M4K4_MOUSE
ID M4K4_MOUSE Reviewed; 1233 AA.
AC P97820;
DT 28-MAR-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1997, sequence version 1.
DT 03-AUG-2022, entry version 173.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase kinase 4;
DE EC=2.7.11.1;
DE AltName: Full=HPK/GCK-like kinase HGK;
DE AltName: Full=MAPK/ERK kinase kinase kinase 4;
DE Short=MEK kinase kinase 4;
DE Short=MEKKK 4;
DE AltName: Full=Nck-interacting kinase;
GN Name=Map4k4; Synonyms=Nik;
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 {ECO:0000312|EMBL:AAC53165.1};
RN [1] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND TISSUE SPECIFICITY.
RC TISSUE=Brain, and Embryo;
RX PubMed=9135144; DOI=10.1093/emboj/16.6.1279;
RA Su Y.-C., Han J., Xu S., Cobb M., Skolnik E.Y.;
RT "NIK is a new Ste20-related kinase that binds NCK and MEKK1 and activates
RT the SAPK/JNK cascade via a conserved regulatory domain.";
RL EMBO J. 16:1279-1290(1997).
RN [2] {ECO:0000305}
RP FUNCTION, AND INTERACTION WITH NCK.
RX PubMed=10669731; DOI=10.1128/mcb.20.5.1537-1545.2000;
RA Becker E., Huynh-Do U., Holland S., Pawson T., Daniel T.O., Skolnik E.Y.;
RT "Nck-interacting Ste20 kinase couples Eph receptors to c-Jun N-terminal
RT kinase and integrin activation.";
RL Mol. Cell. Biol. 20:1537-1545(2000).
RN [3]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic brain;
RX PubMed=15345747; DOI=10.1074/mcp.m400085-mcp200;
RA Ballif B.A., Villen J., Beausoleil S.A., Schwartz D., Gygi S.P.;
RT "Phosphoproteomic analysis of the developing mouse brain.";
RL Mol. Cell. Proteomics 3:1093-1101(2004).
RN [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-323; SER-325; SER-543;
RP SER-629; SER-646; SER-794; SER-795; SER-799 AND SER-894, AND IDENTIFICATION
RP BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Lung, Pancreas, Spleen,
RC and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
CC -!- FUNCTION: Serine/threonine kinase that may play a role in the response
CC to environmental stress and cytokines such as TNF-alpha. Appears to act
CC upstream of the JUN N-terminal pathway. Phosphorylates SMAD1 on Thr-322
CC (By similarity). {ECO:0000250, ECO:0000269|PubMed:10669731,
CC ECO:0000269|PubMed:9135144}.
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=2.7.11.1;
CC Evidence={ECO:0000269|PubMed:10669731, ECO:0000269|PubMed:9135144};
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=2.7.11.1; Evidence={ECO:0000269|PubMed:10669731,
CC ECO:0000269|PubMed:9135144};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:10669731, ECO:0000269|PubMed:9135144};
CC -!- SUBUNIT: Interacts with the SH3 domain of the adapter proteins Nck.
CC Interacts (via its CNH regulatory domain) with ATL1 (via the N-terminal
CC region). Interacts with RAP2A (GTP-bound form preferentially) (By
CC similarity). {ECO:0000250}.
CC -!- INTERACTION:
CC P97820; P26038: MSN; Xeno; NbExp=2; IntAct=EBI-644181, EBI-528768;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Appears to be ubiquitous, expressed in all tissue
CC types examined. Highest levels observed in heart and brain.
CC {ECO:0000269|PubMed:9135144}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. STE20 subfamily. {ECO:0000305}.
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DR EMBL; U88984; AAC53165.1; -; mRNA.
DR PIR; T30989; T30989.
DR RefSeq; NP_001239129.1; NM_001252200.1.
DR RefSeq; NP_001239130.1; NM_001252201.1.
DR RefSeq; NP_001239131.1; NM_001252202.1.
DR RefSeq; NP_032722.2; NM_008696.2.
DR AlphaFoldDB; P97820; -.
DR SMR; P97820; -.
DR BioGRID; 205065; 20.
DR CORUM; P97820; -.
DR DIP; DIP-40973N; -.
DR IntAct; P97820; 12.
DR STRING; 10090.ENSMUSP00000126961; -.
DR iPTMnet; P97820; -.
DR PhosphoSitePlus; P97820; -.
DR EPD; P97820; -.
DR jPOST; P97820; -.
DR MaxQB; P97820; -.
DR PaxDb; P97820; -.
DR PeptideAtlas; P97820; -.
DR PRIDE; P97820; -.
DR ProteomicsDB; 291988; -.
DR DNASU; 26921; -.
DR GeneID; 26921; -.
DR KEGG; mmu:26921; -.
DR CTD; 9448; -.
DR MGI; MGI:1349394; Map4k4.
DR eggNOG; KOG0587; Eukaryota.
DR InParanoid; P97820; -.
DR OrthoDB; 533537at2759; -.
DR PhylomeDB; P97820; -.
DR Reactome; R-MMU-2559580; Oxidative Stress Induced Senescence.
DR BioGRID-ORCS; 26921; 8 hits in 77 CRISPR screens.
DR ChiTaRS; Map4k4; mouse.
DR PRO; PR:P97820; -.
DR Proteomes; UP000000589; Unplaced.
DR RNAct; P97820; protein.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005925; C:focal adhesion; IDA:ARUK-UCL.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0004111; F:creatine kinase activity; ISO:MGI.
DR GO; GO:0008017; F:microtubule binding; ISO:MGI.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0035556; P:intracellular signal transduction; ISO:MGI.
