M3K14_MOUSE
ID M3K14_MOUSE Reviewed; 942 AA.
AC Q9WUL6;
DT 01-JUN-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 03-AUG-2022, entry version 180.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase 14 {ECO:0000312|MGI:MGI:1858204};
DE EC=2.7.11.25;
DE AltName: Full=NF-kappa-beta-inducing kinase {ECO:0000303|PubMed:26029823};
DE AltName: Full=Serine/threonine-protein kinase NIK {ECO:0000250|UniProtKB:Q99558};
GN Name=Map3k14 {ECO:0000312|MGI:MGI:1858204};
GN Synonyms=Nik {ECO:0000303|PubMed:26029823};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], DISRUPTION PHENOTYPE, AND MUTAGENESIS OF
RP GLY-855.
RC STRAIN=C57BL/6J; TISSUE=Spleen;
RX PubMed=10319865; DOI=10.1038/8780;
RA Shinkura R., Kitada K., Matsuda F., Tashiro K., Ikuta K., Suzuki M.,
RA Kogishi K., Serikawa T., Honjo T.;
RT "Alymphoplasia is caused by a point mutation in the mouse gene encoding Nf-
RT kappa b-inducing kinase.";
RL Nat. Genet. 22:74-77(1999).
RN [2]
RP FUNCTION, AND AUTOPHOSPHORYLATION.
RX PubMed=11239468; DOI=10.1016/s1097-2765(01)00187-3;
RA Xiao G., Harhaj E.W., Sun S.-C.;
RT "NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100.";
RL Mol. Cell 7:401-409(2001).
RN [3]
RP INTERACTION WITH PPP3CA AND PPP3CB.
RX PubMed=26029823; DOI=10.1038/srep10758;
RA Shinzawa M., Konno H., Qin J., Akiyama N., Miyauchi M., Ohashi H.,
RA Miyamoto-Sato E., Yanagawa H., Akiyama T., Inoue J.;
RT "Catalytic subunits of the phosphatase calcineurin interact with NF-kappaB-
RT inducing kinase (NIK) and attenuate NIK-dependent gene expression.";
RL Sci. Rep. 5:10758-10758(2015).
CC -!- FUNCTION: Lymphotoxin beta-activated kinase which seems to be
CC exclusively involved in the activation of NF-kappa-B and its
CC transcriptional activity. Promotes proteolytic processing of
CC NFKB2/P100, which leads to activation of NF-kappa-B via the non-
CC canonical pathway. Could act in a receptor-selective manner.
CC {ECO:0000269|PubMed:11239468}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.25;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.25;
CC -!- SUBUNIT: Interacts with TRAF2, TRAF3, TRAF5, TRAF6, IKKA and NF-kappa-
CC B2/P100. Interacts with PELI3. Interacts with NIBP; the interaction is
CC direct. Interacts with ARRB1 and ARRB2. Interacts with GRB10. Interacts
CC with ZFP91 (By similarity). Interacts with NLRP12; this interaction
CC promotes proteasomal degradation of MAP3K14. Directly interacts with
CC DDX3X (By similarity). Interacts (via C-terminus and kinase domain)
CC with PPPC3A (via N-terminus) and PPP3CB (PubMed:26029823).
CC {ECO:0000250|UniProtKB:Q99558, ECO:0000269|PubMed:26029823}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- PTM: Phosphorylation at Thr-561 is required to activates its kinase
CC activity and 'Lys-63'-linked polyubiquitination. Phosphorylated by
CC CHUK/IKKA leading to MAP3K14 destabilization (By similarity).
CC Autophosphorylated. {ECO:0000250}.
