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Mitogen-activated protein kinase kinase kinase 14 (MAP3K14), commonly referred to as NF-κB-inducing kinase. (NIK)

Target
NIK
Molecular classification
Kinase, Enzyme, Protein Serine-Threonine Kinase, MAP kinase kinase kinase (MAP3K)
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Overview

NF-κB-inducing kinase (NIK) is a serine/threonine kinase encoded by the MAP3K14 gene that regulates the activation of the NF-κB transcription factor family, particularly through the non-canonical pathway. It phosphorylates p100, leading to its conversion into active p52 and subsequent nuclear translocation of NF-κB heterodimers, modulating gene expression critical for immune responses, cell survival, inflammation, and apoptosis. Dysregulation of NIK activity is implicated in autoimmunity and cancer, making it a therapeutic target of scientific and clinical interest. Its kinase domain is constitutively active in certain contexts, independent of phosphorylation, and its regulation maintains a balance between pro- and anti-inflammatory signaling events.

Other names
NF-κB-inducing kinaseNIKMAP3K14
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Mechanism of action

Drugs targeting NIK typically act as inhibitors of its kinase activity, blocking non-canonical NF-κB activation and downstream gene transcription relevant to cell survival, proliferation, inflammation, and apoptosis resistance.

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Biological functions

Signal transductionRegulation of NF-κB activation (canonical and non-canonical pathways)Control of gene expressionCell survivalApoptosisImmune responseCell adhesion (including B cell adhesion)
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Disease associations

CancerAutoimmune diseaseInflammation (chronic and acute)Other immune disorders
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Safety considerations

Safety concerns include possible suppression of immune function and increased risk of infection or impaired tissue repair, due to blockade of essential signaling involved in immune responses and cell death regulation
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Interacting drugs

Several experimental inhibitors target MAP3K14/NIK in cancer and autoimmune research, but no approved clinical drugs are highly specific for NIK. Some kinase inhibitors with broader activity may impact NIK. Example: experimental NIK inhibitors (such as AM-0216 in preclinical studies)
07

Biomarkers

No clinical biomarkers are established solely for NIK, but elevated NIK protein/activity or expression of downstream non-canonical NF-κB target genes may serve investigational biomarker roles in disease models

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