Alt. symbols: NIK | HSNIK | FTDCR1B | HS

Approved name: mitogen-activated protein kinase kinase kinase 14
Alt. names: serine/threonine protein-kinase

Location: 17q21.31: 45263119 - 45317029 (-)
Gene type: protein_coding, 6 transcripts.

Scores: LoFtool: | pLI: | LOEUF:

HGNC: 6853

NCBI: 9020, RefSeq: NG_033823.1

Ensembl: ENSG00000006062.18

LRG_1222 | Status: public

OMIM: 604655

Expression | ProteinAtlas

MAP3K14 encodes NIK (NF-κB inducing kinase), a lymphotoxin beta-activated kinase important for the activation of NF-kappaB and its transcriptional activity. NIK promotes the proteolytic processing of NFKB2-encoded p100 into its mature p52 form via its substrate IkappaB kinase alpha (IKKalpha), leading to activation of the non-canonical NF-kappaB pathway. This pathway is controlled by TNF receptor associated factor (TRAF) proteins TRAF2 and NIK’s negative regulator TRAF3 (PMID: 22435551). At baseline, a TRAF3-containing complex continuously targets NIK for degradation, until receptor activation leads to TRAF3 degradation, allowing NIK to accumulate and phosphorylate and activate downstream effectors.

Willmann et al. (2014) identified homozygous missense mutations in MAP3K14 leading to kinase loss-of-function in patients from a large consanguineous family presenting with combined immunodeficiency featuring B-cell lymphopenia and impaired memory B-cell differentiation, abnormal NK-cell development and function, as well as aberrant T-cell responses. Specifically, immunophenotyping found impaired canonical and non-canonical NF-kappaB signaling, leading to the reduced ability to perform class swi tch recombination and somatic hypermutation, decreased frequencies of class-switched memory B cells and hypogammaglobulinemia due to impaired B-cell survival, and impaired ICOSL expression. Although overall T-cell numbers were normal, both follicular helper and memory T cells were perturbed, while NK cells were decreased in number and exhibited defective activation, leading to impaired formation of NK-cell immunological synapses. Of note, the patients showed significant gastrointestinal mucosal lesions on endoscopy and were susceptible to recurrent infections from pathogens such as CMV and Cryptosporidium. One patient also developed granulomatous hepatitis. Beyond this, both noncanonical NK-kappaB signaling and specifically NIK have been implicated in IBD through roles in the maintenance of intestinal immunity and homeostasis and mature B cell development, and some emerging data suggest that NIK expression may impact IBD patient responses to anti-TNF therapy (PMID: 30250187, 34177575, 24776844). [Load More]