MP2K1_RABIT
ID MP2K1_RABIT Reviewed; 393 AA.
AC P29678;
DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 2.
DT 03-AUG-2022, entry version 154.
DE RecName: Full=Dual specificity mitogen-activated protein kinase kinase 1;
DE Short=MAP kinase kinase 1;
DE Short=MAPKK 1;
DE EC=2.7.12.2;
DE AltName: Full=ERK activator kinase 1;
DE AltName: Full=MAPK/ERK kinase 1;
DE Short=MEK 1;
GN Name=MAP2K1; Synonyms=MEK1, PRKMK1;
OS Oryctolagus cuniculus (Rabbit).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Lagomorpha; Leporidae; Oryctolagus.
OX NCBI_TaxID=9986;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PHOSPHORYLATION AT SER-218 AND SER-222 BY
RP RAF.
RX PubMed=8157000; DOI=10.1002/j.1460-2075.1994.tb06424.x;
RA Alessi D.R., Saito Y., Campbell D.G., Cohen P., Sithanadam G., Rapp U.,
RA Ashworth A., Marshall C.J., Cowley S.;
RT "Identification of the sites in MAP kinase kinase-1 phosphorylated by
RT p74raf-1.";
RL EMBO J. 13:1610-1619(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 16-393, AND PARTIAL PROTEIN SEQUENCE.
RC TISSUE=Brain, and Skeletal muscle;
RX PubMed=1461659;
RA Ashworth A., Nakielny S., Cohen P., Marshall C.;
RT "The amino acid sequence of a mammalian MAP kinase kinase.";
RL Oncogene 7:2555-2556(1992).
RN [3]
RP PROTEIN SEQUENCE OF 2-16; 85-96 AND 190-201.
RC TISSUE=Skeletal muscle;
RX PubMed=1499729; DOI=10.1016/0014-5793(92)81271-m;
RA Nakielny S., Campbell D.G., Cohen P.;
RT "MAP kinase kinase from rabbit skeletal muscle. A novel dual specificity
RT enzyme showing homology to yeast protein kinases involved in pheromone-
RT dependent signal transduction.";
RL FEBS Lett. 308:183-189(1992).
RN [4]
RP PROTEIN SEQUENCE OF 85-96 AND 190-201.
RC TISSUE=Skeletal muscle;
RX PubMed=1379797; DOI=10.1042/bj2850701;
RA Wu J., Michel H., Rossomando A., Haystead T., Shabanowitz J., Hunt D.F.,
RA Sturgill T.W.;
RT "Renaturation and partial peptide sequencing of mitogen-activated protein
RT kinase (MAP kinase) activator from rabbit skeletal muscle.";
RL Biochem. J. 285:701-705(1992).
RN [5]
RP X-RAY CRYSTALLOGRAPHY (3.46 ANGSTROMS) IN COMPLEX WITH ATP AND HUMAN KSR2,
RP AND PHOSPHORYLATION.
RX PubMed=21441910; DOI=10.1038/nature09860;
RA Brennan D.F., Dar A.C., Hertz N.T., Chao W.C., Burlingame A.L.,
RA Shokat K.M., Barford D.;
RT "A Raf-induced allosteric transition of KSR stimulates phosphorylation of
RT MEK.";
RL Nature 472:366-369(2011).
CC -!- FUNCTION: Dual specificity protein kinase which acts as an essential
CC component of the MAP kinase signal transduction pathway. Binding of
CC extracellular ligands such as growth factors, cytokines and hormones to
CC their cell-surface receptors activates RAS and this initiates RAF1
CC activation. RAF1 then further activates the dual-specificity protein
CC kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2
CC function specifically in the MAPK/ERK cascade, and catalyze the
CC concomitant phosphorylation of a threonine and a tyrosine residue in a
CC Thr-Glu-Tyr sequence located in the extracellular signal-regulated
CC kinases MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and
CC further transduction of the signal within the MAPK/ERK cascade.
