M4K1_MOUSE
ID M4K1_MOUSE Reviewed; 827 AA.
AC P70218; Q8R3R0; Q99K62;
DT 28-MAR-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1997, sequence version 1.
DT 03-AUG-2022, entry version 184.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase kinase 1;
DE EC=2.7.11.1 {ECO:0000269|PubMed:11509653, ECO:0000269|PubMed:9003777};
DE AltName: Full=Hematopoietic progenitor kinase;
DE Short=HPK;
DE AltName: Full=MAPK/ERK kinase kinase kinase 1;
DE Short=MEK kinase kinase 1;
DE Short=MEKKK 1;
GN Name=Map4k1; Synonyms=Hpk1;
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:CAA70213.1};
RN [1] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, TISSUE
RP SPECIFICITY, AND MUTAGENESIS OF LYS-46.
RC TISSUE=Pre-B cell;
RX PubMed=9003777; DOI=10.1002/j.1460-2075.1996.tb01093.x;
RA Kiefer F., Tibbles L.A., Anafi M., Janssen A., Zanke B.W., Lassam N.,
RA Pawson T., Woodgett J.R., Iscove N.N.;
RT "HPK1, a hematopoietic protein kinase activating the SAPK/JNK pathway.";
RL EMBO J. 15:7013-7025(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Mammary gland;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-439, FUNCTION, CATALYTIC ACTIVITY,
RP INTERACTION WITH CLNK, TISSUE SPECIFICITY, PHOSPHORYLATION, AND MUTAGENESIS
RP OF LYS-46.
RX PubMed=11509653; DOI=10.1128/mcb.21.18.6102-6112.2001;
RA Yu J., Riou C., Davidson D., Minhas R., Robson J.D., Julius M., Arnold R.,
RA Kiefer F., Veillette A.;
RT "Synergistic regulation of immunoreceptor signaling by SLP-76-related
RT adaptor Clnk and serine/threonine protein kinase HPK-1.";
RL Mol. Cell. Biol. 21:6102-6112(2001).
RN [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-373; SER-375 AND SER-419, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Lung, and Spleen;
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-protein kinase, which may play a role in the
CC response to environmental stress (By similarity). Appears to act
CC upstream of the JUN N-terminal pathway (PubMed:9003777). May play a
CC role in hematopoietic lineage decisions and growth regulation
CC (PubMed:9003777). Able to autophosphorylate (PubMed:9003777). Together
CC with CLNK, it enhances CD3-triggered activation of T-cells and
CC subsequent IL2 production (PubMed:11509653).
CC {ECO:0000250|UniProtKB:Q92918, ECO:0000269|PubMed:11509653,
CC ECO:0000269|PubMed:9003777}.
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:11509653, ECO:0000269|PubMed:9003777};
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:11509653,
CC ECO:0000269|PubMed:9003777};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:9003777};
CC -!- SUBUNIT: Interacts with MAP3K1 (By similarity). Interacts with FBXW8
CC (By similarity). Interacts with CLNK (via its SH2 domain)
CC (PubMed:11509653). {ECO:0000250|UniProtKB:Q92918,
CC ECO:0000269|PubMed:11509653}.
CC -!- INTERACTION:
CC P70218; Q9BXL7: CARD11; Xeno; NbExp=2; IntAct=EBI-2906801, EBI-7006141;
CC P70218; Q16584: MAP3K11; Xeno; NbExp=3; IntAct=EBI-2906801, EBI-49961;
CC -!- TISSUE SPECIFICITY: Expressed in hemopoietic cells (at protein level)
CC (PubMed:11509653). Ubiquitously expressed in all tissues examined at
CC embryonic stage 16.5 dpc with high levels in lung, heart and fetal
CC liver. In the neonate, expression is restricted to the tissues which
CC undergo lineage decisions, lung, thymus, liver, kidney and brain. In
CC the adult, expression is limited to hemopoietic organs, thymus, bone
CC marrow, and spleen and to the testis (PubMed:9003777).
