Affinage

MAP4

Microtubule-associated protein 4 · UniProt P27816

Length
1152 aa
Mass
121.0 kDa
Annotated
2026-06-10
84 papers in source corpus 45 papers cited in narrative 45 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 10/10 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAP4 is a ubiquitously expressed structural microtubule-associated protein that controls the assembly, stability, and architecture of the microtubule cytoskeleton through a bipartite organization (PMID:1905296, PMID:9914488). Its C-terminal microtubule-binding domain—built from imperfect 18-amino-acid repeats (present in three-, four-, or five-repeat isoforms generated by alternative splicing) plus a Pro-rich region—binds and stabilizes microtubules, with the Pro-rich region nucleating assembly by bridging protofilaments and an adjacent sequence driving elongation (PMID:1905296, PMID:7857940, PMID:9914488). Overexpression stabilizes microtubules and elevates polymer mass while depletion reduces tubulin polymer and slows regrowth, establishing MAP4 as a positive regulator of microtubule assembly level and cell shape that specifically counteracts catastrophe-promoting destabilizers rather than tubulin sequesterers (PMID:9044058, PMID:10341201, PMID:12123579). The N-terminal projection domain opposes the binding domain by suppressing microtubule bundling in a length-dependent manner and tuning dynamic instability (PMID:12079337, PMID:15840946). MAP4 activity is governed by multisite phosphorylation: cyclin B docks to the Pro-rich region to target the CDC2/cyclin B kinase to microtubules, and phosphorylation at Ser-787 (the dominant site) and Ser-696, as well as MARK-mediated phosphorylation of KXGS motifs, lowers microtubule affinity and increases dynamic instability, providing the switch for microtubule disassembly at the G2/M transition (PMID:7876309, PMID:8631898, PMID:9398320, PMID:10791892, PMID:11683421). Stress kinases including p38/MAPK and PKA, opposed by phosphatases PP2A/PP1, feed into the same regulatory logic, and in cardiomyocytes and endothelium phospho-MAP4 (Ser-696/Ser-787) drives microtubule disruption, mitochondrial translocation, mPTP opening, apoptosis, and barrier dysfunction (PMID:20889984, PMID:24140250, PMID:25232678, PMID:25746230). Beyond stabilization, microtubule-bound MAP4 modulates motor-driven transport—sterically inhibiting organelle motility and receptor recycling, differentially regulating dynein versus kinesin run lengths, biasing bidirectional transport toward minus-ends when phosphorylated by GSK3β, and supporting kinesin-3 transport on tyrosinated microtubules (PMID:9365275, PMID:15528234, PMID:25143402, PMID:36191197). MAP4 physically interacts with the dynein-dynactin machinery to regulate spindle orientation and cortical force generation, with septins that block its binding and bundling, and it directs dynein-dependent BTN3A1 trafficking that activates TBK1-IRF3 antiviral signaling (PMID:16093351, PMID:21822276, PMID:27911820). Distinct muscle-specific isoforms organize paraxial microtubule arrays required for myotube formation and skeletal muscle force generation (PMID:8631255, PMID:25898002, PMID:39473976). Human loss-of-function variants cause centrosome amplification, aberrant ciliogenesis, and Golgi fragmentation (PMID:25323976).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1991 High

    Established that MAP4's microtubule-binding activity resides in a discrete C-terminal domain with tau/MAP2-homologous repeats, separating binding from the projection function.

    Evidence cDNA cloning and in vitro microtubule binding with domain-specific fusion proteins

    PMID:1905296

    Open questions at the time
    • Did not establish how the projection domain contributes function
    • Repeat-number isoform diversity not yet defined
  2. 1991 Medium

    Showed that cell-cycle kinase activity phosphorylates MAP4 and suppresses its assembly-promoting activity, linking MAP4 regulation to the G2/M microtubule reorganization.

    Evidence In vitro cdc2/H1 kinase and microtubule assembly assays; spindle isolation with mitotic kinase

    PMID:1656961 PMID:1667090

    Open questions at the time
    • Phosphorylation sites not yet mapped
    • In vitro inhibition not yet validated in cells
  3. 1995 High

    Resolved the mechanism of cell-cycle control by showing cyclin B directly docks to the Pro-rich region to deliver CDC2 to microtubules and locally abolish stabilization without releasing MAP4.

    Evidence Reconstitution with purified proteins, GST-cyclin B pulldown, fragment mapping, kinase and dynamics assays; isoform/splicing characterization

    PMID:7857940 PMID:7876309

    Open questions at the time
    • The specific phosphoacceptor residues remained unidentified
    • Functional differences among repeat isoforms not addressed
  4. 1996 High

    Identified MARK as a kinase that phosphorylates KXGS motifs to detach MAP4 and amplify dynamic instability, defining a second regulatory input distinct from CDC2.

    Evidence In vitro kinase, co-sedimentation, and dynamics assays

    PMID:8631898

    Open questions at the time
    • Cellular context for MARK regulation of MAP4 not yet defined
  5. 1996 High

    Functionally dissected MAP4 in cells: the C-terminal fragment promotes polymerization, bundling, and stabilization, yet antibody-mediated removal produced no phenotype, indicating non-essentiality for basic microtubule functions in culture.

    Evidence Microinjection of fragments, nocodazole resistance, antibody depletion with photoactivation; muscle isoform antisense depletion

    PMID:8631255 PMID:8636213 PMID:8801031

    Open questions at the time
    • Reconciling overexpression effects with clean depletion phenotype
    • Mechanism of indirect stress-fiber increase unclear
  6. 2000 High

    Mapped the functional phosphorylation hierarchy in vivo, establishing Ser-787 (CDC2, mitosis-specific) as the dominant site reducing polymerization and Ser-696 as proliferation-linked.

