negative regulation of p38MAPK cascade

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of p38MAPK cascade. [GO_REF:0000058, GOC:TermGenie, PMID:18681888]

The p38 mitogen-activated protein kinase (MAPK) cascade is a signaling pathway involved in cellular responses to stress, such as inflammation, oxidative stress, and DNA damage. The cascade is activated by a series of kinases, ultimately leading to the phosphorylation and activation of p38 MAPK. Negative regulation of the p38 MAPK cascade is essential for maintaining cellular homeostasis and preventing excessive or inappropriate activation. This regulation occurs at multiple levels:

1. **Upstream Regulation:**
* **Inhibition of upstream kinases:** Kinases that activate p38 MAPK, such as MKK3 and MKK6, can be inhibited by phosphatases or by the action of inhibitory proteins. For example, MKP-1 (MAPK phosphatase-1) dephosphorylates and inactivates MKK3 and MKK6.
* **Blockade of upstream signaling:** Activation of the p38 MAPK cascade often involves upstream receptor tyrosine kinases (RTKs). Inhibitors of RTKs, such as the small molecule inhibitor imatinib, can prevent the activation of the cascade.
* **Inhibition of scaffold proteins:** Scaffold proteins, such as Ksr1 (kinase suppressor of Ras 1), can facilitate the assembly of the p38 MAPK signaling complex. Inhibiting these scaffold proteins can disrupt the formation of the complex and prevent p38 MAPK activation.

2. **Regulation of p38 MAPK Activity:**
* **Dephosphorylation:** Specific phosphatases, such as MKP-1, can dephosphorylate and inactivate p38 MAPK.
* **Inhibitory proteins:** Proteins such as TAB1 (TGF-β-activated kinase 1-binding protein 1) and p14 can bind to and inhibit p38 MAPK.

3. **Downstream Regulation:**
* **Feedback loops:** Activated p38 MAPK can activate downstream targets that, in turn, inhibit p38 MAPK activity. For example, p38 MAPK can activate MKP-1, which then dephosphorylates and inactivates p38 MAPK.
* **Transcriptional regulation:** p38 MAPK can activate transcription factors that induce the expression of genes encoding inhibitory proteins, further contributing to negative regulation of the cascade.

Overall, the negative regulation of the p38 MAPK cascade is a complex process involving multiple levels of control. This tight regulation is crucial for maintaining cellular health and preventing aberrant signaling that can contribute to various diseases, including inflammation, cancer, and neurodegenerative disorders.'
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Proteins (2)

Compounds (10)