DR GO; GO:0000165; P:MAPK cascade; IBA:GO_Central.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISO:MGI.
DR GO; GO:0048812; P:neuron projection morphogenesis; IBA:GO_Central.
DR GO; GO:0032014; P:positive regulation of ARF protein signal transduction; IMP:ARUK-UCL.
DR GO; GO:0030335; P:positive regulation of cell migration; ISO:MGI.
DR GO; GO:0051894; P:positive regulation of focal adhesion assembly; IMP:ARUK-UCL.
DR GO; GO:0120183; P:positive regulation of focal adhesion disassembly; IMP:ARUK-UCL.
DR GO; GO:0043547; P:positive regulation of GTPase activity; IMP:ARUK-UCL.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IDA:UniProtKB.
DR GO; GO:0051549; P:positive regulation of keratinocyte migration; IMP:ARUK-UCL.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0046328; P:regulation of JNK cascade; ISS:UniProtKB.
DR GO; GO:0043408; P:regulation of MAPK cascade; IBA:GO_Central.
DR InterPro; IPR001180; CNH_dom.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00780; CNH; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00036; CNH; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50219; CNH; 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 Acetylation; ATP-binding; Cytoplasm; Kinase; Nucleotide-binding;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Transferase.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:O95819"
FT CHAIN 2..1233
FT /note="Mitogen-activated protein kinase kinase kinase
FT kinase 4"
FT /id="PRO_0000086281"
FT DOMAIN 25..289
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 920..1207
FT /note="CNH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00795"
FT REGION 305..348
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 401..463
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 489..805
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 852..1206
FT /note="Mediates interaction with RAP2A"
FT /evidence="ECO:0000250"
FT COMPBIAS 305..319
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 320..336
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 517..535
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 540..559
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 560..574
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 577..600
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 618..652
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 667..710
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 713..729
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 740..754
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 764..783
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 787..805
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 152
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 31..39
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 53
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000250|UniProtKB:O95819"
FT MOD_RES 5
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O95819"
FT MOD_RES 323
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 325
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 543
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 619
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O95819"
FT MOD_RES 621
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O95819"
FT MOD_RES 629
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 646
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 691
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O95819"
FT MOD_RES 703
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O95819"
FT MOD_RES 706
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O95819"
FT MOD_RES 785
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O95819"
FT MOD_RES 794
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 795
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 799
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 817
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O95819"
FT MOD_RES 822
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:O95819"
FT MOD_RES 846
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O95819"
FT MOD_RES 849
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O95819"
FT MOD_RES 894
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 907
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O95819"
SQ SEQUENCE 1233 AA; 140602 MW; 869896D414459B19 CRC64;
MANDSPAKSL VDIDLSSLRD PAGIFELVEV VGNGTYGQVY KGRHVKTVTA AIKVMDVTED
EEEEITLEIN MLKKYSHHRN IATYYGAFIK KSPPGHDDQL WLVMEFCGAG SITDLVKNTK
GNTLKEDWIA YISREILRGL AHLHIHHVIH RDIKGQNVLL TENAEVKLVD FGVSAQLDRT
VGRRNTFIGT PYWMAPEVIA CDENPDATYD YRSDLWSCGI TAIEMAEGGP PLCDMHPMRA
LFLIPRNPPP RLKSKKWSKK FFSFIEGCLV KNYMQRPSTE QLLKHPFIRD QPNERQVRIQ
LKDHIDRTRK KRGEKDETEY EYSGSEEEEE EVPEQEGEPS SIVNVPGEST LRRDFLRLQQ
ENKERSEALR RQQLLQEQQL REQEEYKRQL LAERQKRIEQ QKEQRRRLEE QQRREREARR
QQEREQRRRE QEEKRRLEEL ERRRKEEEER RRAEEEKRRV EREQEYIRRQ LEEEQRHLEI
LQQQLLQEQA MLLHDHRRPH AQQQPPPPQQ QDRSKPSFHA PEPKPHYDPA DRAREVQWSH
LASLKNNVSP VSRSHSFSDP SPKFAHHHLR SQDPCPPSRS EGLSQSSDSK SEVPEPTQKA
WSRSDSDEVP PRVPVRTTSR SPVLSRRDSP LQGGGQQNSQ AGQRNSTSSI EPRLLWERVE
KLVPRPGSGS SSGSSNSGSQ PGSHPGSQSG SGERFRVRSS SKSEGSPSPR QESAAKKPDD
KKEVFRSLKP AGEVDLTALA KELRAVEDVR PPHKVTDYSS SSEESGTTDE EEEDVEQEGA
DDSTSGPEDT RAASSPNLSN GETESVKTMI VHDDVESEPA MTPSKEGTLI VRQTQSASST
LQKHKSSSSF TPFIDPRLLQ ISPSSGTTVT SVVGFSCDGL RPEAIRQDPT RKGSVVNVNP
TNTRPQSDTP EIRKYKKRFN SEILCAALWG VNLLVGTESG LMLLDRSGQG KVYPLISRRR
FQQMDVLEGL NVLVTISGKK DKLRVYYLSW LRNKILHNDP EVEKKQGWTT VGDLEGCVHY
KVVKYERIKF LVIALKSSVE VYAWAPKPYH KFMAFKSFGE LLHKPLLVDL TVEEGQRLKV
IYGSCAGFHA VDVDSGSVYD IYLPTHIQCS IKPHAIIILP NTDGMELLVC YEDEGVYVNT
YGRITKDVVL QWGEMPTSVA YIRSNQTMGW GEKAIEIRSV ETGHLDGVFM HKRAQRLKFL
CGRNDKVFFS SVRSGGSSQV YFMTLGRTSL LSW
