negative regulation of JNK cascade

Definition

Target type: biologicalprocess

Any process that stops, prevents, or reduces the frequency, rate or extent of signal transduction mediated by the JNK cascade. [GOC:bf]

The JNK (c-Jun N-terminal kinase) cascade is a critical signaling pathway involved in various cellular processes, including cell proliferation, apoptosis, and inflammation. Negative regulation of the JNK cascade is essential for maintaining cellular homeostasis and preventing aberrant activation. This regulation is achieved through a complex interplay of multiple mechanisms, including:

**1. Deactivation of MAPKKKs:** The JNK cascade is initiated by MAPKKKs (mitogen-activated protein kinase kinase kinases), such as MEKK1, MEKK4, MLK3, and ASK1. These kinases are activated by various stimuli, including stress, cytokines, and growth factors. Deactivation of MAPKKKs through dephosphorylation or ubiquitination can effectively inhibit JNK activation.

**2. Inhibition of MAPKKs:** MAPKKs (mitogen-activated protein kinase kinases) are the immediate upstream kinases of JNK. MAPKK4 and MAPKK7 are the two main kinases responsible for JNK activation. Their inhibition through dephosphorylation or interaction with inhibitory proteins can suppress JNK signaling.

**3. JNK Phosphatases:** JNK can be dephosphorylated and inactivated by specific phosphatases, such as PP2A and MKP-7. These phosphatases can remove phosphate groups from JNK, rendering it inactive.

**4. Scaffolding Proteins:** Scaffold proteins, such as JIP1 and JIP2, can regulate JNK signaling by sequestering JNK or its upstream kinases. This sequestration prevents JNK activation or interaction with its downstream targets.

**5. Feedback Inhibition:** JNK itself can participate in feedback inhibition by activating transcription factors that induce the expression of JNK phosphatases or inhibitory proteins, thus suppressing its own activity.

**6. Ubiquitination and Degradation:** Ubiquitination of JNK or its upstream kinases can target them for proteasomal degradation, effectively reducing their levels and attenuating the JNK cascade.

**7. Competition with Other Signaling Pathways:** Activation of other signaling pathways, such as the ERK pathway, can compete with the JNK pathway for shared components, such as MAPKKKs, thereby modulating JNK signaling.

These various regulatory mechanisms work in concert to ensure the proper control of JNK signaling. Dysregulation of JNK can lead to various diseases, highlighting the importance of its negative regulation.'
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Proteins (7)

Compounds (357)