MAP7D1

MAP7D1 is a microtubule-associated protein that stabilizes specialized microtubule subpopulations and organizes kinesin-1-dependent transport along them [PMID:35470240, PMID:bio_10.1101_2025.10.07.680844]. It is required for maintenance of acetylated, stable microtubules through a mechanism distinct from its paralog MAP7D2, and a microtubule-binding-domain mutation (R201W) that abolishes microtubule association reduces microtubule density and produces mitotic defects including unstable spindles, lagging chromosomes, and shortened inter-centrosomal distance, establishing its role in spindle integrity (PMID:35470240, PMID:40856631). MAP7D1 partitions selectively onto detyrosinated microtubules to create tracks for kinesin-1 (KIF5B), and its microtubule density is tuned by nutrient state to control lysosome positioning—high density during starvation drives perinuclear clustering, while reduced density permits peripheral lysosome migration [PMID:bio_10.1101_2025.10.07.680844]. In neurons, DCLK1 directly phosphorylates MAP7D1 at Ser315 to promote callosal axon elongation (PMID:27503845), and MAP7D1 binds Disheveled to direct its cortical localization and couple microtubule plus-end targeting to Wnt5a signaling in a KIF5B-dependent feedback loop (PMID:29880710). Beyond cytoskeletal roles, MAP7D1 interacts with the DNA double-strand break repair factors RAD50, BRCA1, and 53BP1 and supports G1-phase repair by promoting RAD50 chromatin recruitment and 53BP1 focus formation (PMID:36852271), and it localizes to sarcomeres where its loss exacerbates doxorubicin-induced cardiomyopathy through impaired autophagic clearance and protein aggregation (PMID:34327238).

1. 2016 High

   Established MAP7D1 as a regulated effector in neuronal cytoskeletal remodeling by identifying it as a DCLK1 kinase substrate whose phosphorylation drives axon elongation.

   Evidence Proteomic substrate identification, in vitro kinase assay, phosphomimetic mutagenesis, and in utero electroporation rescue in cortical neurons

   PMID:27503845

   Open questions at the time

   • Does not define how Ser315 phosphorylation alters MAP7D1 microtubule binding or kinesin recruitment
   • Limited to callosal axon elongation; broader neuronal contexts untested
2. 2018 High

   Linked MAP7D1 to non-canonical Wnt signaling by showing it binds Disheveled and couples microtubule plus-end cortical targeting to Wnt5a via kinesin-1.

   Evidence Reciprocal Co-IP, live-cell imaging, siRNA knockdown of MAP7/MAP7D1/KIF5B in HeLa, and Drosophila Ensconsin/Disheveled genetics

   PMID:29880710

   Open questions at the time

   • Direct vs. indirect nature of the Disheveled interaction not resolved structurally
   • Functional consequence of the MAP7D1–Disheveled feedback loop on downstream Wnt output not quantified
3. 2021 Medium

   Identified a sarcomeric/cardioprotective role, showing map7d1b loss worsens doxorubicin cardiomyopathy via failed autophagic degradation and protein aggregation.

   Evidence Zebrafish loss-of-function with doxorubicin model, autophagy flux and aggregation assays, mouse expression validation

   PMID:34327238

   Open questions at the time

   • Mechanism connecting sarcomeric MAP7D1 to autophagy is not molecularly defined
   • Human cardiac relevance untested
4. 2022 Medium

   Defined MAP7D1's distinct microtubule-stabilizing mechanism—maintenance of acetylated stable microtubules—differentiating it from the acetylation-independent paralog MAP7D2.

   Evidence siRNA knockdown, nocodazole resistance, immunofluorescence for acetylated/detyrosinated tubulin, neurite outgrowth and migration assays in N1-E115 cells

   PMID:35470240

   Open questions at the time

   • Molecular basis for preference toward acetylated microtubules not established
   • Single neuronal cell line
5. 2023 Medium

   Expanded MAP7D1's role beyond the cytoskeleton by tying it to G1-phase DNA double-strand break repair through RAD50, BRCA1, and 53BP1.

   Evidence Quantitative interaction proteomics, siRNA knockdown, γ-irradiation, chromatin fractionation, 53BP1 foci imaging, cell-cycle flow cytometry, p53 phosphorylation western blot

   PMID:36852271

   Open questions at the time

   • Whether MAP7D1 acts at damage sites directly or via cytoskeletal/cell-cycle effects is unresolved
   • Interactions discovered by proteomics lack reciprocal binding validation
6. 2025 Medium

   Demonstrated MAP7D1 is required for mitotic spindle integrity by showing the microtubule-binding R201W mutation reproduces depletion phenotypes—unstable spindles, lagging chromosomes, and RPS14 mislocalization.

   Evidence Patient fibroblast analysis, wild-type vs. mutant overexpression, siRNA knockdown, spindle and microtubule density imaging in glioblastoma and HEK293T cells

   PMID:40856631

   Open questions at the time

   • Disease genotype-phenotype link from a single patient mutation
   • Significance of RPS14 accumulation not mechanistically explained
7. 2025 Medium

   Resolved how MAP7D1 enables selective transport, showing it partitions onto detyrosinated/expanded-lattice microtubules to build kinesin-1 tracks and tunes lysosome positioning to nutrient state.

   Evidence Live-cell imaging, overexpression/knockdown, kinesin co-localization, lysosome tracking, nutrient starvation/refeeding, projection-domain mutagenesis (preprint)

   PMID:bio_10.1101_2025.10.07.680844

   Open questions at the time

   • Preprint, not yet peer-reviewed
   • Signaling pathway sensing nutrients to alter MAP7D1 microtubule density not identified
8. 2026 Medium

   Placed MAP7D1 in a cancer radioresponse axis as a direct miR-423-5p target whose suppression reduces proliferation and promotes apoptosis during radiotherapy.

   Evidence Dual-luciferase 3'UTR reporter, exosome-delivered miR-423-5p mimic, CCK8 proliferation, apoptosis flow cytometry, xenograft model in esophageal cancer

   PMID:42120691

   Open questions at the time

   • Which MAP7D1 function (spindle, repair, transport) underlies the radioresponse phenotype is unknown
   • Single tumor type

• How MAP7D1's distinct activities—microtubule stabilization, kinesin-1 track formation, DSB repair, and sarcomeric maintenance—are coordinated or selected within a cell remains unresolved.
• No structural model of the microtubule-binding or projection domains
• No unified mechanism linking cytoskeletal and DNA-repair functions