MP2K6_DANRE
ID MP2K6_DANRE Reviewed; 361 AA.
AC Q9DGE0; Q6IQW6;
DT 02-SEP-2008, integrated into UniProtKB/Swiss-Prot.
DT 02-SEP-2008, sequence version 2.
DT 03-AUG-2022, entry version 136.
DE RecName: Full=Dual specificity mitogen-activated protein kinase kinase 6 {ECO:0000250|UniProtKB:P52564};
DE Short=MAP kinase kinase 6 {ECO:0000250|UniProtKB:P52564};
DE Short=MAPKK 6 {ECO:0000250|UniProtKB:P52564};
DE EC=2.7.12.2;
DE AltName: Full=Mitogen-activated protein kinase kinase 3 {ECO:0000303|PubMed:10995439};
DE Short=zMKK3 {ECO:0000312|EMBL:BAB11809.1};
GN Name=map2k6 {ECO:0000250|UniProtKB:P52564};
GN Synonyms=map2k3 {ECO:0000312|EMBL:AAH71285.1,
GN ECO:0000312|ZFIN:ZDB-GENE-010202-3};
OS Danio rerio (Zebrafish) (Brachydanio rerio).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Actinopterygii; Neopterygii; Teleostei; Ostariophysi; Cypriniformes;
OC Danionidae; Danioninae; Danio.
OX NCBI_TaxID=7955;
RN [1] {ECO:0000305, ECO:0000312|EMBL:BAB11809.1}
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, DEVELOPMENTAL STAGE, AND MUTAGENESIS
RP OF LYS-109 AND 234-SER--THR-238.
RC TISSUE=Embryo {ECO:0000269|PubMed:10995439};
RX PubMed=10995439; DOI=10.1083/jcb.150.6.1335;
RA Fujii R., Yamashita S., Hibi M., Hirano T.;
RT "Asymmetric p38 activation in zebrafish: its possible role in symmetric and
RT synchronous cleavage.";
RL J. Cell Biol. 150:1335-1348(2000).
RN [2] {ECO:0000312|EMBL:AAH44129.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=AB {ECO:0000312|EMBL:AAH44129.1};
RC TISSUE=Embryo {ECO:0000312|EMBL:AAH71285.1};
RG NIH - Zebrafish Gene Collection (ZGC) project;
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Dual specificity protein kinase which acts as an essential
CC component of the MAP kinase signal transduction pathway. Catalyzes the
CC concomitant phosphorylation of a threonine and a tyrosine residue in
CC the MAP kinases p38 and plays an important role in the regulation of
CC cellular responses to cytokines and all kinds of stresses. The p38 MAP
CC kinase signal transduction pathway leads to direct activation of
CC transcription factors. Phosphorylation by MAP2K6 asymmetrically
CC activates p38 on one side of the blastodisc, an event which is
CC necessary for blastomere cleavage. {ECO:0000269|PubMed:10995439}.
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=2.7.12.2;
CC Evidence={ECO:0000305};
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=2.7.12.2; Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.12.2;
CC Evidence={ECO:0000305};
CC -!- ACTIVITY REGULATION: Activated by dual phosphorylation on Ser-234 and
CC Thr-238 in response to a variety of cellular stresses, including UV
CC radiation, osmotic shock, hypoxia, inflammatory cytokines, interferon
CC gamma (IFNG), and less often by growth factors. MAP2K6/MKK6 is
CC activated by the majority of M3Ks (By similarity). {ECO:0000250}.
CC -!- SUBUNIT: Dimer. Interacts (via its D domain) with its MAP kinase
CC substrates. Interacts (via its DVD domain) with MAP3Ks activators.
CC {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250}. Cytoplasm {ECO:0000250}.
CC Cytoplasm, cytoskeleton {ECO:0000250}. Note=Binds to microtubules.
CC {ECO:0000250}.
CC -!- DEVELOPMENTAL STAGE: Expressed both maternally and zygotically. Zygotic
CC expression continues throughout development.
CC {ECO:0000269|PubMed:10995439}.
CC -!- DOMAIN: The DVD domain (residues 338-361) contains a conserved docking
CC site and is found in the mammalian MAP kinase kinases (MAP2Ks). The DVD
CC sites bind to their specific upstream MAP kinase kinase kinases
CC (MAP3Ks) and are essential for activation (By similarity).
CC {ECO:0000250}.
CC -!- DOMAIN: The D domain (residues 30-46) contains a conserved docking site
CC and is required for the binding to MAPK substrates. {ECO:0000250}.
CC -!- PTM: Weakly autophosphorylated (By similarity). Phosphorylated at Ser-
CC 234 and Thr-238 by the majority of M3Ks. {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase subfamily. {ECO:0000255}.
