AURKA (Aurora Kinase A), also known as Aurora A, is a serine/threonine protein kinase encoded by the AURKA gene located on chromosome 20. AURKA is a master regulator of mitosis, controlling centrosome maturation, spindle assembly, and proper chromosome segregation. While primarily studied in the context of cancer biology, AURKA has emerging roles in neuronal development and neurodegenerative diseases.
AURKA is a 403-amino acid protein with a molecular weight of approximately 46 kDa. The protein consists of several functional domains:
¶ Catalytic Domain
- N-terminal domain (residues 1-127): Regulatory region containing the Aurora-box motif
- Kinase domain (residues 128-391): Catalytic serine/threonine kinase domain
- C-terminal domain (residues 392-403): Destruction box (D-box) for degradation
- Activation loop: Contains threonine-288 (T288) that requires phosphorylation for full activity
- Aurora-box: N-terminal motif important for localization and substrate recognition
- D-box: Destruction box mediating ubiquitin-dependent degradation
- A-box: Negative regulatory motif
The crystal structure of AURKA has been solved (PDB: 1OL5, 2DWB), revealing the typical bilobal kinase fold with the catalytic site located in a deep cleft between the N-terminal and C-terminal lobes.
AURKA is essential for mitotic progression through multiple mechanisms:
Centrosome Maturation
- AURKA accumulates at centrosomes during G2/M transition
- Recruits and activates pericentriolar material (PCM) proteins
- Promotes centrosome separation and maturation
- Essential for proper spindle pole formation
Spindle Assembly
- Phosphorylates microtubule-associated proteins (MAPs)
- Stabilizes spindle microtubules
- Promotes bipolar spindle formation
- Regulates spindle assembly checkpoint
Chromosome Segregation
- Phosphorylates histone H3 at serine-10 (H3S10ph)
- Modifies centromere and kinetochore function
- Ensures proper chromosome alignment
- Prevents aneuploidy
Cytokinesis
- Localizes to midbody during cytokinesis
- Regulates abscission
- Controls completion of cell division
Beyond mitosis, AURKA has additional cellular roles:
- DNA damage response: Involved in ATM/ATR pathway activation
- Cellular polarity: Regulates apical-basal polarity in epithelial cells
- Ciliogenesis: Important for primary cilia formation
- Pluripotency maintenance: Regulates stem cell function
AURKA has complex and context-dependent roles in Alzheimer's disease:
Cell Cycle Re-entry
- Neurons in AD brain show mitotic markers, including AURKA activation
- Aberrant cell cycle re-entry is a hallmark of vulnerable neurons
- AURKA may promote inappropriate mitotic attempts in post-mitotic neurons
- Leads to neuronal dysfunction and death
Amyloid-beta Effects
- Aβ oligomers can activate AURKA in neurons
- Creates toxic signaling cascade
- Contributes to synaptic dysfunction
Tau Pathology
- AURKA can phosphorylate tau at multiple sites
- May contribute to tau hyperphosphorylation
- Links cell cycle abnormalities to neurofibrillary pathology
Therapeutic Implications
- AURKA inhibitors show protective effects in AD models
- Alisertib and other AURKA inhibitors in preclinical testing
- Must balance mitotic inhibition with potential side effects
Dopaminergic Neuron Vulnerability
- AURKA expression altered in PD brain
- May affect protein clearance mechanisms
- Links cell cycle dysregulation to dopaminergic neuron loss
Alpha-synuclein Pathology
- AURKA can phosphorylate alpha-synuclein at serine-129
- This phosphorylation promotes aggregation
- AURKA activity may accelerate Lewy body formation
Motor Neuron Development
- AURKA essential for proper motor neuron development
- Mutations cause neurodevelopmental defects
- May affect motor neuron connectivity
Protein Homeostasis
- AURKA regulates autophagy pathways
- Dysfunction may contribute to protein aggregate accumulation
- Links cell cycle to protein quality control
Neural Progenitor Cells
- AURKA critical for neural progenitor cell proliferation
- Regulates symmetric versus asymmetric division
- Microcephaly seen in AURKA gain-of-function mutants
Axon Guidance
- AURKA localizes to growth cones
- Regulates cytoskeletal dynamics
- Important for neuronal connectivity
AURKA is a validated cancer target:
Clinical Inhibitors
- Alisertib (MLN8237): Oral selective AURKA inhibitor in clinical trials
- VX-680 (Tozasertib): Pan-aurora kinase inhibitor
- AMG 900: Potent pan-aurora inhibitor
Mechanism
- Induces mitotic arrest and apoptosis in dividing cells
- Effective in tumors with AURKA amplification
- Being tested in solid tumors and hematological malignancies
Potential applications in AD/PD:
AURKA Inhibitors
- Lower doses than cancer therapy
- Must cross blood-brain barrier
- Protective in cellular and mouse models
Combination Approaches
- AURKA + tau kinase inhibitors
- AURKA + autophagy modulators
- Disease-modifying potential
Studying AURKA in neurodegeneration:
- Kinase activity assays: Measure AURKA activity in brain tissue
- Phospho-antibodies: Detect phosphorylated substrates
- Inhibitor studies: Use Alisertib, VX-680 in models
- Genetic models: Transgenic mice, knockdown/knockout systems
¶ Interactions and Pathways
AURKA interacts with multiple proteins:
| Partner |
Interaction |
Functional Consequence |
| TPX2 |
Direct binding |
spindle localization |
| Ajap1 |
Interaction |
Mitotic regulation |
| p53 |
Phosphorylation |
DNA damage response |
| LKB1 |
Phosphorylation |
Metabolic regulation |
| HDAC6 |
Deacetylation |
Microtubule function |