MGP Database

MGP002089

UniProt Annotations

Entry Information

Gene Name	nuclear factor of kappa light polypeptide gene enhancer in B-cells 2 (p49/p100)
Protein Entry	NFKB2_HUMAN
UniProt ID	Q00653
Species	Human

Comments

Comment type	Description
Alternative Products	Event=Alternative splicing; Named isoforms=3; Name=1; Synonyms=p100; IsoId=Q00653-1; Sequence=Displayed; Name=3; Synonyms=p49; IsoId=Q00653-3; Sequence=VSP_040082, VSP_040083; Note=Ref.1 (CAA43716.1) sequence(s) differ(s) from that shown due to frameshifts in positions 407, 414.; Name=4; IsoId=Q00653-4; Sequence=VSP_040084;
Disease	Immunodeficiency, common variable, 10 (CVID10) [MIM:615577]: A primary immunodeficiency characterized by childhood-onset of recurrent infections, hypogammaglobulinemia, and decreased numbers of memory and marginal zone B-cells. Some patients may develop autoimmune features and have circulating autoantibodies. An unusual feature is central adrenal insufficiency. {ECO:0000269\|PubMed:24140114}. Note=The disease is caused by mutations affecting the gene represented in this entry.
Disease	Note=A chromosomal aberration involving NFKB2 is found in a case of B-cell non Hodgkin lymphoma (B-NHL). Translocation t(10;14)(q24;q32) with IGHA1. The resulting oncogene is also called Lyt-10C alpha variant.
Disease	Note=A chromosomal aberration involving NFKB2 is found in a cutaneous T-cell leukemia (C-TCL) cell line. This rearrangement produces the p80HT gene which codes for a truncated 80 kDa protein (p80HT).
Disease	Note=In B-cell leukemia (B-CLL) cell line, LB40 and EB308, can be found after heterogeneous chromosomal aberrations, such as internal deletions.
Domain	The C-terminus of p100 might be involved in cytoplasmic retention, inhibition of DNA-binding by p52 homodimers, and/or transcription activation. {ECO:0000250}.
Domain	The glycine-rich region (GRR) appears to be a critical element in the generation of p52.
Function	NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF- kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. In a non-canonical activation pathway, the MAP3K14- activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes. The NF-kappa-B heterodimeric RelB-p52 complex is a transcriptional activator. The NF-kappa-B p52-p52 homodimer is a transcriptional repressor. NFKB2 appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins by p100 and generation of p52 by a cotranslational processing. The proteasome-mediated process ensures the production of both p52 and p100 and preserves their independent function. p52 binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. p52 and p100 are respectively the minor and major form; the processing of p100 being relatively poor. Isoform p49 is a subunit of the NF-kappa-B protein complex, which stimulates the HIV enhancer in synergy with p65. In concert with RELB, regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK- ARNTL/BMAL1 heterodimer. {ECO:0000269\|PubMed:7925301}.
Interaction	O00255-2:MEN1; NbExp=3; IntAct=EBI-9869360, EBI-9869387; P19838:NFKB1; NbExp=4; IntAct=EBI-307326, EBI-300010; Q04864:REL; NbExp=3; IntAct=EBI-307326, EBI-307352; Q01201:RELB; NbExp=3; IntAct=EBI-307326, EBI-357837; P63165:SUMO1; NbExp=2; IntAct=EBI-307326, EBI-80140;
Ptm	Constitutive processing is tightly suppressed by its C- terminal processing inhibitory domain, named PID, which contains the death domain.
Ptm	Subsequent to MAP3K14-dependent serine phosphorylation, p100 polyubiquitination occurs then triggering its proteasome-dependent processing. {ECO:0000269\|PubMed:11239468, ECO:0000269\|PubMed:14676825, ECO:0000269\|PubMed:18669648, ECO:0000269\|PubMed:8887665}.
Ptm	While translation occurs, the particular unfolded structure after the GRR repeat promotes the generation of p52 making it an acceptable substrate for the proteasome. This process is known as cotranslational processing. The processed form is active and the unprocessed form acts as an inhibitor (I kappa B-like), being able to form cytosolic complexes with NF-kappa B, trapping it in the cytoplasm. Complete folding of the region downstream of the GRR repeat precludes processing.
Sequence Caution	Sequence=CAA43715.1; Type=Frameshift; Positions=456, 458, 470, 900; Evidence={ECO:0000305};
Similarity	Contains 1 death domain. {ECO:0000305}.
Similarity	Contains 1 RHD (Rel-like) domain. {ECO:0000255\|PROSITE-ProRule:PRU00265}.
Similarity	Contains 7 ANK repeats. {ECO:0000255\|PROSITE- ProRule:PRU00023}.
Subcellular Location	Nucleus. Cytoplasm. Note=Nuclear, but also found in the cytoplasm in an inactive form complexed to an inhibitor (I-kappa-B).
Subunit	Component of the NF-kappa-B RelB-p52 complex. Homodimer; component of the NF-kappa-B p52-p52 complex. Component of the NF- kappa-B p65-p52 complex. Component of the NF-kappa-B p52-c-Rel complex. NFKB2/p52 interacts with NFKBIE. Component of a complex consisting of the NF-kappa-B p50-p50 homodimer and BCL3. Directly interacts with MEN1. {ECO:0000269\|PubMed:11526476, ECO:0000269\|PubMed:16477006, ECO:0000269\|PubMed:7925301, ECO:0000269\|PubMed:8152812, ECO:0000269\|PubMed:8453667, ECO:0000269\|PubMed:9315679}.
Web Resource	Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/NFKB2ID362.html";
Web Resource	Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/nfkb2/";