule imaging, structure determination of MAP7-MT complex","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with single-molecule functional imaging, multiple orthogonal methods revealing mechanistic detail","pmids":["35050657"],"is_preprint":false},{"year":2023,"finding":"MAP7 and MAP7D1 interact with several DNA double-strand break repair proteins including RAD50, BRCA1, and 53BP1 (identified by quantitative proteomics). Downregulation of MAP7 and MAP7D1 in G1-arrested cells impairs DNA repair, reduces RAD50 recruitment to chromatin, and disrupts 53BP1 localization to damage sites, establishing a novel function for MAP7 in DNA double-strand break repair in the G1 phase.","method":"Quantitative proteomics, Co-IP, shRNA knockdown, chromatin fractionation, immunofluorescence of repair foci, gamma-irradiation assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics interaction screen with functional follow-up (repair assays, chromatin recruitment), single lab, multiple methods","pmids":["36852271"],"is_preprint":false},{"year":2024,"finding":"MAP7 promotes tubulin acetylation and inhibits tubulin detyrosination, thereby modulating the tubulin code. These MAP7-driven tubulin PTM changes alter intracellular cargo transport, enabling cellular adaptation to osmotic stress. Human epithelial cells modulate MAP7 association with microtubules in response to changes in cytoplasmic density/osmolarity.","method":"Live-cell imaging, ex vivo enzymatic assays, in vitro reconstitution, quantification of tubulin PTMs under osmotic perturbation","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with enzymatic assays and live-cell imaging with multiple orthogonal methods in one study","pmids":["38574732"],"is_preprint":false},{"year":2024,"finding":"Solid-state and solution-state NMR combined with electron microscopy, fluorescence anisotropy, and isothermal titration calorimetry revealed that MAP7 MTBD binds the MT lattice through interactions extending beyond a single tubulin dimer and including interactions with tubulin C-terminal tails, establishing the atomic-level binding mode of MAP7 to microtubules.","method":"Solid-state and solution-state NMR, electron microscopy, fluorescence anisotropy, isothermal titration calorimetry","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple structural and biophysical methods (NMR, EM, calorimetry, anisotropy) providing atomic-level binding characterization","pmids":["38431715"],"is_preprint":false},{"year":2025,"finding":"MAP7 enhances kinesin-1 engagement with microtubules (increasing run length and MT recruitment) without significantly relieving kinesin-1 auto-inhibition, while BicD relieves auto-inhibition. The combination of BicD and MAP7 produces the most robust kinesin-1 activation, demonstrating complementary mechanisms where MAP7 enables activated kinesin-1 motors to productively engage microtubules.","method":"Single-molecule motility assays with purified Drosophila proteins, quantitative analysis of motor processivity and run length","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified proteins and single-molecule imaging, mechanistic dissection with multiple protein combinations","pmids":["40384341"],"is_preprint":false},{"year":2025,"finding":"Opening of the kinesin-1 heterotetrameric complex (transition from closed/autoinhibited to open state) facilitated by cargo SLiM binding to KLC TPR domains promotes binding to MAP7 on microtubules, establishing that MAP7 binding to kinesin-1 is allosterically coupled to the cargo-activated open conformation of the motor.","method":"Protein design, computational modelling, biophysical analysis, electron microscopy of kinesin-1 holoenzyme","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — structural EM and biophysical analysis of holoenzyme, preprint with multiple methods but not yet peer-reviewed","pmids":["bio_10.1101_2025.04.08.647705"],"is_preprint":true},{"year":2025,"finding":"MAP7 localizes preferentially to apical microtubules in Sertoli cells and MAP7-decorated microtubules become increasingly aligned along the tubule axis during apical domain maturation. In Map7-deficient testes, microtubule higher-order organization is disrupted with persistent luminal F-actin accumulation. Proteomic analysis identified non-muscle myosin II heavy chains MYH9 and MYH10 as MAP7-associated proteins, and MYH9 becomes enriched at luminal regions where microtubules and F-actin converge in a MAP7-dependent manner.","method":"Native-tissue imaging, conditional knockout, proteomics, single-cell RNA sequencing, immunofluorescence","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with structural and proteomic analysis, preprint with multiple methods but not yet peer-reviewed","pmids":["bio_10.1101_2025.09.16.676497"],"is_preprint":true},{"year":2020,"finding":"MAP7 interacts with RC3H1 (identified by Co-IP) in cervical cancer cells, and the two proteins cooperatively enhance cyclin D1/cyclin B1 expression and facilitate cell-cycle progression via activation of canonical IKK/NF-κB signaling (increased P-IKK and P-p65).","method":"Co-immunoprecipitation, knockdown of MAP7 and RC3H1, western blot for NF-κB pathway components, xenograft model","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP interaction, single lab, signaling assay without direct mechanistic dissection of how MAP7 activates NF-κB","pmids":["32446391"],"is_preprint":false},{"year":2025,"finding":"FBXW7 promotes K48-linked polyubiquitination of MAP7, destabilizing MAP7 protein, as demonstrated by stability analysis and immunoprecipitation assays. This FBXW7-MAP7 axis regulates malignant cell phenotypes and paclitaxel sensitivity in lung adenocarcinoma.","method":"Co-immunoprecipitation, protein stability assay, ubiquitination assay, knockdown/overexpression","journal":"European journal of medical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-based ubiquitination assay with stability analysis identifying specific ubiquitination site (K48), single lab","pmids":["41382187"],"is_preprint":false}],"current_model":"MAP7 (E-MAP-115/ensconsin) is a microtubule-associated protein whose N-terminal domain binds the MT lattice as an extended