MAP6 and CRMP2 may be simultaneously phosphorylated by GSK3β at shared or interacting sites, creating a coordinated phosphorylation code that regulates microtubule dynamics in response to guidance cues
Prediction: Simultaneous disruption of MAP6 and CRMP2 phosphorylation sites would produce more severe axon guidance defects than single knockouts, and neuronal activity-dependent phosphorylation events would show correlated changes in both proteins
No AI visual card yet
Curated Mechanism Pathway
Curated pathway diagram from expert analysis
flowchart TD
A["MAPT/Tau Occupancy Dynamic Microtubule Binding"]
B["MAP6 Occupancy Cold-Stable Domain Support"]
C["Shared Microtubule Lattice Domain Allocation Competition"]
D["GSK3B/CRMP2 Cue Integration Plasticity Signaling"]
E["Axonal Remodeling Balance Stable vs Labile Segments"]
F["Transport and Branching Adaptive Circuit Plasticity"]
G["Tau-MAP6 Imbalance Rigid or Unstable Cytoskeleton"]
A --> C
B --> C
C --> D
D --> E
E --> F
G -.->|"disrupts"| C
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style B fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style F fill:#1b5e20,stroke:#81c784,color:#81c784
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
Median TPM across 13 brain regions for MAP6/CRMP2 from GTEx v10.
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8 citations7 with PMID5 mediumValidation: 50%6 supporting / 2 opposing
✓For(6)
5
No opposing evidence
(2)Against✗
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Evidence Matrix — sortable by strength/year, click Abstract to expand
Evidence Types
3
2
3
MECH 3CLIN 2GENE 3EPID 0
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PMIDs
Abstract
Druggability of CRMP2 for Neurodegenerative Diseas…
MAP6 and CRMP2 may be simultaneously phosphorylated by GSK3β at shared or interacting sites, creating a coordi…▼
MAP6 and CRMP2 may be simultaneously phosphorylated by GSK3β at shared or interacting sites, creating a coordinated phosphorylation code that regulates microtubule dynamics in response to guidance cues
Druggability of CRMP2 for Neurodegenerative Diseases.MEDIUM
Balastik M et al., Cell Rep 2015 Oct 27 · PMID:26489457
No claimMODERATE
Uchida Y et al., J Biol Chem 2009 Oct 2 · PMID:19652227
Multi-persona evaluation:
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💬 Discussion
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No DepMap CRISPR Chronos data found for MAP6/CRMP2.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
IF primary rodent hippocampal neurons are treated with a selective GSK3β inhibitor (CHIR99021, 10 μM) for 24 hours, THEN phospho-S9-GSK3β inhibition will produce a coordinated decrease in p-CRMP2(S522) and p-MAP6(S236) levels with a correlation coefficient >0.7 across neuronal preparations, within 48 hours post-treatment
pendingconf: 0.65
Expected outcome: Simultaneous reduction of p-MAP6(S236) and p-CRMP2(S522) by >40% in western blot analysis, with correlated temporal dynamics between the two phosphoproteins
Falsified by: GSK3β inhibition affects phosphorylation of only one protein (MAP6 or CRMP2) while leaving the other unchanged; or phosphorylation changes are anti-correlated (r < 0.0); or neither protein's phosphorylation is significantly altered
Method: Primary hippocampal neurons (E18 Sprague-Dawley, DIV 7-10) treated with GSK3β inhibitor, harvested at 0, 6, 12, 24, 48h for phospho-specific western blot using antibodies against p-CRMP2(S522) (Cell Signaling #9394) and p-MAP6(S236) (custom antibody), normalized to total CRMP2 and MAP6
IF CRISPR-Cas9 is used to generate MAP6 S236A;CRMP2 S522A double knock-in mice (simultaneous alanine substitution at both phosphorylation sites), THEN cortical neurons from these mice will display exaggerated growth cone collapse (>60% collapse rate) and microtubule plus-end instability (>30% reduction in EB3 comet velocity) compared to either single mutant line when exposed to Sema3A (100 ng/mL) for 30 minutes
pendingconf: 0.55
Expected outcome: Double mutants show synergistic increase in growth cone collapse percentage and decrease in microtubule polymerization rate relative to single mutants and wild-type controls
Falsified by: Double mutant phenotype is statistically indistinguishable from wild-type (no facilitation); or single mutant phenotypes are equal to or greater than double mutant (no cooperative requirement); or microtubule dynamics are unaffected in all genotypes
Method: CRISPR-Cas9 editing to create double point mutants in C57BL/6J mice; primary cortical neuron cultures from E14.5 embryos; growth cone collapse assay with semaphorin 3A (Peprotech) after 30 min; EB3-GFP live-cell imaging to measure microtubule plus-end dynamics; blinded manual scoring of 100+ growth cones per condition
Knowledge Subgraph (0 edges)
No knowledge graph edges recorded
Predicted Protein Structure
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MAP6 — AlphaFold Prediction Q96JE9Click to expand 3D viewer
AI-predicted structure from AlphaFold | Powered by Mol* | Rotate: click+drag | Zoom: scroll | Reset: right-click