CC Activates BRAF in a KSR1 or KSR2-dependent manner; by binding to KSR1
CC or KSR2 releases the inhibitory intramolecular interaction between KSR1
CC or KSR2 protein kinase and N-terminal domains which promotes KSR1 or
CC KSR2-BRAF dimerization and BRAF activation (By similarity). Depending
CC on the cellular context, this pathway mediates diverse biological
CC functions such as cell growth, adhesion, survival and differentiation,
CC predominantly through the regulation of transcription, metabolism and
CC cytoskeletal rearrangements. One target of the MAPK/ERK cascade is
CC peroxisome proliferator-activated receptor gamma (PPARG), a nuclear
CC receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has
CC been shown to export PPARG from the nucleus. The MAPK/ERK cascade is
CC also involved in the regulation of endosomal dynamics, including
CC lysosome processing and endosome cycling through the perinuclear
CC recycling compartment (PNRC), as well as in the fragmentation of the
CC Golgi apparatus during mitosis (By similarity). {ECO:0000250,
CC ECO:0000250|UniProtKB:Q02750}.
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 -!- 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;
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 -!- ACTIVITY REGULATION: Ras proteins such as HRAS mediate the activation
CC of RAF proteins such as RAF1 or BRAF which in turn activate
CC extracellular signal-regulated kinases (ERK) through MAPK (mitogen-
CC activated protein kinases) and ERK kinases MAP2K1/MEK1 and MAP2K2/MEK2.
CC Activation occurs through phosphorylation of Ser-218 and Ser-222 (By
CC similarity). MAP2K1/MEK1 binds KSR1 or KSR2 releasing the inhibitory
CC intramolecular interaction between KSR1 or KSR2 protein kinase and N-
CC terminal domains (By similarity). This allows KSR1 or KSR2 dimerization
CC with BRAF leading to BRAF activation and phosphorylation of MAP2K1 (By
CC similarity). MAP2K1/MEK1 is also the target of negative feed-back
CC regulation by its substrate kinases, such as MAPK1/ERK2. These
CC phosphorylate MAP2K1/MEK1 on Thr-292, thereby facilitating
CC dephosphorylation of the activating residues Ser-218 and Ser-222.
CC Inhibited by serine/threonine phosphatase 2A (By similarity).
CC {ECO:0000250|UniProtKB:Q01986, ECO:0000250|UniProtKB:Q02750}.
CC -!- SUBUNIT: Found in a complex with at least BRAF, HRAS, MAP2K1,
CC MAPK3/ERK1 and RGS14 (By similarity). Forms a heterodimer with
CC MAP2K2/MEK2 (By similarity). Forms heterodimers with KSR2 which further
CC dimerize to form tetramers (PubMed:21441910). Interacts with KSR1 or
CC KSR2 and BRAF; the interaction with KSR1 or KSR2 mediates KSR1-BRAF or
CC KSR2-BRAF dimerization (By similarity). Interacts with ARBB2, LAMTOR3,
CC MAPK1/ERK2 and RAF1 (By similarity). Interacts with MAPK1/ERK2 (By
CC similarity). Interacts with MORG1 (By similarity). Interacts with PPARG
CC (By similarity). Interacts with SGK1 (By similarity). Interacts with
CC BIRC6/bruce (By similarity). Interacts with KAT7; the interaction
CC promotes KAT7 phosphorylation (By similarity). Interacts with RAF1 and
CC NEK10; the interaction is required for ERK1/2-signaling pathway
CC activation in response to UV irradiation (By similarity). Interacts
CC with TRAF3IP3 (By similarity). {ECO:0000250|UniProtKB:P31938,
CC ECO:0000250|UniProtKB:Q01986, ECO:0000250|UniProtKB:Q02750,
CC ECO:0000269|PubMed:21441910}.
CC -!- INTERACTION:
CC P29678; P15056: BRAF; Xeno; NbExp=2; IntAct=EBI-1631983, EBI-365980;
CC P29678; Q6VAB6-1: KSR2; Xeno; NbExp=6; IntAct=EBI-1631983, EBI-15916808;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton, microtubule organizing
CC center, centrosome {ECO:0000250|UniProtKB:Q02750}. Cytoplasm,
CC cytoskeleton, microtubule organizing center, spindle pole body
CC {ECO:0000250|UniProtKB:Q02750}. Cytoplasm
CC {ECO:0000250|UniProtKB:Q02750}. Nucleus {ECO:0000250|UniProtKB:Q02750}.