alpha-helix (partially overlapping the kinesin-1 binding site) while its C-terminal projection domain directly binds and recruits kinesin-1, creating biphasic regulation of kinesin-1 motility: at low MAP7 density the projection domain tethers kinesin-1 to MTs and enhances transport, while at high density the competitive MTBD inhibits kinesin-1; MT binding is regulated by cell cycle-dependent threonine phosphorylation (hyperphosphorylation in mitosis prevents MT binding); MAP7 additionally promotes tubulin acetylation and inhibits detyrosination (modulating the tubulin code), stabilizes microtubules at axon branch junctions by binding the acetylated lattice and excluding dynamic plus-ends, is essential for spermatogenesis (manchette and Sertoli cell microtubule organization), and participates in DNA double-strand break repair in G1 through interactions with RAD50, BRCA1, and 53BP1, with MAP7 protein stability itself regulated by FBXW7-mediated K48-linked polyubiquitination."},"narrative":{"mechanistic_narrative":"MAP7 (E-MAP-115/ensconsin) is a microtubule-associated protein that organizes the microtubule cytoskeleton and governs kinesin-1-based intracellular transport [PMID:8408219, PMID:30132755]. Its N-terminal microtubule-binding domain engages the MT lattice as an extended alpha-helix wedged between the protofilament ridge and the lateral contact site, with contacts extending beyond a single tubulin dimer and onto tubulin C-terminal tails [PMID:35050657, PMID:38431715]. A spatially distinct C-terminal projection domain directly binds kinesin-1 and recruits it to microtubules, producing biphasic control of motility: because the MTBD partially overlaps the kinesin-1 footprint, lattice saturation inhibits the motor, whereas at lower density the projection domain tethers kinesin-1 to the lattice, increases its binding rate and run length, and biases ensemble transport toward the plus-end without altering single-motor force [PMID:35050657, PMID:31085585, PMID:30132755]. MAP7 functions as a productive-engagement factor rather than a de-repressor of kinesin-1 autoinhibition, complementing activators such as BicD, and its kinesin-1 binding is coupled to the cargo-activated open conformation of the motor [PMID:40384341]. MAP7 also writes the tubulin code by promoting acetylation and inhibiting detyrosination, thereby tuning cargo transport and enabling adaptation to osmotic stress [PMID:38574732]. At axon collateral branch points it binds the acetylated/stable lattice while avoiding the dynamic plus-end, creating a boundary that prevents depolymerization and branch retraction; its N-terminal microtubule-binding activity drives branch formation while the kinesin-1-binding domain supports branch and axon growth [PMID:28069923, PMID:30132755, PMID:31391261]. MT binding is switched off by cell cycle-dependent threonine hyperphosphorylation in mitosis, releasing MAP7 from interphase microtubules [PMID:7490279]. Genetic loss of MAP7 in mice causes male sterility through disorganized manchette and Sertoli-cell microtubules during spermatogenesis [PMID:10837026]. Beyond its core cytoskeletal role, MAP7 participates in G1-phase DNA double-strand break repair through interactions with RAD50, BRCA1, and 53BP1 [PMID:36852271], and its protein stability is controlled by FBXW7-mediated K48-linked polyubiquitination [PMID:41382187].","teleology":[{"year":1993,"claim":"Established MAP7 as a microtubule-binding protein and mapped its activity to a basic N-terminal alpha-helical domain capable of stabilizing microtubules.","evidence":"In vitro MT-binding assays with domain mutants plus nocodazole-resistance readout in fibroblasts","pmids":["8408219"],"confidence":"High","gaps":["Atomic binding mode unresolved","Whether stabilization reflects physiological function unclear"]},{"year":1995,"claim":"Showed MT binding is regulated by the cell cycle, defining mitotic threonine hyperphosphorylation as a switch that releases MAP7 from microtubules.","evidence":"32P metabolic labeling, mobility shift, in vitro binding of mitotic vs interphase protein, cell-cycle immunolabeling in HeLa cells","pmids":["7490279"],"confidence":"High","gaps":["Responsible kinase(s) not identified","Specific phosphorylated residues not mapped"]},{"year":1999,"claim":"Live imaging at physiological levels overturned the simple stabilizer model, showing MAP7 tracks lattice polymerization/depolymerization without altering dynamics in vivo.","evidence":"Dual-wavelength time-lapse imaging of GFP-EMTB chimeras across expression levels","pmids":["10564643"],"confidence":"High","gaps":["Did not define the in vivo function that replaces stabilization","No partner identified"]},{"year":2000,"claim":"Genetic knockout assigned an essential in vivo role, linking MAP7 to microtubule organization required for spermatogenesis.","evidence":"Gene-trap null mouse with testis histology and microtubule immunolabeling","pmids":["10837026"],"confidence":"High","gaps":["Molecular basis of manchette/Sertoli defect not dissected","No interacting partners identified at this stage"]},{"year":2017,"claim":"Identified MAP7 as a regulator of axon collateral branching, with the N-terminal half driving branch formation independently of kinesin-1.","evidence":"shRNA, overexpression, domain truncation, time-lapse imaging and mutant mouse in DRG neurons","pmids":["28069923"],"confidence":"High","gaps":["Mechanism by which N-terminus nucleates branches unclear","Relationship to tubulin PTMs not addressed"]},{"year":2018,"claim":"Defined MAP7 as a kinesin-1 recruiter, separating a kinesin-1-binding domain (needed for axon/branch growth and organelle transport) from MT-binding sites (needed for branch formation).","evidence":"Domain deletions, Co-IP, live organelle transport imaging in sensory neurons","pmids":["30132755"],"confidence":"High","gaps":["Did not resolve structural overlap between MAP7 and kinesin-1 sites","Quantitative effect on motor engagement not measured"]},{"year":2018,"claim":"Connected MAP7/MAP7D1 to Wnt5a signaling via Disheveled cortical targeting in a kinesin-1-dependent, evolutionarily conserved feedback loop.","evidence":"Co-IP, shRNA, live imaging, KIF5B