PLK3 (Polo-Like Kinase 3) is a serine/threonine protein kinase that plays critical roles in stress response, DNA damage repair, and cell cycle regulation. While initially studied in cancer biology, PLK3 has emerged as an important player in neurodegenerative diseases through its functions in neuronal survival, DNA repair, and cell cycle control.
| PLK3 Protein |
|---|
| Protein Name | Polo-Like Kinase 3 (PLK3) |
| Gene | [PLK3](/genes/plk3) |
| UniProt ID | [O14987](https://www.uniprot.org/uniprot/O14987) |
| Molecular Weight | ~70 kDa |
| Subcellular Localization | Centrosome, nucleus, cytoplasm |
| Protein Family | Serine/threonine protein kinase (PLK family) |
| Expression | Ubiquitous; high in brain, heart, kidney |
PLK3 contains the characteristic architecture of polo-like kinases:
- N-terminal serine/threonine kinase domain: Catalytic domain with activation loop
- Polo-box domain (PBD): C-terminal regulatory domain with two polo boxes that recognize phosphorylated substrates
- Regulatory phosphorylation sites: Multiple sites for activation and feedback control
- Nuclear localization signals: NLS sequences for nuclear import
The PBD mediates substrate recognition and subcellular localization.
PLK3 is activated by various genotoxic stresses:
- ATM/ATR activation: Responds to DNA double-strand breaks and replication stress
- Chk1/Chk2 phosphorylation: Activates downstream checkpoint kinases
- Centrosome maturation: Maintains centrosome function during stress
- Cell cycle arrest: Induces G2/M checkpoint to allow DNA repair
- Oxidative stress: Activated by reactive oxygen species (ROS)
- Hypoxia: Responds to oxygen deprivation
- Apoptosis regulation: Modulates both pro- and anti-apoptotic pathways
- G2/M checkpoint: Prevents mitotic entry with damaged DNA
- Centrosome separation: Regulates mitotic spindle formation
- Cytokinesis: Functions in late mitosis
PLK3 contributes to AD pathogenesis through several mechanisms:
- Cell cycle re-entry: Neurons in AD show aberrant cell cycle activation; PLK3 may drive this process
- DNA damage accumulation: Impaired PLK3-mediated repair contributes to genomic instability
- Tau phosphorylation: PLK3 can phosphorylate tau at pathological sites
- Neuronal apoptosis: Dysregulated PLK3 may promote neuronal death
- Oxidative stress response: PLK3 activation by ROS may be impaired in PD
- Alpha-synuclein toxicity: Interactions with synucleinopathy
- Mitochondrial dysfunction: PLK3 responds to mitochondrial DNA damage
- Dopaminergic neuron survival: Critical for survival pathways in substantia nigra
Multiple PLK3 inhibitors have been developed:
- Volasertib: Potent PLK inhibitor in clinical trials
- BI 2536: Selectively targets PLK1-3
Potential therapeutic strategies:
- Modulation: Small molecules that normalize PLK3 activity
- Gene therapy: Viral delivery of PLK3 constructs
- Combination approaches: Targeting PLK3 with DNA repair enhancers