CC -!- PTM: Ubiquitinated. Undergoes both 'Lys-48'- and 'Lys-63'-linked
CC polyubiquitination. 'Lys-48'-linked polyubiquitination leads to its
CC degradation by the proteasome, while 'Lys-63'-linked polyubiquitination
CC stabilizes and activates it (By similarity). {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: Mice display the alymphoplasia phenotype (aly),
CC which is characterized by systemic absence of lymph nodes and Peyer
CC patches and disorganized splenic and thymic structures with
CC immunodeficiency. {ECO:0000269|PubMed:10319865}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase kinase subfamily.
CC {ECO:0000305}.
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DR EMBL; AF143094; AAD31512.1; -; mRNA.
DR CCDS; CCDS25516.1; -.
DR RefSeq; NP_058592.1; NM_016896.3.
DR PDB; 4G3C; X-ray; 2.15 A; A/B=329-675.
DR PDB; 4G3E; X-ray; 2.50 A; A/B=329-675.
DR PDB; 4G3F; X-ray; 1.64 A; A=345-675.
DR PDB; 4G3G; X-ray; 2.50 A; A=345-675.
DR PDB; 5T8O; X-ray; 2.41 A; A/B=329-675.
DR PDB; 5T8P; X-ray; 2.32 A; A/B=329-675.
DR PDB; 5T8Q; X-ray; 2.63 A; A/B=329-675.
DR PDB; 6G4Y; X-ray; 2.65 A; A/B=329-675.
DR PDB; 6G4Z; X-ray; 2.84 A; A/B=329-675.
DR PDB; 6MYN; X-ray; 2.74 A; A/B=329-675.
DR PDBsum; 4G3C; -.
DR PDBsum; 4G3E; -.
DR PDBsum; 4G3F; -.
DR PDBsum; 4G3G; -.
DR PDBsum; 5T8O; -.
DR PDBsum; 5T8P; -.
DR PDBsum; 5T8Q; -.
DR PDBsum; 6G4Y; -.
DR PDBsum; 6G4Z; -.
DR PDBsum; 6MYN; -.
DR AlphaFoldDB; Q9WUL6; -.
DR SMR; Q9WUL6; -.
DR BioGRID; 207493; 3.
DR IntAct; Q9WUL6; 2.
DR STRING; 10090.ENSMUSP00000021324; -.
DR ChEMBL; CHEMBL4523500; -.
DR GuidetoPHARMACOLOGY; 2074; -.
DR iPTMnet; Q9WUL6; -.
DR PhosphoSitePlus; Q9WUL6; -.
DR PaxDb; Q9WUL6; -.
DR PRIDE; Q9WUL6; -.
DR Antibodypedia; 3862; 354 antibodies from 41 providers.
DR DNASU; 53859; -.
DR Ensembl; ENSMUST00000021324; ENSMUSP00000021324; ENSMUSG00000020941.
DR GeneID; 53859; -.
DR KEGG; mmu:53859; -.
DR UCSC; uc007lua.1; mouse.
DR CTD; 9020; -.
DR MGI; MGI:1858204; Map3k14.
DR VEuPathDB; HostDB:ENSMUSG00000020941; -.
DR eggNOG; KOG0198; Eukaryota.
DR GeneTree; ENSGT00940000156497; -.
DR HOGENOM; CLU_010641_1_0_1; -.
DR InParanoid; Q9WUL6; -.
DR OMA; HRMKDKQ; -.
DR OrthoDB; 162528at2759; -.
DR PhylomeDB; Q9WUL6; -.
DR TreeFam; TF105120; -.
DR Reactome; R-MMU-389357; CD28 dependent PI3K/Akt signaling.
DR Reactome; R-MMU-5607761; Dectin-1 mediated noncanonical NF-kB signaling.
DR Reactome; R-MMU-5668541; TNFR2 non-canonical NF-kB pathway.
DR Reactome; R-MMU-5676590; NIK-->noncanonical NF-kB signaling.
DR Reactome; R-MMU-5676594; TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway.
DR BioGRID-ORCS; 53859; 4 hits in 72 CRISPR screens.