depletion, Drosophila genetics","pmids":["29880710"],"confidence":"Medium","gaps":["Single-lab interaction data","Direct vs indirect MAP7-Dvl binding not fully resolved"]},{"year":2019,"claim":"Quantified the transport mechanism, showing MAP7 biases plus-end-directed motility by increasing kinesin-1 binding rate and engaged motor number rather than per-motor force.","evidence":"In vitro phagosome reconstitution, single-molecule imaging, optical trapping","pmids":["31085585"],"confidence":"High","gaps":["Did not address concentration-dependent inhibition","Structural basis of recruitment not shown"]},{"year":2019,"claim":"Explained branch stability mechanistically: MAP7 binds the acetylated/stable lattice and excludes the dynamic plus-end to form a boundary preventing depolymerization and retraction.","evidence":"Live single-MT imaging, laser severing, shRNA depletion, acetylated-tubulin colocalization","pmids":["31391261"],"confidence":"High","gaps":["Whether acetylation recruits MAP7 or vice versa unresolved","In vivo branch-stability requirement not tested"]},{"year":2022,"claim":"Cryo-EM resolved the binding mode and reconciled opposing transport effects into a biphasic model: MTBD overlaps the kinesin-1 site (inhibition when saturated) while the projection domain tethers kinesin-1 (enhancement at low density).","evidence":"Cryo-EM structure of MAP7-MT complex plus single-molecule imaging","pmids":["35050657"],"confidence":"High","gaps":["Conformational coupling to kinesin-1 activation state not addressed here","Role of tubulin tails not resolved"]},{"year":2023,"claim":"Extended MAP7 function beyond the cytoskeleton, implicating it in G1 DNA double-strand break repair through interactions with RAD50, BRCA1 and 53BP1.","evidence":"Quantitative proteomics, Co-IP, chromatin fractionation, repair-foci IF, gamma-irradiation in G1-arrested cells","pmids":["36852271"],"confidence":"Medium","gaps":["Direct vs indirect interactions not separated","Mechanism linking MT-binding to chromatin repair unclear","Single-lab finding"]},{"year":2024,"claim":"Defined MAP7 as a tubulin-code modulator that promotes acetylation and inhibits detyrosination to tune transport and osmotic-stress adaptation.","evidence":"In vitro reconstitution with enzymatic assays and live-cell imaging under osmotic perturbation","pmids":["38574732"],"confidence":"High","gaps":["Whether MAP7 directly recruits modifying enzymes not established","Acetylase/detyrosinase partners not identified"]},{"year":2024,"claim":"Provided atomic-level detail of lattice engagement, showing MAP7 MTBD contacts span beyond one tubulin dimer and include tubulin C-terminal tails.","evidence":"Solid- and solution-state NMR, EM, fluorescence anisotropy, ITC","pmids":["38431715"],"confidence":"High","gaps":["Functional consequence of tail contacts for transport untested","Phosphoregulation of this interface not mapped"]},{"year":2025,"claim":"Clarified MAP7's role relative to autoinhibition: it enhances productive kinesin-1 engagement (run length, MT recruitment) without relieving autoinhibition, acting complementarily to BicD.","evidence":"Single-molecule motility assays with purified Drosophila proteins","pmids":["40384341"],"confidence":"High","gaps":["Mammalian motor combinations not tested","In vivo coordination of BicD and MAP7 unknown"]},{"year":2025,"claim":"Linked MAP7 binding to the cargo-activated open conformation of kinesin-1, indicating allosteric coupling between motor activation and MAP7 engagement.","evidence":"Protein design, computational modelling, biophysics and EM of kinesin-1 holoenzyme (preprint)","pmids":["bio_10.1101_2025.04.08.647705"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Structural state of MAP7-bound open motor not directly resolved"]},{"year":2025,"claim":"Refined the spermatogenesis mechanism, showing MAP7 aligns apical Sertoli-cell microtubules and associates with non-muscle myosin II (MYH9/MYH10) to coordinate MT and F-actin.","evidence":"Conditional knockout, native-tissue imaging, proteomics, scRNA-seq (preprint)","pmids":["bio_10.1101_2025.09.16.676497"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Direct MAP7-myosin binding vs co-recruitment unresolved"]},{"year":2025,"claim":"Identified post-translational control of MAP7 abundance through FBXW7-mediated K48 polyubiquitination affecting tumor phenotypes and paclitaxel sensitivity.","evidence":"Co-IP, protein stability and ubiquitination assays, knockdown/overexpression in lung adenocarcinoma","pmids":["41382187"],"confidence":"Medium","gaps":["Degron site on MAP7 not mapped","Single-lab finding"]},{"year":null,"claim":"How MAP7's cytoskeletal, transport, tubulin-code, signaling, and DNA-repair activities are integrated in a single cell, and which kinase enforces its mitotic phosphoregulation, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["Mitotic kinase for threonine hyperphosphorylation unidentified","Mechanistic basis of the non-cytoskeletal DNA-repair role unclear","Whether tubulin-PTM modulation is direct enzymatic recruitment unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,9,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,7,9,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,6]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,2,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[5,7,13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,8]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[10]}],"complexes":[],"partners":["KIF5B","RAD50","BRCA1","53BP1","DVL","MAP7D1","MYH9","FBXW7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14244","full_name":"Ensconsin","aliases":["Epithelial microtubule-associated protein of 115 kDa","E-MAP-115","Microtubule-associated protein 7","MAP-7"],"length_aa":749,"mass_kda":84.1,"function":"Microtubule-stabilizing protein that may play an important role during reorganization of microtubules during polarization and differentiation of epithelial cells. Associates with microtubules in a dynamic manner. May play a role in the formation of intercellular contacts. Colocalization with TRPV4 results in the redistribution of TRPV4 toward the membrane and may link cytoskeletal