NIK/MAP3K14

NIK/MAP3K14 is a serine/threonine MAP3K that binds TRAF2 and stimulates NF-κB activation^[1]. Mechanistically, NIK integrates TNF/NGF-family, CD95, and IL-1 receptor signals into an NF-κB-inducing cascade^[1]. In the non-canonical NF-κB pathway, stabilized NIK activates IKKα, drives p100 phosphorylation and ubiquitin-dependent processing, and generates p52/RelB transcriptional signaling^[2][3]. This function distinguishes MAP3K14 from broader MAP3K isoforms because NIK is the central kinase controlling non-canonical NF-κB rather than a general MAPK-cascade activator^[2][3]. In human disease, biallelic MAP3K14 loss-of-function mutations cause primary immunodeficiency with B-cell lymphopenia, hypogammaglobulinemia, perturbed follicular helper and memory T cells, and defective NK-cell activation^[4]. In cancer models, NIK also regulates mitochondrial fission, mitochondrial trafficking, and cytokine-induced invasion independently of canonical NF-κB signaling^[5]. For experimental applications, selective NIK inhibitors provide tools to suppress non-canonical NF-κB signaling and test anti-inflammatory mechanisms in vitro and in vivo^[6].