CC Membrane {ECO:0000250|UniProtKB:Q02750}; Peripheral membrane protein
CC {ECO:0000250|UniProtKB:Q02750}. Note=Localizes at centrosomes during
CC prometaphase, midzone during anaphase and midbody during
CC telophase/cytokinesis. Membrane localization is probably regulated by
CC its interaction with KSR1. {ECO:0000250|UniProtKB:Q02750}.
CC -!- DOMAIN: The proline-rich region localized between residues 270 and 307
CC is important for the binding to RAF1 and activation of MAP2K1/MEK1.
CC {ECO:0000250}.
CC -!- PTM: Phosphorylation at Ser-218 and Ser-222 by MAP kinase kinase
CC kinases (RAF or MEKK1) regulates positively the kinase activity (By
CC similarity). Also phosphorylated at Thr-292 by MAPK1/ERK2 and at Ser-
CC 298 by PAK (By similarity). MAPK1/ERK2 phosphorylation of Thr-292
CC occurs in response to cellular adhesion and leads to inhibition of Ser-
CC 298 phosphorylation by PAK (By similarity). Autophosphorylated at Ser-
CC 218 and Ser-222, autophosphosphorylation is promoted by NEK10 following
CC UV irradiation (By similarity). {ECO:0000250|UniProtKB:Q02750}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase subfamily. {ECO:0000305}.
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DR EMBL; Z30163; CAA82912.1; -; mRNA.
DR PIR; S42068; S42068.
DR RefSeq; NP_001076098.1; NM_001082629.1.
DR PDB; 2Y4I; X-ray; 3.46 A; C=1-393.
DR PDB; 5KKR; X-ray; 3.51 A; C=1-393.
DR PDB; 7JUQ; X-ray; 3.22 A; C=35-393.
DR PDB; 7JUR; X-ray; 2.82 A; C=35-393.
DR PDB; 7JUS; X-ray; 2.99 A; C=35-393.
DR PDB; 7JUT; X-ray; 3.09 A; C=35-393.
DR PDB; 7JUU; X-ray; 3.19 A; C=35-393.
DR PDB; 7JUV; X-ray; 3.36 A; C=35-393.
DR PDB; 7JUW; X-ray; 2.88 A; C=35-393.
DR PDB; 7JUX; X-ray; 3.34 A; C=35-393.
DR PDB; 7JUY; X-ray; 3.10 A; C=35-393.
DR PDB; 7JUZ; X-ray; 3.21 A; C=35-393.
DR PDB; 7JV0; X-ray; 3.63 A; C=35-393.
DR PDB; 7JV1; X-ray; 3.62 A; C=35-393.
DR PDBsum; 2Y4I; -.
DR PDBsum; 5KKR; -.
DR PDBsum; 7JUQ; -.
DR PDBsum; 7JUR; -.
DR PDBsum; 7JUS; -.
DR PDBsum; 7JUT; -.
DR PDBsum; 7JUU; -.
DR PDBsum; 7JUV; -.
DR PDBsum; 7JUW; -.
DR PDBsum; 7JUX; -.
DR PDBsum; 7JUY; -.
DR PDBsum; 7JUZ; -.
DR PDBsum; 7JV0; -.
DR PDBsum; 7JV1; -.
DR AlphaFoldDB; P29678; -.
DR SMR; P29678; -.
DR DIP; DIP-40535N; -.
DR IntAct; P29678; 3.
DR STRING; 9986.ENSOCUP00000007582; -.
DR BindingDB; P29678; -.
DR ChEMBL; CHEMBL5740; -.
DR iPTMnet; P29678; -.
DR GeneID; 100009316; -.
DR KEGG; ocu:100009316; -.
DR CTD; 5604; -.
DR eggNOG; KOG0581; Eukaryota.