microfilaments","subcellular_location":"Cytoplasm, perinuclear region; Basolateral cell membrane; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q14244/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAP7","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PSME3","stoichiometry":0.2},{"gene":"TUBB4B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MAP7","total_profiled":1310},"omim":[{"mim_id":"621363","title":"MAP7 DOMAIN-CONTAINING PROTEIN 1; MAP7D1","url":"https://www.omim.org/entry/621363"},{"mim_id":"604108","title":"MICROTUBULE-ASSOCIATED PROTEIN 7; MAP7","url":"https://www.omim.org/entry/604108"},{"mim_id":"602809","title":"KINESIN FAMILY MEMBER 5B; KIF5B","url":"https://www.omim.org/entry/602809"},{"mim_id":"301121","title":"MAP7 DOMAIN-CONTAINING PROTEIN 2; MAP7D2","url":"https://www.omim.org/entry/301121"},{"mim_id":"300930","title":"MAP7 DOMAIN-CONTAINING PROTEIN 3; MAP7D3","url":"https://www.omim.org/entry/300930"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Microtubules","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":85.6}],"url":"https://www.proteinatlas.org/search/MAP7"},"hgnc":{"alias_symbol":["E-MAP-115"],"prev_symbol":[]},"alphafold":{"accession":"Q14244","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14244","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14244-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14244-F1-predicted_aligned_error_v6.png","plddt_mean":60.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAP7","jax_strain_url":"https://www.jax.org/strain/search?query=MAP7"},"sequence":{"accession":"Q14244","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14244.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14244/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14244"}},"corpus_meta":[{"pmid":"10564643","id":"PMC_10564643","title":"E-MAP-115 (ensconsin) associates dynamically with microtubules in vivo and is not a physiological modulator of microtubule dynamics.","date":"1999","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/10564643","citation_count":113,"is_preprint":false},{"pmid":"8408219","id":"PMC_8408219","title":"Identification and molecular characterization of E-MAP-115, a novel microtubule-associated protein predominantly expressed in epithelial cells.","date":"1993","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/8408219","citation_count":96,"is_preprint":false},{"pmid":"35050657","id":"PMC_35050657","title":"Structural and functional insight into regulation of kinesin-1 by microtubule-associated protein MAP7.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35050657","citation_count":81,"is_preprint":false},{"pmid":"10837026","id":"PMC_10837026","title":"E-MAP-115, encoding a microtubule-associated protein, is a retinoic acid-inducible gene required for spermatogenesis.","date":"2000","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/10837026","citation_count":62,"is_preprint":false},{"pmid":"30132755","id":"PMC_30132755","title":"MAP7 regulates axon morphogenesis by recruiting kinesin-1 to microtubules and modulating organelle transport.","date":"2018","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/30132755","citation_count":56,"is_preprint":false},{"pmid":"7490279","id":"PMC_7490279","title":"Binding of E-MAP-115 to microtubules is regulated by cell cycle-dependent phosphorylation.","date":"1995","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/7490279","citation_count":54,"is_preprint":false},{"pmid":"31085585","id":"PMC_31085585","title":"MAP7 regulates organelle transport by recruiting kinesin-1 to microtubules.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31085585","citation_count":50,"is_preprint":false},{"pmid":"28069923","id":"PMC_28069923","title":"MAP7 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Its microtubule-binding site was localized to a basic alpha-helical region in the NH2-terminal domain using in vitro microtubule-binding assays and expression of mutant polypeptides. Overexpression of this domain in fibroblasts rendered microtubules stable to nocodazole, identifying it as a microtubule-stabilizing protein.\",\n      \"method\": \"In vitro microtubule-binding assays, mutant polypeptide expression, nocodazole resistance assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding assay with domain mutants plus in vivo functional readout (nocodazole resistance), foundational paper replicated by subsequent work\",\n      \"pmids\": [\"8408219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Binding of E-MAP-115 (MAP7) to microtubules is regulated by cell cycle-dependent phosphorylation. In mitotic HeLa cells, E-MAP-115 is hyperphosphorylated (~15-fold increase in 32P incorporation) specifically on threonine residues, and this hyperphosphorylated form cannot stably bind microtubules in vitro. The protein dissociates from microtubules in early prophase and progressively reassociates after late prophase, suggesting phosphorylation drives mitotic spindle assembly by releasing MAP7 from interphase microtubules.\",\n      \"method\": \"32P metabolic labeling, SDS-PAGE mobility shift, in vitro microtubule-binding assay with mitotic vs. interphase protein, immunolabeling across cell cycle stages\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical methods (radiolabeling, in vitro binding, immunofluorescence at cell cycle stages) in a single rigorous study\",\n      \"pmids\": [\"7490279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"E-MAP-115 (ensconsin/MAP7) associates dynamically with microtubule lattices immediately upon polymerization and dissociates concomitant with depolymerization in vivo, as shown by dual-wavelength time-lapse fluorescence imaging with GFP-EMTB chimeras. Cells expressing four to ten times the physiological level of MAP7 showed microtubule dynamics indistinguishable from untransfected cells, establishing that MAP7 at physiological levels is NOT a microtubule stabilizer in vivo.