    Evidence In vivo 32P labeling, inhibitors, phospho-specific antibodies, and phosphomimetic mutagenesis

    PMID:10791892 PMID:15216889 PMID:9398320

    Open questions at the time
    • How multiple kinases integrate on the same sites in vivo not resolved
  7. 2001 High

    Confirmed in cells that phosphorylation at Ser-696/Ser-787 lowers microtubule affinity and stability, using non-phosphorylatable and phosphomimetic mutants.

    Evidence Inducible mutant cell lines, co-sedimentation, nocodazole resistance

    PMID:11683421

    Open questions at the time
    • Did not address upstream signaling triggering phosphorylation in physiological contexts
  8. 2002 High

    Defined the projection domain as a length-dependent suppressor of bundling and identified mechanistic specificity of MAP4 stabilization against catastrophe-promoters but not tubulin sequesterers.

    Evidence In vitro assembly/EM with truncation constructs; co-expression epistasis with distinct destabilizers

    PMID:12079337 PMID:12123579

    Open questions at the time
    • Molecular basis of catastrophe-factor antagonism not determined
  9. 2005 High

    Identified septins as direct negative regulators that bind the Pro-rich region to block MAP4 binding/bundling, and isolated a projection-domain role in tuning dynamic instability.

    Evidence MS identification, purified-protein binding, RNAi epistasis; in vitro dynamics with projection deletions

    PMID:15840946 PMID:16093351

    Open questions at the time
    • Septin-MAP4 regulation in specific cellular processes not mapped
  10. 2011 High

    Placed MAP4 in mitotic and transport machinery by showing direct dynein-dynactin interaction, inhibition of dynein-driven sliding, and control of spindle orientation, plus a cardioprotective MT-DYNLT1-VDAC1 axis.

    Evidence Co-IP, in vitro dynein sliding, RNAi spindle orientation; yeast two-hybrid and Co-IP for DYNLT1/VDAC1

    PMID:21822276 PMID:22164227

    Open questions at the time
    • Whether MAP4 acts as motor regulator or steric obstacle not fully separated
    • DYNLT1-VDAC1 axis Medium-confidence single lab
  11. 2014 High

    Connected stress-kinase phosphorylation to pathological outcomes: phospho-MAP4 translocates to mitochondria to trigger mPTP opening and apoptosis, and MAP4 directs dynein-dependent BTN3A1 trafficking feeding TBK1-IRF3 antiviral signaling.

    Evidence Fractionation with phospho-antibodies and rescue mutant; RNAi, Co-IP, IFN-β reporter; melanophore dual-motor run-length analysis

    PMID:25143402 PMID:25232678 PMID:27911820

    Open questions at the time
    • Mechanism of phospho-MAP4 mitochondrial targeting unresolved
    • BTN3A1 finding Medium-confidence single lab
  12. 2014 Medium

    Linked MAP4 to human disease by identifying loss-of-function variants causing centrosome amplification, ciliogenesis defects, and Golgi fragmentation.

    Evidence Homozygosity mapping/NGS with patient fibroblast phenotyping

    PMID:25323976

    Open questions at the time
    • Single family
    • Direct causality versus correlation not fully established
  13. 2015 High

    Defined isoform-specialized roles in muscle: a differentiation-induced isoform (oMAP4) builds antiparallel arrays resistant to motor forces and is required for myotube formation.

    Evidence In vitro bundling with purified oMAP4, RNAi, live imaging, motor-resistance assay; p38-driven endothelial permeability via phospho-MAP4

    PMID:25746230 PMID:25898002

    Open questions at the time
    • How isoform-specific projection domains achieve distinct mechanics not detailed
  14. 2022 High

    Established that phosphorylation reprograms MAP4 from stabilizer to transport regulator: GSK3β-phosphorylated MAP4 tethers cargo via its projection domain, impairs kinesin-1 force, and biases transport minus-ward.

    Evidence Optical-trap force assay, organelle tracking, Co-IP, GSK3β manipulation

    PMID:36191197

    Open questions at the time
    • In vivo relevance of the cargo-tethering mode not established
  15. 2023 Medium

    Extended MAP4 regulation to ubiquitin-dependent turnover and autophagy: FBXW7/CHEK1 control MAP4 degradation, while MAP4 engages LC3 and harbors BH3/LIR domains enabling mitophagy-coupled self-degradation.

    Evidence Co-IP, MS, phosphosite mapping; LC3 Co-IP, domain mutagenesis, autophagy flux assays

    PMID:36835542 PMID:36991467 PMID:37198170

    Open questions at the time
    • Each mechanism from single lab
    • Integration of degradation and autophagy roles unresolved
  16. 2024 Medium

    Implicated MAP4 in oncogenic signaling and isoform-specific muscle physiology: MAP4 localizes p110α PI3K to microtubules for endosomal PI3K/Akt activation, and a muscle isoform knockout disrupts microtubule architecture and force generation.

    Evidence Knockdown with endosomal fractionation and signaling assays; in vivo exon-deletion mouse with force measurement

    PMID:38630589 PMID:39473976

    Open questions at the time
    • PI3K localization mechanism via MAP4 not structurally defined
    • Tissue specificity of signaling role unclear
  17. 2025 Medium

    Showed MAP4 reads the tubulin tyrosination code, partitioning onto tyrosinated microtubules to favor kinesin-3 transport and modulating lysosome positioning in response to nutrient status.