CC {ECO:0000269|PubMed:11509653, ECO:0000269|PubMed:9003777}.
CC -!- PTM: Autophosphorylates: phosphorylation promotes ubiquitination by the
CC Cul7-RING(FBXW8) ubiquitin-protein ligase complex, leading to its
CC degradation by the proteasome. {ECO:0000250|UniProtKB:Q92918}.
CC -!- PTM: Tyrosine-phosphorylated after activation of hemopoietic cells.
CC {ECO:0000269|PubMed:11509653}.
CC -!- PTM: Ubiquitinated by the Cul7-RING(FBXW8) ubiquitin-protein ligase
CC complex following autophosphorylation, leading to its degradation by
CC the proteasome. {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. STE20 subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH05433.1; Type=Miscellaneous discrepancy; Note=Intron retention.; Evidence={ECO:0000305};
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DR EMBL; Y09010; CAA70213.1; -; mRNA.
DR EMBL; BC005433; AAH05433.1; ALT_SEQ; mRNA.
DR EMBL; BC024832; AAH24832.1; -; mRNA.
DR CCDS; CCDS39865.1; -.
DR RefSeq; NP_032305.2; NM_008279.2.
DR PDB; 1UTI; X-ray; 1.50 A; D=465-480.
DR PDBsum; 1UTI; -.
DR AlphaFoldDB; P70218; -.
DR SMR; P70218; -.
DR BioGRID; 204964; 6.
DR DIP; DIP-42073N; -.
DR IntAct; P70218; 7.
DR MINT; P70218; -.
DR STRING; 10090.ENSMUSP00000082995; -.
DR iPTMnet; P70218; -.
DR PhosphoSitePlus; P70218; -.
DR EPD; P70218; -.
DR jPOST; P70218; -.
DR MaxQB; P70218; -.
DR PaxDb; P70218; -.
DR PeptideAtlas; P70218; -.
DR PRIDE; P70218; -.
DR ProteomicsDB; 291987; -.
DR Antibodypedia; 2067; 582 antibodies from 40 providers.
DR DNASU; 26411; -.
DR Ensembl; ENSMUST00000085835; ENSMUSP00000082995; ENSMUSG00000037337.
DR GeneID; 26411; -.
DR KEGG; mmu:26411; -.
DR UCSC; uc009gam.1; mouse.
DR CTD; 11184; -.
DR MGI; MGI:1346882; Map4k1.
DR VEuPathDB; HostDB:ENSMUSG00000037337; -.
DR eggNOG; KOG0576; Eukaryota.
DR GeneTree; ENSGT00940000160308; -.
DR HOGENOM; CLU_006347_1_1_1; -.
DR InParanoid; P70218; -.
DR OMA; FLCCALD; -.
DR OrthoDB; 996262at2759; -.
DR PhylomeDB; P70218; -.
DR TreeFam; TF105121; -.
DR BioGRID-ORCS; 26411; 1 hit in 74 CRISPR screens.
DR ChiTaRS; Map4k1; mouse.
DR EvolutionaryTrace; P70218; -.
DR PRO; PR:P70218; -.
DR Proteomes; UP000000589; Chromosome 7.
DR RNAct; P70218; protein.
DR Bgee; ENSMUSG00000037337; Expressed in mesenteric lymph node and 115 other tissues.
DR ExpressionAtlas; P70218; baseline and differential.
DR Genevisible; P70218; MM.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0008349; F:MAP kinase kinase kinase 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; IDA:UniProtKB.
DR GO; GO:0008283; P:cell population proliferation; ISS:UniProtKB.
DR GO; GO:1904628; P:cellular response to phorbol 13-acetate 12-myristate; ISO:MGI.
DR GO; GO:0035556; P:intracellular signal transduction; IDA:UniProtKB.
DR GO; GO:0007254; P:JNK cascade; ISO:MGI.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; ISS:UniProtKB.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; ISO:MGI.
DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR IDEAL; IID50083; -.