\",\n      \"method\": \"Dual-wavelength time-lapse fluorescence live imaging, stable GFP-EMTB chimera cell lines, microinjection with labeled tubulin\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct live-cell imaging with quantitative dynamics analysis, functional negative result robustly supported by multiple expression levels\",\n      \"pmids\": [\"10564643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Genetic knockout of E-MAP-115 (MAP7) in mice causes male sterility due to deformation of spermatid nuclei and gradual loss of germ cells. Microtubule associations in the manchette of spermatids and in Sertoli cells were morphologically abnormal in null mice, establishing an essential in vivo role for MAP7 in microtubule organization required for spermatogenesis.\",\n      \"method\": \"Gene trap mutagenesis generating null allele, histological and morphological analysis of testes, immunolabeling of microtubule structures\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null in mice with specific cellular and structural phenotype, replicated by subsequent localization studies\",\n      \"pmids\": [\"10837026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MAP7 is expressed at the onset of axon collateral branch formation in dorsal root ganglion (DRG) neurons, localizes to branch points colocalizing with stable microtubules, and its loss or overexpression alters axon branching. Domain analysis of a gain-of-function truncated MAP7 mutant mouse showed the amino-terminal half is responsible for branch formation independently of kinesin-1 interaction, establishing MAP7 as a regulator of axon collateral branch morphogenesis.\",\n      \"method\": \"shRNA knockdown, overexpression, domain truncation analysis, time-lapse imaging, spontaneous mutant mouse analysis, in vitro DRG culture branching assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple loss- and gain-of-function approaches in vitro and in vivo with defined phenotypic readouts and domain dissection\",\n      \"pmids\": [\"28069923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MAP7 recruits kinesin-1 to microtubules via direct interaction, using a kinesin-1-binding domain distinct from its two microtubule-binding sites. The kinesin-1-interacting domain is required for axon and branch growth but not branch formation, while both microtubule-binding sites are required for branch formation. MAP7 localizes to branch sites and dynamically recruits kinesin-1, altering organelle transport behaviors (pause/speed switching).\",\n      \"method\": \"Structure-function analysis with domain deletions, live-cell imaging of organelle transport, co-immunoprecipitation, sensory neuron culture knockdown/overexpression\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain dissection with multiple mutants, live transport imaging, reciprocal functional rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"30132755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MAP7 and its paralog MAP7D1 bind Disheveled (Dvl), direct its cortical localization, and facilitate cortical targeting of microtubule plus-ends in response to Wnt5a signaling. Wnt5a signaling also promotes MAP7/7D1 movement toward MT plus-ends, and depletion of KIF5B (Kinesin-1) abolishes this MAP7/7D1 dynamics and Disheveled localization. This MAP7-Disheveled feedback loop and its role in Wnt5a signaling is evolutionarily conserved (shown also in Drosophila Ensconsin/Disheveled).\",\n      \"method\": \"Co-IP (MAP7/Dvl interaction), shRNA knockdown, live imaging, cortical localization assay, Drosophila genetic analysis\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional imaging in HeLa cells and Drosophila, single lab but multiple methods and cross-species validation\",\n      \"pmids\": [\"29880710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAP7 shifts organelle (phagosome) transport toward the microtubule plus-end (~80% plus-end directed vs. ~50% without MAP7) by increasing the binding rate of kinesin-1 to microtubules without altering the force of individual motors. For ensembles of kinesin-1, MAP7 leads to more simultaneously engaged motors generating force, thereby biasing transport direction.\",\n      \"method\": \"In vitro phagosome motility reconstitution, single-molecule imaging of kinesin-1, optical trapping force measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified organelles and motors, single-molecule imaging and force measurements, multiple orthogonal biophysical methods\",\n      \"pmids\": [\"31085585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAP7 prevents axon branch retraction by binding to the acetylated/stable region of individual microtubules while avoiding the dynamic plus-end, creating a boundary that prevents microtubule depolymerization and rescues polymerization. This boundary function maintains stable microtubules at branch junctions and can prevent branch retraction caused by laser-induced severing or nocodazole treatment.\",\n      \"method\": \"Live-cell imaging, MAP7 depletion (shRNA), laser-induced microtubule severing, single-microtubule dynamics analysis, colocalization with acetylated tubulin\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct live imaging of single microtubule dynamics plus laser severing experiments with functional branch retraction readout, multiple orthogonal approaches\",\n      \"pmids\": [\"31391261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM and single-molecule imaging revealed that the MAP7 microtubule-binding domain (MTBD) binds as an extended alpha-helix between the protofilament ridge and lateral contact site, partially overlapping with the kinesin-1 binding site, thereby inhibiting kinesin-1 motility when MTs are saturated with MAP7. However, the projection domain of MAP7 tethers kinesin-1 to the MT, preventing dissociation and facilitating binding to available neighboring sites, resulting in biphasic (concentration-dependent) regulation of kinesin-1 by MAP7.\",\n      \"method\": \"Cryo-electron microscopy, single-molecule imaging, structure determination of MAP7-MT complex\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with single-molecule functional imaging, multiple orthogonal methods revealing mechanistic detail\",\n      \"pmids\": [\"35050657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MAP7 and MAP7D1 interact with several DNA double-strand break repair proteins including RAD50, BRCA1, and 53BP1 (identified by quantitative proteomics). Downregulation of MAP7 and MAP7D1 in G1-arrested cells impairs DNA repair, reduces RAD50 recruitment to chromatin, and disrupts 53BP1 localization to damage sites, establishing a novel function for MAP7 in DNA double-strand break repair in the G1 phase.