activation of NF-kappaB-inducing kinase activity

Definition

Target type: biologicalprocess

The stimulation of the activity of NF-kappaB-inducing kinase through phosphorylation at specific residues. [GOC:jl, PMID:12773372]

NF-kappaB-inducing kinase (NIK) is a serine/threonine kinase that plays a crucial role in the activation of the non-canonical NF-kappaB pathway. This pathway is distinct from the canonical NF-kappaB pathway and is primarily involved in the regulation of immune responses, development, and cell survival.

The activation of NIK involves a complex interplay of signaling events and protein interactions. Here's a detailed description of the process:

1. **Stimulus Recognition:** The non-canonical NF-kappaB pathway is typically triggered by specific stimuli, such as tumor necrosis factor alpha (TNF-alpha), lymphotoxin-beta (LT-beta), or CD40 ligand (CD40L). These stimuli bind to their respective receptors, leading to the recruitment of adaptor proteins and the formation of signaling complexes.

2. **IKK Complex Formation:** The activation of NIK requires the formation of a specific IKK complex, which includes the kinases IKKalpha, IKKbeta, and NEMO (NF-kappaB essential modulator). Unlike the canonical pathway, where IKKalpha and IKKbeta are activated, the non-canonical pathway relies on the activation of NIK.

3. **c-IAP-mediated Degradation:** Initially, NIK is held in check by a family of E3 ubiquitin ligases known as c-IAPs (cellular inhibitor of apoptosis proteins). These ligases target NIK for ubiquitination and subsequent degradation via the proteasome.

4. **Stimulus-induced c-IAP Inhibition:** Upon receptor activation, the signaling complex triggers the activation of TRAF2 and TRAF3 adaptor proteins. These adaptor proteins interact with c-IAPs and promote their ubiquitination and degradation. This inactivation of c-IAPs relieves the inhibitory pressure on NIK.

5. **NIK Stabilization and Activation:** With c-IAPs removed, NIK is no longer targeted for degradation and becomes stabilized. Furthermore, the signaling complex activates NIK through phosphorylation, enhancing its kinase activity.

6. **IKKalpha Activation and NF-kappaB Signaling:** Activated NIK phosphorylates IKKalpha, leading to its activation. IKKalpha then phosphorylates the NF-kappaB transcription factors p100 and RelB. Phosphorylation of p100 triggers its processing, generating the active p52 subunit. The p52 subunit forms a heterodimer with RelB, which translocates to the nucleus and regulates the expression of target genes involved in immune responses and development.

7. **Feedback Regulation:** The activation of the non-canonical NF-kappaB pathway involves feedback mechanisms that further fine-tune its activity. For example, NF-kappaB-induced genes can encode proteins that either promote or inhibit the pathway, ensuring appropriate regulation of downstream responses.

In summary, the activation of NIK is a tightly regulated process that involves multiple steps, including the recruitment of signaling components, the removal of inhibitory proteins, and the activation of downstream kinases. This pathway plays a vital role in immune responses, development, and cell survival.'
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Proteins (1)

Compounds (1)