    Evidence Live imaging of MAP/track partitioning, rigor-kinesin and lysosome tracking, starvation experiments (preprint)

    PMID:bio_10.1101_2025.10.07.680844

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Molecular basis of tyrosination preference not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many kinases, phosphatases, ubiquitin ligases, and binding partners are integrated to switch MAP4 between stabilizer, transport regulator, and cell-death effector in a tissue-specific manner remains unresolved.
  • No unified model linking phosphosite combinations to functional outputs
  • Structural basis of partner competition (cyclin B vs septin vs dynein) on the Pro-rich region undefined
  • Isoform-specific regulatory networks not systematically compared

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 5 GO:0005198 structural molecule activity 4 GO:0098772 molecular function regulator activity 4
Localization
GO:0005856 cytoskeleton 4 GO:0005739 mitochondrion 3 GO:0005829 cytosol 2 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-9612973 Autophagy 2 R-HSA-168256 Immune System 1 R-HSA-5357801 Programmed Cell Death 1
Partners
BTN3A1CCNB1DYNLT1FBXW7LC3MAPK14SEPT2VDAC1

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 MAP4 contains a C-terminal microtubule-binding domain with three imperfect 18-amino acid repeats homologous to those in neuronal MAP2 and tau; fusion proteins containing this domain bind microtubules in vitro, while projection-domain-only constructs do not. cDNA cloning, in vitro microtubule binding assay with fusion proteins Journal of cell science High 1905296
1991 Phosphorylation of the Pro-rich region of MAP4 by cdc2/H1 histone kinase suppresses MAP4's microtubule assembly-promoting activity, providing a mechanism for microtubule disassembly at the G2/M transition. In vitro kinase assay, microtubule assembly assay Biochemical and biophysical research communications Medium 1656961
1991 An M-phase-specific kinase (related to p34cdc2/cyclin B) associates with isolated mitotic spindles and phosphorylates MAP4 (and MAP1B) in a cell-cycle-dependent manner. Spindle isolation, in vitro kinase assay, immunofluorescence with anti-thiophosphoprotein antibody Cell regulation Medium 1667090
1994 A 230 kDa MAP4-like protein in Xenopus egg extracts is heat-stable, phosphorylated, and promotes elongation of microtubules from axonemes, confirming MAP4 ortholog function in a non-mammalian model. Microtubule co-sedimentation, immunological characterization, microtubule assembly assay Cell motility and the cytoskeleton Medium 8087870
1995 Cyclin B directly binds to the Pro-rich C-terminal region of MAP4, thereby targeting the p34cdc2/cyclin B kinase complex to microtubules; the kinase then phosphorylates MAP4 within the complex and abolishes MAP4's microtubule-stabilizing activity without preventing its microtubule binding. Co-sedimentation with purified proteins, GST-cyclin B pulldown, recombinant MAP4 fragment mapping, in vitro kinase assay, microtubule dynamics assay The Journal of cell biology High 7876309
1995 MAP4 isoforms with three, four, or five microtubule-binding repeats are expressed in a tissue- and developmental-stage-specific manner via alternative RNA splicing from a single-copy gene on chromosome 3p21. cDNA cloning, RNase protection analysis, chromosomal mapping Biochemistry Medium 7857940
1996 MARK kinase (p110mark) phosphorylates KXGS motifs in the microtubule-binding domain of MAP4 in vitro, causing MAP4 dissociation from microtubules and a pronounced increase in dynamic instability. In vitro kinase assay, microtubule co-sedimentation, microtubule dynamics assay The Journal of biological chemistry High 8631898
1996 A muscle-specific MAP4 isoform (encoded by a 3.2 kb insertion in the projection domain) is required for myotube formation: antisense depletion of this isoform in C2C12 cells allows cell fusion but produces short, apolar syncytia with disorganized microtubules and absent myofibrils. Stable antisense cell lines, in situ hybridization, immunofluorescence, differentiation assay Development High 8631255
1996 Microinjection of intact MAP4 or its C-terminal PA4 fragment into PtK2 cells promotes microtubule polymerization and bundling and stabilizes microtubules against nocodazole; the N-terminal NR fragment has no effect. The PA4 fragment also indirectly increases stress fibers without direct binding to actin. Microinjection, immunofluorescence, nocodazole resistance assay, in vitro binding assay Cell motility and the cytoskeleton Medium 8801031
1996 Antibody-mediated removal of MAP4 from microtubules in living cells produces no detectable phenotype: MT dynamics, tubulin modifications, organelle distribution, and mitotic spindle morphology are all normal, indicating MAP4 is not essential for these functions in cultured cells. Antibody microinjection, tubulin photoactivation, nocodazole sensitivity, immunofluorescence The Journal of cell biology High 8636213