\",\n      \"method\": \"Quantitative proteomics, Co-IP, shRNA knockdown, chromatin fractionation, immunofluorescence of repair foci, gamma-irradiation assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics interaction screen with functional follow-up (repair assays, chromatin recruitment), single lab, multiple methods\",\n      \"pmids\": [\"36852271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MAP7 promotes tubulin acetylation and inhibits tubulin detyrosination, thereby modulating the tubulin code. These MAP7-driven tubulin PTM changes alter intracellular cargo transport, enabling cellular adaptation to osmotic stress. Human epithelial cells modulate MAP7 association with microtubules in response to changes in cytoplasmic density/osmolarity.\",\n      \"method\": \"Live-cell imaging, ex vivo enzymatic assays, in vitro reconstitution, quantification of tubulin PTMs under osmotic perturbation\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with enzymatic assays and live-cell imaging with multiple orthogonal methods in one study\",\n      \"pmids\": [\"38574732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Solid-state and solution-state NMR combined with electron microscopy, fluorescence anisotropy, and isothermal titration calorimetry revealed that MAP7 MTBD binds the MT lattice through interactions extending beyond a single tubulin dimer and including interactions with tubulin C-terminal tails, establishing the atomic-level binding mode of MAP7 to microtubules.\",\n      \"method\": \"Solid-state and solution-state NMR, electron microscopy, fluorescence anisotropy, isothermal titration calorimetry\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple structural and biophysical methods (NMR, EM, calorimetry, anisotropy) providing atomic-level binding characterization\",\n      \"pmids\": [\"38431715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MAP7 enhances kinesin-1 engagement with microtubules (increasing run length and MT recruitment) without significantly relieving kinesin-1 auto-inhibition, while BicD relieves auto-inhibition. The combination of BicD and MAP7 produces the most robust kinesin-1 activation, demonstrating complementary mechanisms where MAP7 enables activated kinesin-1 motors to productively engage microtubules.\",\n      \"method\": \"Single-molecule motility assays with purified Drosophila proteins, quantitative analysis of motor processivity and run length\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified proteins and single-molecule imaging, mechanistic dissection with multiple protein combinations\",\n      \"pmids\": [\"40384341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Opening of the kinesin-1 heterotetrameric complex (transition from closed/autoinhibited to open state) facilitated by cargo SLiM binding to KLC TPR domains promotes binding to MAP7 on microtubules, establishing that MAP7 binding to kinesin-1 is allosterically coupled to the cargo-activated open conformation of the motor.\",\n      \"method\": \"Protein design, computational modelling, biophysical analysis, electron microscopy of kinesin-1 holoenzyme\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural EM and biophysical analysis of holoenzyme, preprint with multiple methods but not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.04.08.647705\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MAP7 localizes preferentially to apical microtubules in Sertoli cells and MAP7-decorated microtubules become increasingly aligned along the tubule axis during apical domain maturation. In Map7-deficient testes, microtubule higher-order organization is disrupted with persistent luminal F-actin accumulation. Proteomic analysis identified non-muscle myosin II heavy chains MYH9 and MYH10 as MAP7-associated proteins, and MYH9 becomes enriched at luminal regions where microtubules and F-actin converge in a MAP7-dependent manner.\",\n      \"method\": \"Native-tissue imaging, conditional knockout, proteomics, single-cell RNA sequencing, immunofluorescence\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with structural and proteomic analysis, preprint with multiple methods but not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.09.16.676497\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MAP7 interacts with RC3H1 (identified by Co-IP) in cervical cancer cells, and the two proteins cooperatively enhance cyclin D1/cyclin B1 expression and facilitate cell-cycle progression via activation of canonical IKK/NF-κB signaling (increased P-IKK and P-p65).\",\n      \"method\": \"Co-immunoprecipitation, knockdown of MAP7 and RC3H1, western blot for NF-κB pathway components, xenograft model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP interaction, single lab, signaling assay without direct mechanistic dissection of how MAP7 activates NF-κB\",\n      \"pmids\": [\"32446391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXW7 promotes K48-linked polyubiquitination of MAP7, destabilizing MAP7 protein, as demonstrated by stability analysis and immunoprecipitation assays. This FBXW7-MAP7 axis regulates malignant cell phenotypes and paclitaxel sensitivity in lung adenocarcinoma.