negative regulation of tau-protein kinase activity

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of tau-protein kinase activity. [GO_REF:0000059, GOC:sjp, GOC:TermGenie, PMID:15897157, PMID:22986780]

Negative regulation of tau-protein kinase activity is a crucial process that controls the phosphorylation of tau protein, a microtubule-associated protein. Dysregulation of this process is implicated in neurodegenerative disorders like Alzheimer's disease. The intricate network of mechanisms involved in this regulation includes:

1. **Protein Kinase Inhibition:**
- **Specific Kinase Inhibitors:** Certain kinases, such as glycogen synthase kinase 3 beta (GSK-3β), are directly inhibited by molecules that bind to their active site, preventing their ability to phosphorylate tau.
- **Post-translational Modifications:** Kinases themselves can be regulated by phosphorylation, acetylation, or ubiquitination, altering their activity and subsequently affecting tau phosphorylation.

2. **Phosphatase Activation:**
- **Protein Phosphatases:** Enzymes like protein phosphatase 2A (PP2A) dephosphorylate tau, removing phosphate groups and counteracting the effects of kinases.
- **Phosphatase Activators:** Factors that promote phosphatase activity, such as calcineurin and okadaic acid, can enhance tau dephosphorylation.

3. **Tau Protein Interactions:**
- **Microtubule Binding:** Tau's interaction with microtubules can influence its phosphorylation state. Binding to microtubules can reduce tau's accessibility to kinases, while dissociation from microtubules may increase its susceptibility to phosphorylation.
- **Chaperone Proteins:** Chaperone proteins, such as heat shock proteins (HSPs), can interact with tau and prevent its aggregation, potentially influencing its phosphorylation status.

4. **Signaling Pathways:**
- **Neurotrophic Factors:** Growth factors like nerve growth factor (NGF) can activate signaling pathways that promote tau dephosphorylation and neuronal survival.
- **Stress Response:** Cellular stress responses, such as oxidative stress, can trigger kinase activation and lead to increased tau phosphorylation.

5. **Other Mechanisms:**
- **MicroRNAs:** Small non-coding RNAs called microRNAs can regulate gene expression, including the expression of kinases and phosphatases involved in tau phosphorylation.
- **Metabolic Factors:** Glucose metabolism and insulin signaling pathways can influence tau phosphorylation, potentially through their effects on kinase activity.

The interplay of these intricate mechanisms ensures proper regulation of tau phosphorylation, crucial for maintaining microtubule stability and neuronal function. Disruption of this delicate balance can contribute to the pathological accumulation of hyperphosphorylated tau, leading to neurodegeneration and cognitive decline.'
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Proteins (1)

Compounds (1)