1997 CDC2 kinase is the major M-phase MAP4 kinase in HeLa cells; Ser-787 (in SPSK) is phosphorylated specifically at mitosis while Ser-696 (in SPEK) is phosphorylated in both mitosis and interphase, both lying in the proline-rich region of the microtubule-binding domain. Metabolic 32P labeling, butyrolactone I inhibitor, phosphopeptide mapping, phospho-specific antibodies Biochemistry High 9398320
1997 Overexpression of full-length MAP4 or its MT-binding domain stabilizes microtubules in vivo (increased detyrosinated tubulin, nocodazole resistance) and inhibits cell growth without causing mitotic arrest or cell death. Stable transfection, nocodazole resistance assay, tubulin modification immunoblotting, growth curves Journal of cell science High 9044058
1997 MAP4 overexpression directly inhibits MT-based organelle motility and vesicle transport in vivo (reduced LDL receptor recycling, Golgi redistribution), in a manner not reproduced by taxol-mediated MT stabilization, indicating a direct steric effect of MAP4 on motor-driven transport. DIC live microscopy, receptor trafficking assays, Golgi redistribution assay, brefeldin A washout Journal of cell science High 9365275
1999 MARK1/MARK2 kinases phosphorylate MAP4 on its microtubule-binding domain in transfected CHO cells, causing microtubule disruption, vimentin network breakdown, and cell detachment; actin fibers are unaffected. Inducible expression of MARK kinases in CHO cells, immunofluorescence, phosphorylation analysis Cell motility and the cytoskeleton Medium 10542369
1999 MAP4 depletion (antisense RNA to ~33% of normal) decreases total tubulin content, shifts tubulin partitioning from polymer to protomer, slows MT regrowth after depolymerization, and flattens cell morphology, demonstrating MAP4 regulates MT assembly level and cell shape. Stable antisense RNA expression, tubulin fractionation, MT regrowth assay, immunofluorescence Journal of cell science High 10341201
1999 The Pro-rich region of MAP4 promotes nucleation of microtubule assembly by bridging protofilaments, whereas the AP sequence region promotes elongation; the tail region is required for the nucleation step when combined with the AP sequence region. In vitro microtubule assembly assay with truncated recombinant fragments, electron microscopy, binding stoichiometry European journal of biochemistry High 9914488
1999 MAP kinase phosphorylates Ser-696 of MAP4 in vitro and in cell extracts; serum starvation causes dephosphorylation of Ser-696 in HeLa cells and fibroblasts, and serum re-addition restores phosphorylation, linking this site to proliferation/quiescence status. In vitro kinase assay, MAP kinase inhibitor in cell extract, phospho-specific antibodies, serum starvation experiments Cell structure and function Medium 15216889
2000 Phosphorylation of Ser-787 by p34cdc2 kinase is the critical site that reduces MAP4's microtubule-polymerization activity; the Ser787Glu phosphomimetic mutant dramatically reduces this activity, while Ser696Glu does not, establishing site-specific functional hierarchy. Site-directed mutagenesis, in vitro MT polymerization assay with phosphomimetic mutants Cell structure and function High 10791892
2001 Nonphosphorylatable MAP4 mutants (AA, KK) bind microtubules more avidly and confer greater nocodazole resistance than wild-type or phosphomimetic (EE) MAP4; EE mutant behaves like WT, demonstrating that phosphorylation of Ser-696/Ser-787 reduces MAP4-MT interaction and MT stability in vivo. Stable inducible cell lines expressing phosphorylation mutants, MT co-sedimentation, nocodazole resistance assay Journal of cell science High 11683421
2002 The projection (PJ) domain of MAP4 suppresses the microtubule-bundling activity of the MT-binding domain; longer PJ domains progressively reduce bundle formation, and this suppression correlates with PJ domain length rather than amino acid sequence. In vitro microtubule assembly with truncated MAP4 constructs, negative-staining EM, dark-field microscopy Journal of molecular biology High 12079337
2002 MAP4 counteracts microtubule catastrophe promoters (XKCM1, non-sequestering Op18) but not tubulin-sequestering destabilizers in intact cells, revealing mechanistic specificity in its stabilizing activity. Inducible co-transfection, co-expression with catastrophe promoters vs. tubulin sequesterers, cell imaging Current biology Medium 12123579
2003 MAP4 overexpression in cardiocytes stabilizes microtubules (shifts tubulin to polymerized fraction) and increases total tubulin levels; beta1-tubulin overexpression has no independent or additive effect, identifying MAP4 as the causative factor for microtubule network densification in cardiac hypertrophy. Adenoviral overexpression in isolated cardiocytes, transgenic mice, tubulin fractionation, immunofluorescence American journal of physiology. Heart and circulatory physiology High 12855424
