Q99558 · M3K14_HUMAN
- ProteinMitogen-activated protein kinase kinase kinase 14
- GeneMAP3K14
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids947 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Lymphotoxin beta-activated kinase which seems to be exclusively involved in the activation of NF-kappa-B and its transcriptional activity. Phosphorylates CHUK/IKKA, thereby promoting proteolytic processing of NFKB2/P100, which leads to NF-kappa-B activation via the non-canonical pathway (PubMed:25406581, PubMed:29230214).
Has an essential role in the non-canonical NF-kappa-B signaling that regulates genes encoding molecules involved in B-cell survival, lymphoid organogenesis, and immune response (PubMed:25406581).
Could act in a receptor-selective manner
Has an essential role in the non-canonical NF-kappa-B signaling that regulates genes encoding molecules involved in B-cell survival, lymphoid organogenesis, and immune response (PubMed:25406581).
Could act in a receptor-selective manner
Catalytic activity
- ATP + L-seryl-[protein] = ADP + H+ + O-phospho-L-seryl-[protein]
Features
Showing features for binding site, active site.
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | cytosol | |
Cellular Component | fibrillar center | |
Cellular Component | intracellular membrane-bounded organelle | |
Cellular Component | nucleoplasm | |
Molecular Function | ATP binding | |
Molecular Function | MAP kinase kinase kinase activity | |
Molecular Function | protein kinase activity | |
Molecular Function | protein serine kinase activity | |
Molecular Function | protein serine/threonine kinase activity | |
Biological Process | canonical NF-kappaB signal transduction | |
Biological Process | cellular response to mechanical stimulus | |
Biological Process | defense response to virus | |
Biological Process | immune response | |
Biological Process | non-canonical NF-kappaB signal transduction |
Keywords
- Molecular function
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameMitogen-activated protein kinase kinase kinase 14
- EC number
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionQ99558
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
Disease & Variants
Involvement in disease
Immunodeficiency 112 (IMD112)
- Note
- DescriptionAn autosomal recessive, primary immunologic disorder characterized by variable abnormalities affecting lymphoid immunity, including hypogammaglobulinemia, lymphopenia or paradoxical lymphocytosis, and recurrent bacterial, viral, and fungal infections.
- See alsoMIM:620449
Natural variants in IMD112
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_088815 | 345 | V>M | in IMD112; uncertain significance; decreased phosphorylation of CHUK/IKKA | |
VAR_088816 | 565 | P>R | in IMD112; likely pathogenic; loss of function in non-canonical NF-kappaB signal transduction; unable to phosphorylate CHUK/IKKA |
Features
Showing features for natural variant, mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_040711 | 140 | in dbSNP:rs11574819 | |||
Sequence: S → N | ||||||
Natural variant | VAR_051641 | 255 | in dbSNP:rs11574820 | |||
Sequence: T → M | ||||||
Natural variant | VAR_088815 | 345 | in IMD112; uncertain significance; decreased phosphorylation of CHUK/IKKA | |||
Sequence: V → M | ||||||
Mutagenesis | 429-430 | Loss of autophosphorylation and 'Lys-63'-linked ubiquitination. Unable to phosphorylate CHUK/IKKA. | ||||
Sequence: KK → AA | ||||||
Natural variant | VAR_040712 | 514 | in a lung neuroendocrine carcinoma sample; somatic mutation; requires 2 nucleotide substitutions | |||
Sequence: G → K | ||||||
Mutagenesis | 559 | Abolishes 'Lys-63'-linked ubiquitination. | ||||
Sequence: T → A | ||||||
Natural variant | VAR_088816 | 565 | in IMD112; likely pathogenic; loss of function in non-canonical NF-kappaB signal transduction; unable to phosphorylate CHUK/IKKA | |||
Sequence: P → R | ||||||
Natural variant | VAR_051642 | 674 | in dbSNP:rs11867907 | |||
Sequence: H → Y | ||||||
Natural variant | VAR_040713 | 764 | in dbSNP:rs56302559 | |||
Sequence: T → A | ||||||
Natural variant | VAR_040714 | 852 | in an ovarian mucinous carcinoma sample; somatic mutation | |||
Sequence: T → I | ||||||
Natural variant | VAR_040715 | 928 | in dbSNP:rs56036201 | |||
Sequence: P → H |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 905 variants from UniProt as well as other sources including ClinVar and dbSNP.