DR PRO; PR:Q9WUL6; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; Q9WUL6; protein.
DR Bgee; ENSMUSG00000020941; Expressed in granulocyte and 117 other tissues.
DR ExpressionAtlas; Q9WUL6; baseline and differential.
DR Genevisible; Q9WUL6; MM.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0001650; C:fibrillar center; ISO:MGI.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004709; F:MAP kinase kinase kinase activity; IBA:GO_Central.
DR GO; GO:0004704; F:NF-kappaB-inducing kinase activity; IDA:UniProtKB.
DR GO; GO:0004672; F:protein kinase activity; ISO:MGI.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; ISO:MGI.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEA:Ensembl.
DR GO; GO:0051607; P:defense response to virus; ISO:MGI.
DR GO; GO:0007249; P:I-kappaB kinase/NF-kappaB signaling; IDA:UniProtKB.
DR GO; GO:0006955; P:immune response; IDA:UniProtKB.
DR GO; GO:0000165; P:MAPK cascade; IBA:GO_Central.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; ISO:MGI.
DR GO; GO:0006468; P:protein phosphorylation; ISO:MGI.
DR CDD; cd13991; STKc_NIK; 1.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR042787; M3K14_STKc.
DR InterPro; IPR017425; MAPKKK14.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR PANTHER; PTHR48016:SF9; PTHR48016:SF9; 1.
DR Pfam; PF00069; Pkinase; 1.
DR PIRSF; PIRSF038175; MAPKKK14; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding; Cytoplasm; Kinase; Nucleotide-binding;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Transferase; Ubl conjugation.
FT CHAIN 1..942
FT /note="Mitogen-activated protein kinase kinase kinase 14"
FT /id="PRO_0000086267"
FT DOMAIN 402..657
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 136..156
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 291..326
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 403..655
FT /note="Interaction with ZFP91"
FT /evidence="ECO:0000250"
FT REGION 660..756
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 801..823
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 136..153
FT /note="Basic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 703..721
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 517
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 408..416
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 431
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 561
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q99558"
FT MUTAGEN 855
FT /note="G->R: In ALY; no binding to IKKA."
FT /evidence="ECO:0000269|PubMed:10319865"
FT HELIX 335..343
FT /evidence="ECO:0007829|PDB:4G3C"
FT STRAND 346..349
FT /evidence="ECO:0007829|PDB:4G3F"
FT HELIX 352..359
FT /evidence="ECO:0007829|PDB:4G3F"
FT TURN 360..362
FT /evidence="ECO:0007829|PDB:4G3F"
FT STRAND 379..383
