positive regulation of JNK cascade

Definition

Target type: biologicalprocess

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

The JNK (c-Jun N-terminal kinase) cascade, also known as the SAPK (stress-activated protein kinase) pathway, is a crucial signaling pathway involved in cellular responses to various stresses, including oxidative stress, DNA damage, and inflammatory stimuli. It plays a critical role in regulating a wide range of cellular processes, including apoptosis, proliferation, inflammation, and differentiation. Positive regulation of the JNK cascade involves a complex interplay of signaling molecules, receptors, and protein modifications that ultimately lead to the activation of JNK kinases.

The JNK cascade can be activated by a variety of upstream signals, including:

1. **Growth factor receptors:** Members of the TNF receptor superfamily, such as TNF-α receptor (TNFR1), Fas receptor (CD95), and TRAIL receptor, can activate the JNK pathway upon ligand binding. These receptors recruit adaptor proteins, such as TRADD and FADD, which assemble a death-inducing signaling complex (DISC). The DISC activates caspase-8, which then cleaves and activates Bid, a pro-apoptotic protein. Bid translocates to mitochondria and triggers the release of cytochrome c, which activates the apoptotic cascade.
2. **Stress-activated receptors:** Receptors that respond to various stresses, such as UV radiation, heat shock, and osmotic stress, can activate the JNK pathway. These receptors include toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns (PAMPs), and receptor tyrosine kinases (RTKs), which are activated by growth factors.
3. **GTPases:** Small GTPases, such as Rac1 and Cdc42, which are involved in cytoskeletal remodeling and cell migration, can also activate the JNK pathway. These GTPases can activate the JNK pathway through the activation of downstream kinases, such as MEKK1 and MEKK4.

Once activated, the JNK cascade involves a series of phosphorylation events that lead to the activation of JNK kinases. These kinases then phosphorylate a variety of downstream substrates, including transcription factors, such as c-Jun, ATF2, and Elk-1, and other kinases, such as MAPKAPK2 (MK2) and MSK1.

**Key steps involved in positive regulation of the JNK cascade:**

1. **Upstream signal transduction:** The upstream signals described above activate various adaptor proteins and kinases, including TRAF2, TRAF6, ASK1, and TAK1.
2. **Activation of MEKKs:** These adaptor proteins and kinases activate the mitogen-activated protein kinase kinase kinases (MEKKs), such as MEKK1, MEKK4, and MEKK7.
3. **Activation of MKKs:** MEKKs activate the mitogen-activated protein kinase kinases (MKKs), such as MKK4 and MKK7, by phosphorylating them on specific residues.
4. **Activation of JNKs:** MKK4 and MKK7 phosphorylate JNKs, leading to their activation. JNKs are a family of serine/threonine kinases that are highly conserved in eukaryotes.
5. **Phosphorylation of downstream substrates:** Activated JNKs phosphorylate a variety of downstream substrates, including transcription factors, kinases, and other proteins. This phosphorylation can modulate the activity of these substrates, leading to a wide range of cellular responses.

**Negative regulation of the JNK cascade:**

The JNK pathway is tightly regulated to prevent its inappropriate activation. Several mechanisms are involved in negative regulation, including:

1. **Protein phosphatases:** Protein phosphatases, such as PP2A and PP2C, dephosphorylate JNKs and other components of the pathway, leading to their inactivation.
2. **Ubiquitination and degradation:** JNKs and other signaling molecules involved in the pathway can be ubiquitinated and degraded by the proteasome, which further reduces their activity.
3. **Negative feedback loops:** The JNK pathway itself can activate negative feedback loops that inhibit its further activation. For example, activated JNKs can phosphorylate and activate JNK-interacting proteins (JIPs), which act as scaffolding proteins to sequester JNKs and prevent their further activation.

The JNK cascade plays a critical role in a wide range of cellular processes, including apoptosis, proliferation, inflammation, and differentiation. Dysregulation of the JNK pathway has been implicated in various diseases, including cancer, inflammation, and neurodegenerative diseases. Therefore, understanding the complex mechanisms underlying the positive and negative regulation of the JNK cascade is crucial for developing targeted therapies for these diseases.'"

Proteins (40)

Compounds (578)