Keywords
- Disease
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain, modified residue.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000086266 | 1-947 | Mitogen-activated protein kinase kinase kinase 14 | |||
Sequence: MAVMEMACPGAPGSAVGQQKELPKAKEKTPPLGKKQSSVYKLEAVEKSPVFCGKWEILNDVITKGTAKEGSEAGPAAISIIAQAECENSQEFSPTFSERIFIAGSKQYSQSESLDQIPNNVAHATEGKMARVCWKGKRRSKARKKRKKKSSKSLAHAGVALAKPLPRTPEQESCTIPVQEDESPLGAPYVRNTPQFTKPLKEPGLGQLCFKQLGEGLRPALPRSELHKLISPLQCLNHVWKLHHPQDGGPLPLPTHPFPYSRLPHPFPFHPLQPWKPHPLESFLGKLACVDSQKPLPDPHLSKLACVDSPKPLPGPHLEPSCLSRGAHEKFSVEEYLVHALQGSVSSGQAHSLTSLAKTWAARGSRSREPSPKTEDNEGVLLTEKLKPVDYEYREEVHWATHQLRLGRGSFGEVHRMEDKQTGFQCAVKKVRLEVFRAEELMACAGLTSPRIVPLYGAVREGPWVNIFMELLEGGSLGQLVKEQGCLPEDRALYYLGQALEGLEYLHSRRILHGDVKADNVLLSSDGSHAALCDFGHAVCLQPDGLGKSLLTGDYIPGTETHMAPEVVLGRSCDAKVDVWSSCCMMLHMLNGCHPWTQFFRGPLCLKIASEPPPVREIPPSCAPLTAQAIQEGLRKEPIHRVSAAELGGKVNRALQQVGGLKSPWRGEYKEPRHPPPNQANYHQTLHAQPRELSPRAPGPRPAEETTGRAPKLQPPLPPEPPEPNKSPPLTLSKEESGMWEPLPLSSLEPAPARNPSSPERKATVPEQELQQLEIELFLNSLSQPFSLEEQEQILSCLSIDSLSLSDDSEKNPSKASQSSRDTLSSGVHSWSSQAEARSSSWNMVLARGRPTDTPSYFNGVKVQIQSLNGEHLHIREFHRVKVGDIATGISSQIPAAAFSLVTKDGQPVRYDMEVPDSGIDLQCTLAPDGSFAWSWRVKHGQLENRP | ||||||
Modified residue | 559 | Phosphothreonine | ||||
Sequence: T |
Post-translational modification
Autophosphorylated. Phosphorylation at Thr-559 is required to activate its kinase activity and 'Lys-63'-linked polyubiquitination. Phosphorylated by CHUK/IKKA leading to MAP3K14 destabilization.
Ubiquitinated. Undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. 'Lys-48'-linked polyubiquitination leads to its degradation by the proteasome, while 'Lys-63'-linked polyubiquitination stabilizes and activates it.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Weakly expressed in testis, small intestine, spleen, thymus, peripheral blood leukocytes, prostate, ovary and colon.
Gene expression databases
Organism-specific databases
Interaction
Subunit
Interacts with TRAF2, TRAF5, TRAF6, IKKA and NFKB2/P100 (By similarity).
Interacts with TRAF3 and PELI3. Interacts with NIBP; the interaction is direct. Interacts with ARRB1 and ARRB2. Interacts with GRB10. Interacts with ZFP91. Interacts with NLRP12; this interaction promotes proteasomal degradation of MAP3K14. Directly interacts with DDX3X (PubMed:30341167).
Interacts (via C-terminus and kinase domain) with PPPC3A (via N-terminus) and PPP3CB (By similarity).
Interacts with TRAF3 and PELI3. Interacts with NIBP; the interaction is direct. Interacts with ARRB1 and ARRB2. Interacts with GRB10. Interacts with ZFP91. Interacts with NLRP12; this interaction promotes proteasomal degradation of MAP3K14. Directly interacts with DDX3X (PubMed:30341167).
