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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Protein | Definition | Taxonomy |
---|---|---|
E3 ubiquitin-protein ligase ZFP91 | An E3 ubiquitin-protein ligase ZFP91 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q96JP5] | Homo sapiens (human) |
Compound | Definition | Classes | Roles |
---|---|---|---|
pomalidomide | 3-aminophthalimidoglutarimide: structure in first source | aromatic amine; dicarboximide; isoindoles; piperidones | angiogenesis inhibitor; antineoplastic agent; immunomodulator |