2004 MAP4 decoration of microtubules in cardiocytes inhibits beta-adrenergic receptor recycling after agonist withdrawal, reducing cell-surface beta-AR number and cAMP responsiveness; confirmed in MAP4-transgenic mouse cardiocytes. Adenoviral MAP4 overexpression, [3H]CGP-12177 receptor binding assay, cAMP measurement, transgenic mouse confirmation American journal of physiology. Heart and circulatory physiology High 15528234
2005 Septins (Sept2:6:7 heterotrimer and Sept2 monomer) directly bind the proline-rich C-terminal region of MAP4; this interaction blocks MAP4's ability to bind and bundle microtubules in vitro. In cells, septin depletion increases microtubule stability in a MAP4-dependent manner. Mass spectrometry identification, direct binding assay with purified proteins, domain mapping, RNA interference, microtubule bundling assay Molecular biology of the cell High 16093351
2005 Truncation of MAP4's projection domain attenuates microtubule dynamic instability at higher MAP4 concentrations, demonstrating that the projection domain modulates dynamic instability independently of its bundling suppression function. In vitro dark-field microscopy of microtubule dynamics with projection-domain deletion mutants Cell structure and function Medium 15840946
2009 In hypoxic cells, activated p38/MAPK phosphorylates MAP4 (increasing phosphorylation) and dephosphorylates Op18/stathmin, both contributing to microtubule disruption; p38-MAP4 interaction was confirmed by co-immunoprecipitation. Co-immunoprecipitation, p38 inhibitor (SB203580), MKK6(Glu) overexpression, immunofluorescence, cell viability assay Cellular and molecular life sciences Medium 19915797
2010 PP2A and PP1 dephosphorylate MAP4 at Ser-924 and Ser-1056 in pressure-overloaded hypertrophied myocardium; overexpression of PP2A or PP1 in normal hearts reproduces the microtubule densification and MAP4 dephosphorylation phenotype of hypertrophy. Phosphatase activity assays, phospho-specific antibodies, adenoviral overexpression in hearts, transgenic comparison The Journal of biological chemistry High 20889984
2011 MAP4 physically interacts with dynein-dynactin in vivo and inhibits dynein-mediated microtubule sliding in vitro; depletion of MAP4 causes spindle misorientation in the vertical plane in human cells, placing MAP4 as a regulator of cortical force generation during mitosis. Co-immunoprecipitation, in vitro dynein-mediated MT sliding assay, RNAi depletion, spindle orientation measurement Nature cell biology High 21822276
2011 MAP4 overexpression promotes microtubule stabilization in hypoxic cardiomyocytes; MAP4 also interacts with DYNLT1 (dynein light chain Tctex-1) which in turn interacts with VDAC1, linking MAP4 to mitochondrial permeability stabilization via the microtubule-DYNLT1-VDAC1 axis. Yeast two-hybrid, co-immunoprecipitation, immunofluorescence, MT polymerization assay, cell viability/ATP measurement PloS one Medium 22164227
2013 cAMP/PKA signaling phosphorylates MAP4, disrupting microtubule cytoskeleton and inhibiting bladder cancer cell invasion and migration; the interaction between PKA and MAP4 was confirmed by co-immunoprecipitation. Co-immunoprecipitation, siRNA knockdown, matrigel invasion assay, immunofluorescence/immunoblotting Urologic oncology Medium 24140250
2014 Phosphorylated MAP4 (at Ser-696 and Ser-787) translocates from the cytosol to mitochondria in hypoxic cardiomyocytes, where it induces mitochondrial permeability transition pore (mPTP) opening and apoptosis; the non-phosphorylatable MAP4(Ala) mutant suppresses this translocation and apoptosis. Subcellular fractionation, phospho-specific antibodies, MAP4(Ala) mutant expression, mPTP assay, apoptosis assay Cell death & disease High 25232678
2014 MAP4 controls dynein-dependent transport of BTN3A1 to the perinuclear region upon nucleic acid stimulation; MAP4 depletion impairs BTN3A1 redistribution and consequently reduces TBK1-IRF3-mediated type I interferon production, placing MAP4 upstream of the TBK1-IRF3 antiviral signaling axis. RNAi depletion, co-immunoprecipitation, immunofluorescence localization, IFN-β reporter assay Proceedings of the National Academy of Sciences Medium 27911820
2014 MAP4 regulation of microtubule-based transport operates differentially on kinesin-2 vs. dynein in Xenopus melanophores: MAP4 on microtubules shortens dynein-dependent runs and lengthens kinesin-2 runs; phosphorylation of threonine residues in the MT-binding domain during aggregation signals reduces MAP4-MT binding, increasing dynein-dependent and decreasing kinesin-2-dependent motility. Overexpression and removal of XMAP4 in melanophores, run-length analysis of melanosome movement, phosphorylation analysis Molecular biology of the cell High 25143402
2014 Loss-of-function variants in MAP4 in humans cause centrosome amplification, aberrant ciliogenesis, and Golgi fragmentation in fibroblasts; the variant affects kinase binding sites required for dynamic instability of microtubule formation. Homozygosity mapping/NGS, patient fibroblast centrosome counting, cilia assay, Golgi morphology analysis Human mutation Medium 25323976