DR InterPro; IPR001180; CNH_dom.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR021160; MAPKKKK.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR Pfam; PF00780; CNH; 1.
DR Pfam; PF00069; Pkinase; 1.
DR PIRSF; PIRSF038172; MAPKKKK; 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.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding; Kinase; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Serine/threonine-protein kinase; Transferase;
KW Ubl conjugation.
FT CHAIN 1..827
FT /note="Mitogen-activated protein kinase kinase kinase
FT kinase 1"
FT /id="PRO_0000086274"
FT DOMAIN 17..274
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 501..806
FT /note="CNH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00795"
FT REGION 296..315
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 359..485
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 296..312
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 387..401
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 430..444
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 137
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 23..31
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 46
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000269|PubMed:9003777"
FT MOD_RES 165
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q92918"
FT MOD_RES 171
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q92918"
FT MOD_RES 175
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q92918"
FT MOD_RES 354
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q92918"
FT MOD_RES 373
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 375
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 403
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92918"
FT MOD_RES 405
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92918"
FT MOD_RES 419
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 592
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92918"
FT MUTAGEN 46
FT /note="K->E: Loss of kinase activity and ability to
FT activate JNK family. Inhibits the ability of CLNK to up-
FT regulate CD3-triggered activation of the IL2 promoter."
FT /evidence="ECO:0000269|PubMed:9003777"
FT CONFLICT 411
FT /note="G -> V (in Ref. 2; AAH24832)"
FT /evidence="ECO:0000305"
FT CONFLICT 444
FT /note="C -> R (in Ref. 2; AAH05433/AAH24832)"
FT /evidence="ECO:0000305"
FT CONFLICT 807
FT /note="V -> I (in Ref. 2; AAH24832)"
FT /evidence="ECO:0000305"
FT HELIX 473..476
FT /evidence="ECO:0007829|PDB:1UTI"
SQ SEQUENCE 827 AA; 91535 MW; 82341BE9D13036BA CRC64;
MALVDPDIFN KDPREHYDLL QRLGGGTYGE VFKARDKVSK DLVALKMVKM EPDDDVATLQ
KEILMLKTCR HANIVAYHGS YLWLQKLWIC MEFCGAGSLQ DIYQVTGSLS ELQISYVCRE
VLQGLAYLHS EKKIHRDIKG ANILINDCGE VKLADFGISA QIGATLARRL SFIGTPYWMA
PEVAAVALKG GYNELCDIWS LGITAIELAE LQPPLFDVHP LRVLFLMTKS GYQPPRLKEK
SRWSSSFHNF VKVTLTKNSK KRPSATKMLS HQLVSQPGLN RGLILDLLDK MKNPGKGLPV
DIEDEEPEPP PAIPRRIRST YRASSLGIPD ADCCRRQMEF QRPRCVDCRP QAETVRLYPP
AHFGSTSPRS QLSDSDDDYD DVDIPAPSEN IPPPLPPKPK FRSPSDDGSG GIRDDGQLSP
GVLVRCASGP PPRTPRPGPP PATCSPHLTA RSDPSLWNPA APEPGQPPLV PPRKEKMRGK
MENEKRREKY PLLVKLFNGC PLQIHSTAAW THPSTKDQNL LLGAEEGIFI LNRNDQEATL
EMIFPGRTTW LYCINNLLMS LSGKTPYLYS HSILGLLERK DGRTGSPIAH ISPHRLLARK
NMVSSKIQDT KGCRACCVAE SASSGGPFLC GALETSVVLL QWYQPMNKFL LVRQVLFPLP
TPLPVFTLLT TPGSELPAVC IGVSPGQAAK SVLFHTVRFG ALSCWLDDSS TEHKGPVQVI
QVKEDMVMVL MDGSLKLVTP EGAPAPGLRT PEIPMTEAVE AVAMVEDRLE AFWKHGVQVW
APGLKQPLQE LRDPTLTFRL LCSPRPVVVE TRPTDDPTAP SNLYIQE