CC -!- CAUTION: Was originally thought to be a Map2k3 protein but sequence
CC analysis shows closer similarity to the Map2k6 proteins. {ECO:0000305,
CC ECO:0000305|PubMed:10995439}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH71285.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AB030899; BAB11809.1; -; mRNA.
DR EMBL; BC044129; AAH44129.1; -; mRNA.
DR EMBL; BC071285; AAH71285.1; ALT_INIT; mRNA.
DR RefSeq; NP_001299799.1; NM_001312870.1.
DR AlphaFoldDB; Q9DGE0; -.
DR SMR; Q9DGE0; -.
DR STRING; 7955.ENSDARP00000111296; -.
DR PaxDb; Q9DGE0; -.
DR Ensembl; ENSDART00000171268; ENSDARP00000141647; ENSDARG00000099184.
DR GeneID; 65239; -.
DR KEGG; dre:65239; -.
DR CTD; 5608; -.
DR ZFIN; ZDB-GENE-010202-3; map2k6.
DR eggNOG; KOG0984; Eukaryota.
DR GeneTree; ENSGT00940000157836; -.
DR HOGENOM; CLU_000288_63_23_1; -.
DR InParanoid; Q9DGE0; -.
DR OMA; YTVQFYG; -.
DR OrthoDB; 688282at2759; -.
DR PhylomeDB; Q9DGE0; -.
DR TreeFam; TF350701; -.
DR Reactome; R-DRE-168638; NOD1/2 Signaling Pathway.
DR Reactome; R-DRE-2559580; Oxidative Stress Induced Senescence.
DR Reactome; R-DRE-450302; activated TAK1 mediates p38 MAPK activation.
DR PRO; PR:Q9DGE0; -.
DR Proteomes; UP000000437; Genome assembly.
DR Proteomes; UP000814640; Chromosome 12.
DR Bgee; ENSDARG00000099184; Expressed in gastrula and 26 other tissues.
DR ExpressionAtlas; Q9DGE0; baseline and differential.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004708; F:MAP kinase kinase activity; IBA:GO_Central.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IEA:RHEA.
DR GO; GO:0000165; P:MAPK cascade; IBA:GO_Central.
DR GO; GO:1900745; P:positive regulation of p38MAPK cascade; IMP:UniProtKB.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Cytoplasm; Cytoskeleton; Kinase; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Stress response; Transcription; Transcription regulation; Transferase.
FT CHAIN 1..361
FT /note="Dual specificity mitogen-activated protein kinase
FT kinase 6"
FT /id="PRO_0000345633"
FT DOMAIN 80..341
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..61
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 30..46
FT /note="D domain"
FT /evidence="ECO:0000250"
FT REGION 338..361
FT /note="DVD domain"
FT /evidence="ECO:0000250"
FT COMPBIAS 32..46
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 206
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 86..94
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 109
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT MOD_RES 234
FT /note="Phosphoserine; by MAPK3"
FT /evidence="ECO:0000250"
FT MOD_RES 238
FT /note="Phosphothreonine; by MAPK3"
FT /evidence="ECO:0000250"
FT MUTAGEN 109
FT /note="K->A: Acts as dominant negative. Inhibits activation
FT of MAP kinase p38 and disrupts cleavage."
FT /evidence="ECO:0000269|PubMed:10995439"
FT MUTAGEN 234..238
FT /note="SVAKT->EVAKE: Constitutively active."
FT /evidence="ECO:0000269|PubMed:10995439"
FT CONFLICT 28
FT /note="S -> SNV (in Ref. 1; BAB11809 and 2; AAH44129)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 361 AA; 40594 MW; D942485DE14864B9 CRC64;
MEGGSDKESK VFCDSPSPNP KGEMSVPSNV RGKKKLPKEL KLPKEVFEKP APAPTPPRDL
DSKAYVTIGE KNFVVKADDL EQIGELGRGA YGVVDKMRHV PSGVIMAVKR IRATVNTQEQ
KRLLMDLDIS MRTVDCFYTV TFYGALFREG DVWICMELMD TSLDKFYKQV HEKGKTIPED
ILGKITVSIV KALEHLHSNL SVIHRDVKPS NVLINMQGQV KMCDFGISGY LVDSVAKTMD
AGCKPYMAPE RINPETNQKG YNVKSDIWSL GITMIELAIL RFPYDSWGTP FQQLKQVVEE
PSPQLPADRF SADFVDFTSQ CLRKNSTERP TYTELMQHPF FTLHDSKDTD VASFVKTILG
D