Interacts (via C-terminus and kinase domain) with PPPC3A (via N-terminus) and PPP3CB (By similarity).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | Q99558 | CDC37 Q16543 | 6 | EBI-358011, EBI-295634 | |
BINARY | Q99558 | CHUK O15111 | 13 | EBI-358011, EBI-81249 | |
XENO | Q99558 | Chuk Q60680-2 | 3 | EBI-358011, EBI-646264 | |
BINARY | Q99558 | HRAS P01112 | 3 | EBI-358011, EBI-350145 | |
BINARY | Q99558 | HSP90AA1 P07900 | 5 | EBI-358011, EBI-296047 | |
BINARY | Q99558 | HSP90AB1 P08238 | 5 | EBI-358011, EBI-352572 | |
BINARY | Q99558 | IKBKB O14920 | 7 | EBI-358011, EBI-81266 | |
BINARY | Q99558 | IKBKG Q9Y6K9 | 5 | EBI-358011, EBI-81279 | |
BINARY | Q99558 | KPNB1 Q14974 | 2 | EBI-358011, EBI-286758 | |
BINARY | Q99558 | RPL4 P36578 | 3 | EBI-358011, EBI-348313 | |
BINARY | Q99558 | RPL6 Q02878 | 3 | EBI-358011, EBI-359655 | |
BINARY | Q99558 | RPL8 P62917 | 3 | EBI-358011, EBI-438527 | |
BINARY | Q99558 | RPS11 P62280 | 3 | EBI-358011, EBI-1047710 | |
BINARY | Q99558 | RPS13 P62277 | 3 | EBI-358011, EBI-351850 | |
BINARY | Q99558 | TRAF2 Q12933 | 9 | EBI-358011, EBI-355744 | |
BINARY | Q99558 | TRAF3 Q13114 | 9 | EBI-358011, EBI-357631 | |
BINARY | Q99558 | YWHAE P62258 | 2 | EBI-358011, EBI-356498 |
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for region, compositional bias, domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 1-37 | Disordered | ||||
Sequence: MAVMEMACPGAPGSAVGQQKELPKAKEKTPPLGKKQS | ||||||
Compositional bias | 135-153 | Basic residues | ||||
Sequence: KGKRRSKARKKRKKKSSKS | ||||||
Region | 135-171 | Disordered | ||||
Sequence: KGKRRSKARKKRKKKSSKSLAHAGVALAKPLPRTPEQ | ||||||
Domain | 400-655 | Protein kinase | ||||
Sequence: ATHQLRLGRGSFGEVHRMEDKQTGFQCAVKKVRLEVFRAEELMACAGLTSPRIVPLYGAVREGPWVNIFMELLEGGSLGQLVKEQGCLPEDRALYYLGQALEGLEYLHSRRILHGDVKADNVLLSSDGSHAALCDFGHAVCLQPDGLGKSLLTGDYIPGTETHMAPEVVLGRSCDAKVDVWSSCCMMLHMLNGCHPWTQFFRGPLCLKIASEPPPVREIPPSCAPLTAQAIQEGLRKEPIHRVSAAELGGKVNRAL | ||||||
Region | 401-653 | Interaction with ZFP91 | ||||
Sequence: THQLRLGRGSFGEVHRMEDKQTGFQCAVKKVRLEVFRAEELMACAGLTSPRIVPLYGAVREGPWVNIFMELLEGGSLGQLVKEQGCLPEDRALYYLGQALEGLEYLHSRRILHGDVKADNVLLSSDGSHAALCDFGHAVCLQPDGLGKSLLTGDYIPGTETHMAPEVVLGRSCDAKVDVWSSCCMMLHMLNGCHPWTQFFRGPLCLKIASEPPPVREIPPSCAPLTAQAIQEGLRKEPIHRVSAAELGGKVNR | ||||||
Region | 662-766 | Disordered | ||||
Sequence: KSPWRGEYKEPRHPPPNQANYHQTLHAQPRELSPRAPGPRPAEETTGRAPKLQPPLPPEPPEPNKSPPLTLSKEESGMWEPLPLSSLEPAPARNPSSPERKATVP | ||||||
Compositional bias | 712-728 | Pro residues | ||||
Sequence: KLQPPLPPEPPEPNKSP | ||||||
Region | 805-830 | Disordered | ||||
Sequence: LSDDSEKNPSKASQSSRDTLSSGVHS |
Sequence similarities
Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length947
- Mass (Da)104,042
- Last updated2006-04-04 v2
- ChecksumC9D10F67FF7F48AC
Computationally mapped potential isoform sequences
There are 2 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
A0A7P0Z419 | A0A7P0Z419_HUMAN | MAP3K14 | 266 | ||
A0A087WXF1 | A0A087WXF1_HUMAN | MAP3K14 | 98 |
Features
Showing features for sequence conflict, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 25 | in Ref. 1; CAA71306 | ||||
Sequence: A → P | ||||||
Compositional bias | 135-153 | Basic residues | ||||
Sequence: KGKRRSKARKKRKKKSSKS | ||||||
Sequence conflict | 348 | in Ref. 1; CAA71306 | ||||
Sequence: G → S | ||||||
Compositional bias | 712-728 | Pro residues | ||||
Sequence: KLQPPLPPEPPEPNKSP | ||||||
Sequence conflict | 880 | in Ref. 2; BAF82892 | ||||
Sequence: R → G |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
Y10256 EMBL· GenBank· DDBJ | CAA71306.1 EMBL· GenBank· DDBJ | mRNA | ||
AK290203 EMBL· GenBank· DDBJ | BAF82892.1 EMBL· GenBank· DDBJ | mRNA | ||
DQ314874 EMBL· GenBank· DDBJ | ABC40733.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471178 EMBL· GenBank· DDBJ | EAW51529.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471178 EMBL· GenBank· DDBJ | EAW51530.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC035576 EMBL· GenBank· DDBJ | AAH35576.1 EMBL· GenBank· DDBJ | mRNA |