2015 p38/MAPK activation by LPS/TNF-α phosphorylates MAP4 at Ser-696 and Ser-787, inducing microtubule disassembly and endothelial hyperpermeability; the phosphorylation-resistant MAP4(Ala) mutant or p38 inhibitor prevents MT disruption and barrier dysfunction. Phospho-specific antibodies, p38 inhibitor SB203580, MKK6(Glu) activation, MAP4(Ala) mutant, transendothelial resistance measurement Scientific reports High 25746230
2015 A novel MAP4 isoform (oMAP4), expressed upon muscle differentiation, is required for paraxial microtubule array organization; purified oMAP4 aligns dynamic microtubules into antiparallel bundles that withstand dynein- and kinesin-driven sliding forces in vitro, and its depletion impairs cell elongation, fusion, and paraxial array formation. In vitro microtubule bundling assay with purified oMAP4, RNAi depletion, live cell imaging, motor resistance assay eLife High 25898002
2019 HPV16 oncoprotein E7 directly binds the C-terminus of MAP4, inhibiting Mps1-mediated phosphorylation of MAP4 (at T927/S928), thereby blocking phosphorylation-dependent MAP4 degradation, stabilizing microtubule polymerization, and retarding mitotic progression. MAP4 T927E/S928E mutations reduce E7 binding and rescue mitotic progression. Co-immunoprecipitation, kinase assay, site-directed mutagenesis, mitotic timing assay Oncogene High 31253867
2022 MAP4, when phosphorylated by GSK3β, tethers cargo (organelles) to microtubules via its projection domain, impairs kinesin-1 force generation, and biases bidirectional transport toward minus-ends; MAP4 physically interacts with dynein and dynactin and the phosphorylated form associates with the cargo-motor complex. Co-immunoprecipitation, organelle tracking, optical trap force assay, GSK3β manipulation, MAP4 domain analysis Proceedings of the National Academy of Sciences High 36191197
2023 MAP4 interacts with autophagy marker LC3 (confirmed by co-immunoprecipitation) and colocalizes with LC3 in myoblast cytoplasm; this interaction promotes autophagy during C2C12 differentiation. miR-103-3p suppresses MAP4 expression and thereby inhibits both autophagy and myotube formation. Co-immunoprecipitation, dual-luciferase reporter, immunofluorescence co-localization, autophagy assays International journal of molecular sciences Medium 36835542
2023 FBXW7 ubiquitin ligase targets MAP4 for degradation; CHEK1-mediated phosphorylation of MAP4 at Thr-521 is required for FBXW7-dependent MAP4 degradation. Loss of FBXW7 elevates MAP4 levels and ERK phosphorylation, promoting ESCC progression. GST-pulldown, LC-MS/MS, co-immunoprecipitation, site-directed phosphorylation analysis Journal of experimental & clinical cancer research Medium 36991467
2023 Phosphorylated MAP4 undergoes self-degradation via mitophagy in hypoxic keratinocytes; MAP4 contains both BH3 and LIR domains that allow it to simultaneously act as a mitophagy initiator and substrate receptor. Mutation of either domain abolishes p-MAP4 self-degradation and impairs hypoxia-induced keratinocyte migration and proliferation. Domain mutagenesis (BH3 and LIR), autophagy flux assays, LC3 co-localization, cell migration/proliferation assays Cell death discovery Medium 37198170
2024 p110α (PI3Kα catalytic subunit) localizes to microtubules via MAP4 and is recruited with receptor tyrosine kinases to endosomes for PI3K/Akt signaling; MAP4 knockdown abrogates the tumor-promoting effects of p85α loss, placing MAP4 upstream of endosomal PI3K/Akt activation. Knockdown studies, endosomal fractionation, PI3K/Akt signaling assays, tumorsphere formation assay Cell reports Medium 38630589
2024 Muscle-specific MAP4 isoform (mMAP4) exhibits enhanced microtubule association compared to ubiquitous MAP4 (uMAP4); loss of mMAP4 in mice (exon 8 deletion) causes disorganized microtubule architecture and intrinsic loss of skeletal muscle force generation, demonstrating isoform-specific function in muscle homeostasis. Genomic exon deletion in mice, microtubule co-sedimentation, ex vivo force measurement, immunofluorescence iScience High 39473976
2025 MAP4 preferentially partitions onto tyrosinated microtubules (via its projection domain) while MAP7D1 decorates detyrosinated microtubules; MAP4-decorated tracks preferentially support kinesin-3 (KIF1A) transport, and MAP4 density on microtubules decreases during nutrient starvation to promote perinuclear lysosome positioning, coordinating lysosome repositioning in response to nutrient availability. Live imaging of MAP4/MAP7D1 on microtubule subsets, rigor kinesin localization assays, lysosome tracking, nutrient starvation/stimulation experiments, projection domain mutant analysis bioRxivpreprint Medium bio_10.1101_2025.10.07.680844
2025 MAP4 phosphorylation by PI3K (activated downstream of ARID1A loss) reduces MAP4's microtubule-stabilizing activity, disrupts bipolar spindle formation, and sensitizes colorectal cancer cells to the antimicrotubule drug EMP (synthetic lethality with ARID1A loss). ARID1A isogenic cell lines, drug screening, phosphorylation analysis, spindle imaging, PI3K pathway manipulation Cell death & disease Medium 41360780