\",\n      \"method\": \"Co-immunoprecipitation, protein stability assay, ubiquitination assay, knockdown/overexpression\",\n      \"journal\": \"European journal of medical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-based ubiquitination assay with stability analysis identifying specific ubiquitination site (K48), single lab\",\n      \"pmids\": [\"41382187\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAP7 (E-MAP-115/ensconsin) is a microtubule-associated protein whose N-terminal domain binds the MT lattice as an extended alpha-helix (partially overlapping the kinesin-1 binding site) while its C-terminal projection domain directly binds and recruits kinesin-1, creating biphasic regulation of kinesin-1 motility: at low MAP7 density the projection domain tethers kinesin-1 to MTs and enhances transport, while at high density the competitive MTBD inhibits kinesin-1; MT binding is regulated by cell cycle-dependent threonine phosphorylation (hyperphosphorylation in mitosis prevents MT binding); MAP7 additionally promotes tubulin acetylation and inhibits detyrosination (modulating the tubulin code), stabilizes microtubules at axon branch junctions by binding the acetylated lattice and excluding dynamic plus-ends, is essential for spermatogenesis (manchette and Sertoli cell microtubule organization), and participates in DNA double-strand break repair in G1 through interactions with RAD50, BRCA1, and 53BP1, with MAP7 protein stability itself regulated by FBXW7-mediated K48-linked polyubiquitination.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAP7 (E-MAP-115/ensconsin) is a microtubule-associated protein that organizes the microtubule cytoskeleton and governs kinesin-1-based intracellular transport [#0, #5]. Its N-terminal microtubule-binding domain engages the MT lattice as an extended alpha-helix wedged between the protofilament ridge and the lateral contact site, with contacts extending beyond a single tubulin dimer and onto tubulin C-terminal tails [#9, #12]. A spatially distinct C-terminal projection domain directly binds kinesin-1 and recruits it to microtubules, producing biphasic control of motility: because the MTBD partially overlaps the kinesin-1 footprint, lattice saturation inhibits the motor, whereas at lower density the projection domain tethers kinesin-1 to the lattice, increases its binding rate and run length, and biases ensemble transport toward the plus-end without altering single-motor force [#9, #7, #5]. MAP7 functions as a productive-engagement factor rather than a de-repressor of kinesin-1 autoinhibition, complementing activators such as BicD, and its kinesin-1 binding is coupled to the cargo-activated open conformation of the motor [#13]. MAP7 also writes the tubulin code by promoting acetylation and inhibiting detyrosination, thereby tuning cargo transport and enabling adaptation to osmotic stress [#11]. At axon collateral branch points it binds the acetylated/stable lattice while avoiding the dynamic plus-end, creating a boundary that prevents depolymerization and branch retraction; its N-terminal microtubule-binding activity drives branch formation while the kinesin-1-binding domain supports branch and axon growth [#4, #5, #8]. MT binding is switched off by cell cycle-dependent threonine hyperphosphorylation in mitosis, releasing MAP7 from interphase microtubules [#1]. Genetic loss of MAP7 in mice causes male sterility through disorganized manchette and Sertoli-cell microtubules during spermatogenesis [#3]. Beyond its core cytoskeletal role, MAP7 participates in G1-phase DNA double-strand break repair through interactions with RAD50, BRCA1, and 53BP1 [#10], and its protein stability is controlled by FBXW7-mediated K48-linked polyubiquitination [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established MAP7 as a microtubule-binding protein and mapped its activity to a basic N-terminal alpha-helical domain capable of stabilizing microtubules.\",\n      \"evidence\": \"In vitro MT-binding assays with domain mutants plus nocodazole-resistance readout in fibroblasts\",\n      \"pmids\": [\"8408219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic binding mode unresolved\", \"Whether stabilization reflects physiological function unclear\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Showed MT binding is regulated by the cell cycle, defining mitotic threonine hyperphosphorylation as a switch that releases MAP7 from microtubules.\",\n      \"evidence\": \"32P metabolic labeling, mobility shift, in vitro binding of mitotic vs interphase protein, cell-cycle immunolabeling in HeLa cells\",\n      \"pmids\": [\"7490279\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Responsible kinase(s) not identified\", \"Specific phosphorylated residues not mapped\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Live imaging at physiological levels overturned the simple stabilizer model, showing MAP7 tracks lattice polymerization/depolymerization without altering dynamics in vivo.\",\n      \"evidence\": \"Dual-wavelength time-lapse imaging of GFP-EMTB chimeras across expression levels\",\n      \"pmids\": [\"10564643\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the in vivo function that replaces stabilization\", \"No partner identified\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Genetic knockout assigned an essential in vivo role, linking MAP7 to microtubule organization required for spermatogenesis.\",\n      \"evidence\": \"Gene-trap null mouse with testis histology and microtubule immunolabeling\",\n      \"pmids\": [\"10837026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of manchette/Sertoli defect not dissected\", \"No interacting partners identified at this stage\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified MAP7 as a regulator of axon collateral branching, with the N-terminal half driving branch formation independently of kinesin-1.\",\n      \"evidence\": \"shRNA, overexpression, domain truncation, time-lapse imaging and mutant mouse in DRG neurons\",\n      \"pmids\": [\"28069923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which N-terminus nucleates branches unclear\", \"Relationship to tubulin PTMs not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined MAP7 as a kinesin-1 recruiter, separating a kinesin-1-binding domain (needed for axon/branch growth and organelle transport) from MT-binding sites (needed for branch formation).\",\n      \"evidence\": \"Domain deletions, Co-IP, live organelle transport imaging in sensory neurons\",\n      \"pmids\": [\"30132755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve structural overlap between MAP7 and kinesin-1 sites\", \"Quantitative effect on motor engagement not measured\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected MAP7/MAP7D1 to Wnt5a signaling via Disheveled cortical targeting in a kinesin-1-dependent, evolutionarily conserved feedback loop.