MAPRE1

MAPRE1 (EB1) is a microtubule plus-end-associated protein that regulates microtubule dynamics and feeds into cell cycle progression. It inhibits α-tubulin acetylation and promotes dynamic microtubule assembly, an activity linked to enhanced invasion and migration of nasopharyngeal carcinoma cells (PMID:33122825). MAPRE1 also binds CDK2 and promotes its hyperphosphorylation at Thr161, advancing cell cycle progression in hepatocellular carcinoma cells (PMID:32770827); a MAPRE1–CDK2 complex was independently confirmed in granulosa cells, where MAPRE1 suppression reduces CDK2 expression and blocks cell cycle progression (PMID:36084389). At microtubule plus ends MAPRE1 directly interacts and co-localizes with CLASP2, and this association supports proliferation and cisplatin resistance in bladder cancer cells (PMID:40382315). The protein normally resides in a microtubule-associated cytoplasmic compartment; an MLL-EB1 chromosomal translocation produces a fusion protein that mislocalizes to the nucleus (PMID:15751040). MAPRE1 functions as a dimer and can be sequestered into a 2:2:2 FKBP12:glue:MAPRE1 ternary complex by a macrocyclic molecular-glue ligand, which sterically blocks its native intracellular interactions (PMID:40059881).

1. 2005 Medium

   Establishing where MAPRE1 acts: the native protein occupies a microtubule-associated cytoplasmic compartment, and disrupting this localization through an MLL-EB1 fusion redirects it to the nucleus, linking the protein to oncogenic chromosomal rearrangement.

   Evidence Immunofluorescence and PCR/Southern characterization of an MLL-EB1 translocation

   PMID:15751040

   Open questions at the time

   • No functional consequence of nuclear mislocalization defined
   • Wild-type MAPRE1 microtubule activity not assayed here
2. 2020 Medium

   Defined a biochemical activity of MAPRE1 on the cytoskeleton: it inhibits α-tubulin acetylation and promotes dynamic microtubule assembly, connecting this to tumor cell invasion and migration.

   Evidence Proteomic comparison plus invasion/migration assays in nasopharyngeal carcinoma cells

   PMID:33122825

   Open questions at the time

   • No in vitro reconstitution of the acetylation effect
   • Mechanism by which MAPRE1 affects acetylation undefined
3. 2020 Medium

   Linked MAPRE1 to cell cycle control by showing it binds CDK2 and drives CDK2 Thr161 hyperphosphorylation to advance the cycle.

   Evidence Co-IP and phospho-western in HCC cell lines with knockdown/overexpression

   PMID:32770827

   Open questions at the time

   • Whether MAPRE1 directly recruits the Thr161 kinase unknown
   • Single lab; no reciprocal validation of phosphorylation mechanism
4. 2022 Medium

   Reinforced the MAPRE1–CDK2 axis in a second system, showing MAPRE1 supports CDK2 expression and cell cycle/progesterone output and is itself under miR-10a-5p control.

   Evidence Co-IP and multiple proliferation/cell cycle assays in chicken granulosa cells

   PMID:36084389

   Open questions at the time

   • Chicken model may not recapitulate human biology
   • Direct versus indirect regulation of CDK2 levels not resolved
5. 2025 Medium

   Identified a direct microtubule plus-end partner: CLASP2 binds and co-localizes with MAPRE1, and the axis promotes proliferation and chemoresistance.

   Evidence Co-IP, immunofluorescence, and proliferation/resistance assays plus xenograft in bladder cancer

   PMID:40382315

   Open questions at the time

   • Mechanistic link between the interaction and functional output limited
   • Binding interface not mapped
6. 2025 High

   Established MAPRE1 as a druggable dimeric target by showing a molecular-glue ligand sequesters it into a cooperative ternary complex with FKBP12 that blocks its native partner interactions.

   Evidence Protein array, TR-FRET, native MS, NMR, X-ray crystallography, and cellular NanoBiT

   PMID:40059881

   Open questions at the time

   • Phenotypic consequence of blocking native interactions in disease cells not shown
   • Which native partners are most affected not defined

• How MAPRE1's microtubule plus-end tracking is mechanistically coupled to its CDK2-dependent cell cycle role remains unresolved.
• No structure of native MAPRE1 partner complexes (CDK2, CLASP2)
• No reconstitution linking microtubule activity to cell cycle progression