Source papers

Stage 0 corpus · 84 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 A GFP-MAP4 reporter gene for visualizing cortical microtubule rearrangements in living epidermal cells. The Plant cell 313 9811799
1995 Cyclin B interaction with microtubule-associated protein 4 (MAP4) targets p34cdc2 kinase to microtubules and is a potential regulator of M-phase microtubule dynamics. The Journal of cell biology 245 7876309
2007 A MAP4 kinase related to Ste20 is a nutrient-sensitive regulator of mTOR signalling. The Biochemical journal 196 17253963
2005 Mammalian septins regulate microtubule stability through interaction with the microtubule-binding protein MAP4. Molecular biology of the cell 165 16093351
1996 Phosphorylation of microtubule-associated proteins MAP2 and MAP4 by the protein kinase p110mark. Phosphorylation sites and regulation of microtubule dynamics. The Journal of biological chemistry 164 8631898
1998 The role of MAP4 expression in the sensitivity to paclitaxel and resistance to vinca alkaloids in p53 mutant cells. Oncogene 136 9569030
1991 Non-neuronal 210 x 10(3) Mr microtubule-associated protein (MAP4) contains a domain homologous to the microtubule-binding domains of neuronal MAP2 and tau. Journal of cell science 131 1905296
1999 Phosphorylation of MAP2c and MAP4 by MARK kinases leads to the destabilization of microtubules in cells. Cell motility and the cytoskeleton 127 10542369
2018 The MAP4 Kinase SIK1 Ensures Robust Extracellular ROS Burst and Antibacterial Immunity in Plants. Cell host & microbe 121 30212650
1995 Distinct presynaptic metabotropic receptors for L-AP4 and CCG1 on GABAergic terminals: pharmacological evidence using novel alpha-methyl derivative mGluR antagonists, MAP4 and MCCG, in the rat thalamus in vivo. Neuroscience 104 7753406
2011 MAP4 and CLASP1 operate as a safety mechanism to maintain a stable spindle position in mitosis. Nature cell biology 99 21822276
1997 Overexpression of full- or partial-length MAP4 stabilizes microtubules and alters cell growth. Journal of cell science 85 9044058
2015 P38/MAPK contributes to endothelial barrier dysfunction via MAP4 phosphorylation-dependent microtubule disassembly in inflammation-induced acute lung injury. Scientific reports 75 25746230
2009 The p38/MAPK pathway regulates microtubule polymerization through phosphorylation of MAP4 and Op18 in hypoxic cells. Cellular and molecular life sciences : CMLS 71 19915797
1997 MAP4 is the in vivo substrate for CDC2 kinase in HeLa cells: identification of an M-phase specific and a cell cycle-independent phosphorylation site in MAP4. Biochemistry 69 9398320
1997 Overexpression of MAP4 inhibits organelle motility and trafficking in vivo. Journal of cell science 64 9365275
1995 Differential expression of alternatively spliced forms of MAP4: a repertoire of structurally different microtubule-binding domains. Biochemistry 64 7857940
1996 Removal of MAP4 from microtubules in vivo produces no observable phenotype at the cellular level. The Journal of cell biology 63 8636213
2001 Phosphorylation of MAP4 affects microtubule properties and cell cycle progression. Journal of cell science 62 11683421
1991 Specific association of an M-phase kinase with isolated mitotic spindles and identification of two of its substrates as MAP4 and MAP1B. Cell regulation 61 1667090
1999 Microtubule-associated protein 4 (MAP4) regulates assembly, protomer-polymer partitioning and synthesis of tubulin in cultured cells. Journal of cell science 50 10341201
1996 A muscle-specific variant of microtubule-associated protein 4 (MAP4) is required in myogenesis. Development (Cambridge, England) 48 8631255
2013 Activation of cyclic AMP/PKA pathway inhibits bladder cancer cell invasion by targeting MAP4-dependent microtubule dynamics. Urologic oncology 46 24140250
1995 Pharmacological characterization of MCCG and MAP4 at the mGluR1b, mGluR2 and mGluR4a human metabotropic glutamate receptor subtypes. Neuropharmacology 45 8532159
2019 Development of MAP4 Kinase Inhibitors as Motor Neuron-Protecting Agents. Cell chemical biology 44 31676236
2015 A novel isoform of MAP4 organises the paraxial microtubule array required for muscle cell differentiation. eLife 40 25898002
2003 Phenotypic consequences of beta1-tubulin expression and MAP4 decoration of microtubules in adult cardiocytes. American journal of physiology. Heart and circulatory physiology 39 12855424
1994 Cellular microtubules heterogeneous in their content of microtubule-associated protein 4 (MAP4). Cell motility and the cytoskeleton 38 7909279
1991 Microtubule destabilization by cdc2/H1 histone kinase: phosphorylation of a "pro-rich region" in the microtubule-binding domain of MAP-4. Biochemical and biophysical research communications 37 1656961
2014 Phosphorylation-dependent mitochondrial translocation of MAP4 is an early step in hypoxia-induced apoptosis in cardiomyocytes. Cell death & disease 36 25232678
2002 MAP4 counteracts microtubule catastrophe promotion but not tubulin-sequestering activity in intact cells. Current biology : CB 36 12123579
2018 Paclitaxel Sensitivity of Ovarian Cancer Can be Enhanced by Knocking Down Pairs of Kinases that Regulate MAP4 Phosphorylation and Microtubule Stability. Clinical cancer research : an official journal of the American Association for Cancer Research 34 30084832
2014 Regulation of microtubule-based transport by MAP4. Molecular biology of the cell 33 25143402
2010 Basis for MAP4 dephosphorylation-related microtubule network densification in pressure overload cardiac hypertrophy. The Journal of biological chemistry 32 20889984
2023 Effects of three microtubule-associated proteins (MAP2, MAP4, and Tau) on microtubules' physical properties and neurite morphology. Scientific reports 31 37258650
2000 Ser787 in the proline-rich region of human MAP4 is a critical phosphorylation site that reduces its activity to promote tubulin polymerization. Cell structure and function 31 10791892
2016 MAP4-regulated dynein-dependent trafficking of BTN3A1 controls the TBK1-IRF3 signaling axis. Proceedings of the National Academy of Sciences of the United States of America 29 27911820
2011 MAP4 mechanism that stabilizes mitochondrial permeability transition in hypoxia: microtubule enhancement and DYNLT1 interaction with VDAC1. PloS one 29 22164227
1996 Microinjection of intact MAP-4 and fragments induces changes of the cytoskeleton in PtK2 cells. Cell motility and the cytoskeleton 25 8801031
1999 A new model for microtubule-associated protein (MAP)-induced microtubule assembly. The Pro-rich region of MAP4 promotes nucleation of microtubule assembly in vitro. European journal of biochemistry 24 9914488
2014 MAP4-dependent regulation of microtubule formation affects centrosome, cilia, and Golgi architecture as a central mechanism in growth regulation. Human mutation 22 25323976