FT /evidence="ECO:0007829|PDB:4G3F"
FT TURN 397..399
FT /evidence="ECO:0007829|PDB:4G3F"
FT STRAND 400..411
FT /evidence="ECO:0007829|PDB:4G3F"
FT STRAND 414..421
FT /evidence="ECO:0007829|PDB:4G3F"
FT TURN 422..424
FT /evidence="ECO:0007829|PDB:4G3F"
FT STRAND 427..434
FT /evidence="ECO:0007829|PDB:4G3F"
FT TURN 435..437
FT /evidence="ECO:0007829|PDB:4G3F"
FT HELIX 441..444
FT /evidence="ECO:0007829|PDB:4G3F"
FT TURN 445..448
FT /evidence="ECO:0007829|PDB:4G3F"
FT STRAND 457..463
FT /evidence="ECO:0007829|PDB:4G3F"
FT STRAND 466..471
FT /evidence="ECO:0007829|PDB:4G3F"
FT HELIX 479..486
FT /evidence="ECO:0007829|PDB:4G3F"
FT HELIX 491..509
FT /evidence="ECO:0007829|PDB:4G3F"
FT TURN 510..512
FT /evidence="ECO:0007829|PDB:4G3F"
FT HELIX 520..522
FT /evidence="ECO:0007829|PDB:4G3F"
FT STRAND 523..525
FT /evidence="ECO:0007829|PDB:4G3F"
FT STRAND 527..530
FT /evidence="ECO:0007829|PDB:6G4Z"
FT STRAND 532..534
FT /evidence="ECO:0007829|PDB:4G3F"
FT TURN 545..547
FT /evidence="ECO:0007829|PDB:5T8O"
FT STRAND 550..552
FT /evidence="ECO:0007829|PDB:5T8O"
FT STRAND 553..556
FT /evidence="ECO:0007829|PDB:5T8Q"
FT HELIX 562..564
FT /evidence="ECO:0007829|PDB:4G3F"
FT HELIX 567..570
FT /evidence="ECO:0007829|PDB:4G3F"
FT HELIX 578..593
FT /evidence="ECO:0007829|PDB:4G3F"
FT TURN 599..601
FT /evidence="ECO:0007829|PDB:4G3F"
FT HELIX 607..612
FT /evidence="ECO:0007829|PDB:4G3F"
FT HELIX 616..619
FT /evidence="ECO:0007829|PDB:4G3F"
FT HELIX 626..635
FT /evidence="ECO:0007829|PDB:4G3F"
FT HELIX 640..642
FT /evidence="ECO:0007829|PDB:4G3F"
FT HELIX 646..659
FT /evidence="ECO:0007829|PDB:4G3F"
FT STRAND 667..670
FT /evidence="ECO:0007829|PDB:4G3F"
SQ SEQUENCE 942 AA; 103080 MW; 3BE4E4BA2D25C200 CRC64;
MAVMEVACPG TPGSAVGQQK ELAKAKEKTQ SLGKKQSCIF KLEAVEKSPV FCGKWEILND
VITKGTAKDG SEGGPPAISI IAQAECENSQ EFSPTFSERI FIAGSQQYSQ SESLDQIPNN
VAHATEGKMA RVCRRGKRHG KARKKRRKKR SKSLAQAGVA LAKPLPRTPE QESCTIPVQE
DESPLGNLYA RNVSQFTKPL GGPGLGHLCF KKQDEGLRPV LPRPELHKLI SPLQCLNHVW
KLHHPQATGP RPHPTHPFPY SGMPHPFPFY PLEPWKPYML DSAVLDKLAG VSGQRPLPGP
PHLSQLAHGD SQKPLPGPHL ESSCPSRGAL EKVPVEEYLV HALQGSVSSG QAHSLASLAK
TWSSGSAKLQ RLGPETEDNE GVLLTEKLKP VDYEYREEVH WMTHQPRVGR GSFGEVHRMK
DKQTGFQCAV KKVRLEVFRV EELVACAGLS SPRIVPLYGA VREGPWVNIF MELLEGGSLG
QLIKQMGCLP EDRALYYLGQ ALEGLEYLHT RRILHGDVKA DNVLLSSDGS RAALCDFGHA
LCLQPDGLGK SLLTGDYIPG TETHMAPEVV MGKPCDAKVD IWSSCCMMLH MLNGCHPWTQ
YFRGPLCLKI ASEPPPIREI PPSCAPLTAQ AIQEGLRKEP VHRASAMELR RKVGKALQEV
GGLKSPWKGE YKEPRPPPQD QATCHQTLPT PPRENPPAKA NTDGAPEPQP PLPPEPPEPS
KAPALNLSKE ESGTWEPLPL SSLDPATAKG PSFPDRRATL PELELQQLEI ELFLNSLSQP
FSLEEQEQIL SCLSIDSLSL SDDSEKNPSK ASQSSRDTLS SGVHSWNSQA EARTCSCSTA
LARGRPTDIP SYFNGVKVQI QSLNGEHLHI REFHRVKVGD IATGISSQIP ATAFSLVTKD
GQPVCYDMEV PDSGIDLQCT LAPDGSFAWT WRVKHGQLEN RP