\",\n      \"evidence\": \"Co-IP, shRNA, live imaging, KIF5B depletion, Drosophila genetics\",\n      \"pmids\": [\"29880710\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab interaction data\", \"Direct vs indirect MAP7-Dvl binding not fully resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Quantified the transport mechanism, showing MAP7 biases plus-end-directed motility by increasing kinesin-1 binding rate and engaged motor number rather than per-motor force.\",\n      \"evidence\": \"In vitro phagosome reconstitution, single-molecule imaging, optical trapping\",\n      \"pmids\": [\"31085585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address concentration-dependent inhibition\", \"Structural basis of recruitment not shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Explained branch stability mechanistically: MAP7 binds the acetylated/stable lattice and excludes the dynamic plus-end to form a boundary preventing depolymerization and retraction.\",\n      \"evidence\": \"Live single-MT imaging, laser severing, shRNA depletion, acetylated-tubulin colocalization\",\n      \"pmids\": [\"31391261\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether acetylation recruits MAP7 or vice versa unresolved\", \"In vivo branch-stability requirement not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Cryo-EM resolved the binding mode and reconciled opposing transport effects into a biphasic model: MTBD overlaps the kinesin-1 site (inhibition when saturated) while the projection domain tethers kinesin-1 (enhancement at low density).\",\n      \"evidence\": \"Cryo-EM structure of MAP7-MT complex plus single-molecule imaging\",\n      \"pmids\": [\"35050657\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational coupling to kinesin-1 activation state not addressed here\", \"Role of tubulin tails not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended MAP7 function beyond the cytoskeleton, implicating it in G1 DNA double-strand break repair through interactions with RAD50, BRCA1 and 53BP1.\",\n      \"evidence\": \"Quantitative proteomics, Co-IP, chromatin fractionation, repair-foci IF, gamma-irradiation in G1-arrested cells\",\n      \"pmids\": [\"36852271\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect interactions not separated\", \"Mechanism linking MT-binding to chromatin repair unclear\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined MAP7 as a tubulin-code modulator that promotes acetylation and inhibits detyrosination to tune transport and osmotic-stress adaptation.\",\n      \"evidence\": \"In vitro reconstitution with enzymatic assays and live-cell imaging under osmotic perturbation\",\n      \"pmids\": [\"38574732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MAP7 directly recruits modifying enzymes not established\", \"Acetylase/detyrosinase partners not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided atomic-level detail of lattice engagement, showing MAP7 MTBD contacts span beyond one tubulin dimer and include tubulin C-terminal tails.\",\n      \"evidence\": \"Solid- and solution-state NMR, EM, fluorescence anisotropy, ITC\",\n      \"pmids\": [\"38431715\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of tail contacts for transport untested\", \"Phosphoregulation of this interface not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Clarified MAP7's role relative to autoinhibition: it enhances productive kinesin-1 engagement (run length, MT recruitment) without relieving autoinhibition, acting complementarily to BicD.\",\n      \"evidence\": \"Single-molecule motility assays with purified Drosophila proteins\",\n      \"pmids\": [\"40384341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian motor combinations not tested\", \"In vivo coordination of BicD and MAP7 unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked MAP7 binding to the cargo-activated open conformation of kinesin-1, indicating allosteric coupling between motor activation and MAP7 engagement.\",\n      \"evidence\": \"Protein design, computational modelling, biophysics and EM of kinesin-1 holoenzyme (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.04.08.647705\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Structural state of MAP7-bound open motor not directly resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Refined the spermatogenesis mechanism, showing MAP7 aligns apical Sertoli-cell microtubules and associates with non-muscle myosin II (MYH9/MYH10) to coordinate MT and F-actin.\",\n      \"evidence\": \"Conditional knockout, native-tissue imaging, proteomics, scRNA-seq (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.09.16.676497\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Direct MAP7-myosin binding vs co-recruitment unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified post-translational control of MAP7 abundance through FBXW7-mediated K48 polyubiquitination affecting tumor phenotypes and paclitaxel sensitivity.\",\n      \"evidence\": \"Co-IP, protein stability and ubiquitination assays, knockdown/overexpression in lung adenocarcinoma\",\n      \"pmids\": [\"41382187\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degron site on MAP7 not mapped\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MAP7's cytoskeletal, transport, tubulin-code, signaling, and DNA-repair activities are integrated in a single cell, and which kinase enforces its mitotic phosphoregulation, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mitotic kinase for threonine hyperphosphorylation unidentified\", \"Mechanistic basis of the non-cytoskeletal DNA-repair role unclear\", \"Whether tubulin-PTM modulation is direct enzymatic recruitment unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 9, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 7, 9, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [5, 7, 13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KIF5B\", \"RAD50\", \"BRCA1\", \"53BP1\", \"DVL\", \"MAP7D1\", \"MYH9\", \"FBXW7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}