2005 Truncation of the projection domain of MAP4 (microtubule-associated protein 4) leads to attenuation of microtubule dynamic instability. Cell structure and function 21 15840946
2018 Ral Signals through a MAP4 Kinase-p38 MAP Kinase Cascade in C. elegans Cell Fate Patterning. Cell reports 20 30184501
1994 Purification of microtubule proteins from Xenopus egg extracts: identification of a 230K MAP4-like protein. Cell motility and the cytoskeleton 20 8087870
2020 MAP4 as a New Candidate in Cardiovascular Disease. Frontiers in physiology 19 32982783
2006 The fission yeast Map4 protein is a novel adhesin required for mating. FEBS letters 19 16857197
2003 Interphase and monoastral-mitotic phenotypes of overexpressed MAP4 are modulated by free tubulin concentrations. Journal of cell science 19 12890753
2002 The projection domain of MAP4 suppresses the microtubule-bundling activity of the microtubule-binding domain. Journal of molecular biology 19 12079337
1999 Serum-dependent phosphorylation of human MAP4 at Ser696 in cultured mammalian cells. Cell structure and function 19 15216889
2024 A p85 isoform switch enhances PI3K activation on endosomes by a MAP4- and PI3P-dependent mechanism. Cell reports 18 38630589
2023 FBXW7 loss of function promotes esophageal squamous cell carcinoma progression via elevating MAP4 and ERK phosphorylation. Journal of experimental & clinical cancer research : CR 18 36991467
2004 Inhibition of beta-adrenergic receptor trafficking in adult cardiocytes by MAP4 decoration of microtubules. American journal of physiology. Heart and circulatory physiology 18 15528234
2006 Microtubule-associated protein-4 (MAP-4) inhibits microtubule-dependent distribution of mRNA in isolated neonatal cardiocytes. Cardiovascular research 16 16750521
2022 The ubiquitous microtubule-associated protein 4 (MAP4) controls organelle distribution by regulating the activity of the kinesin motor. Proceedings of the National Academy of Sciences of the United States of America 14 36191197
1992 Mouse microtubule-associated protein 4 (MAP4) transcript diversity generated by alternative polyadenylation. Gene 14 1487151
2022 Troxerutin alleviates kidney injury in rats via PI3K/AKT pathway by enhancing MAP4 expression. Food & nutrition research 13 35844954
2021 The combination therapy of targeting both paclitaxel and Dendrophthoe pentandra leaves extract nanoparticles for improvement breast cancer treatment efficacy by reducing TUBB3 and MAP4 expressions. Acta biochimica Polonica 13 34264566
2021 Microtubule associated protein 4 (MAP4) phosphorylation reduces cardiac microvascular density through NLRP3-related pyroptosis. Cell death discovery 13 34381021
2016 Association of rare haplotypes on ULK4 and MAP4 genes with hypertension. BMC proceedings 13 27980663
2008 The Schizosaccharomyces pombe Map4 adhesin is a glycoprotein that can be extracted from the cell wall with alkali but not with beta-glucanases and requires the C-terminal DIPSY domain for function. Molecular microbiology 13 18673459
2008 Schistosoma mansoni triose phosphate isomerase peptide MAP4 is able to trigger naïve donor immune response towards a type-1 cytokine profile. Scandinavian journal of immunology 12 18565118
2003 Adenovirus 2 E1B-55K protein relieves p53-mediated transcriptional repression of the survivin and MAP4 promoters. FEBS letters 12 14527689
2019 Expression of Syk and MAP4 proteins in ovarian cancer. Journal of cancer research and clinical oncology 11 30737623
1999 Functional analysis of microtubule-binding domain of bovine MAP4. Cell structure and function 11 15216891
2022 Novel MAP4::RAF1 Fusion in a Primary Bone Sarcoma: Expanding the spectrum of RAF1 Fusion Sarcoma. International journal of surgical pathology 9 35156861
2018 MAP4 regulates Tctex-1 and promotes the migration of epidermal cells in hypoxia. Experimental dermatology 7 30091292
2023 miR-103-3p Regulates the Differentiation and Autophagy of Myoblasts by Targeting MAP4. International journal of molecular sciences 6 36835542
2019 Human Papillomavirus 16 oncoprotein E7 retards mitotic progression by blocking Mps1-MAP4 signaling cascade. Oncogene 6 31253867
2006 A novel fusion of the MALT1 gene and the microtubule-associated protein 4 (MAP4) gene occurs in diffuse large B-cell lymphoma. Genes, chromosomes & cancer 6 16804917
2024 RAP-2 and CNH-MAP4 Kinase MIG-15 confer resistance in bystander epithelium to cell-fate transformation by excess Ras or Notch activity. Proceedings of the National Academy of Sciences of the United States of America 4 39739816
2023 Mitophagy associated self-degradation of phosphorylated MAP4 guarantees the migration and proliferation responses of keratinocytes to hypoxia. Cell death discovery 4 37198170
2023 CHKB-AS1 enhances proliferation and resistance to NVP-BEZ235 of renal cancer cells via regulating the phosphorylation of MAP4 and PI3K/AKT/mTOR signaling. European journal of medical research 4 38093375
2003 Different protofilament-dependence of the microtubule binding between MAP2 and MAP4. Biochemical and biophysical research communications 3 12732198
1996 Chicken microtubule-associated protein 4 (MAP4): a novel member of the MAP4 family. Histochemistry and cell biology 3 8897075
2025 MAP4 kinase-regulated reduced CLSTN1 expression in medulloblastoma is associated with increased invasiveness. Scientific reports 2 39762313
2025 Hypoxia impairs autophagy of cardiomyocytes via p38/MAPK/MAP4 pathway. Burns : journal of the International Society for Burn Injuries 2 40318591
2025 Case report: Successful use of MEK inhibitors as an adjuvant approach in the treatment of pediatric MAP4-RAF1 fusion-positive solid tumor. NPJ precision oncology 2 40544160
2024 Alternatively spliced MAP4 isoforms have key roles in maintaining microtubule organization and skeletal muscle function. iScience 1 39473976
2014 An exploration of heterogeneity in genetic analysis of complex pedigrees: linkage and association using whole genome sequencing data in the MAP4 region. BMC proceedings 1 25519361
2025 Integrative bioinformatics and machine learning identify iron metabolism genes MAP4, GPT, and HIRIP3 as diagnostic biomarkers and therapeutic targets in Alzheimer's disease. Frontiers in cellular neuroscience 0 40547214
2025 Rufy3 Knockdown Induces PANoptosis Through MAP4/CDK1 Axis to Inhibit Colorectal Cancer Growth: Evidence From In Vitro and In Vivo Models. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 40879686
2025 MAP4 phosphorylation induced by ARID1A loss sensitizes colorectal cancer cells to EMP. Cell death & disease 0 41360780
2022 [Establishment and Preliminary Analysis of Lung Cancer Cell Line A549 with Stable MAP4 K4 Knockdown]. Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition 0 35871731
1997 Insertion of MAP4-VP1 peptide into lipid monolayers and bilayers. Biomedical chromatography : BMC 0 9192112

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