DR InParanoid; P29678; -.
DR OrthoDB; 688282at2759; -.
DR BRENDA; 2.7.12.2; 1749.
DR PRO; PR:P29678; -.
DR Proteomes; UP000001811; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005815; C:microtubule organizing center; 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; IEA:UniProtKB-EC.
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:UniProtKB-KW.
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; PF00069; Pkinase; 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; Cytoskeleton;
KW Direct protein sequencing; Kinase; Membrane; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Transferase; Tyrosine-protein kinase.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:1499729"
FT CHAIN 2..393
FT /note="Dual specificity mitogen-activated protein kinase
FT kinase 1"
FT /id="PRO_0000086368"
FT DOMAIN 68..361
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..27
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 270..307
FT /note="RAF1-binding"
FT /evidence="ECO:0000250"
FT ACT_SITE 190
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 74..82
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000269|PubMed:21441910"
FT BINDING 97
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000269|PubMed:21441910"
FT SITE 8..9
FT /note="Cleavage; by anthrax lethal factor"
FT /evidence="ECO:0000250"
FT MOD_RES 218
FT /note="Phosphoserine; by RAF"
FT /evidence="ECO:0000269|PubMed:8157000"
FT MOD_RES 222
FT /note="Phosphoserine; by RAF"
FT /evidence="ECO:0000269|PubMed:8157000"
FT MOD_RES 286
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q02750"
FT MOD_RES 292
FT /note="Phosphothreonine; by MAPK1"
FT /evidence="ECO:0000250|UniProtKB:Q01986"
FT MOD_RES 298
FT /note="Phosphoserine; by PAK"
FT /evidence="ECO:0000250|UniProtKB:Q02750"
FT HELIX 44..53
FT /evidence="ECO:0007829|PDB:7JUR"
FT TURN 54..59
FT /evidence="ECO:0007829|PDB:7JUR"
FT HELIX 65..67
FT /evidence="ECO:0007829|PDB:7JUR"
FT STRAND 68..73
FT /evidence="ECO:0007829|PDB:7JUR"
FT STRAND 82..90
FT /evidence="ECO:0007829|PDB:7JUR"
FT STRAND 93..97
FT /evidence="ECO:0007829|PDB:7JUR"
FT HELIX 106..115
FT /evidence="ECO:0007829|PDB:7JUR"
FT HELIX 117..120
FT /evidence="ECO:0007829|PDB:7JUR"
FT STRAND 129..134
FT /evidence="ECO:0007829|PDB:7JUR"
FT STRAND 136..144
FT /evidence="ECO:0007829|PDB:7JUR"
FT STRAND 147..150
FT /evidence="ECO:0007829|PDB:7JUR"
FT HELIX 151..157
FT /evidence="ECO:0007829|PDB:7JUR"
FT STRAND 158..160
FT /evidence="ECO:0007829|PDB:7JUR"
FT HELIX 163..184
FT /evidence="ECO:0007829|PDB:7JUR"
FT HELIX 193..195
FT /evidence="ECO:0007829|PDB:7JUR"
FT STRAND 196..198
FT /evidence="ECO:0007829|PDB:7JUR"
FT STRAND 204..206
FT /evidence="ECO:0007829|PDB:7JUR"
FT HELIX 213..218
FT /evidence="ECO:0007829|PDB:7JUR"
FT STRAND 221..226
FT /evidence="ECO:0007829|PDB:7JUR"
FT HELIX 232..235
FT /evidence="ECO:0007829|PDB:7JUR"
FT HELIX 243..258
FT /evidence="ECO:0007829|PDB:7JUR"
FT HELIX 268..274
FT /evidence="ECO:0007829|PDB:7JUR"
FT HELIX 310..319
FT /evidence="ECO:0007829|PDB:7JUR"
FT TURN 327..329
FT /evidence="ECO:0007829|PDB:7JUR"
FT HELIX 332..341
FT /evidence="ECO:0007829|PDB:7JUR"
FT TURN 346..348
FT /evidence="ECO:0007829|PDB:7JUR"
FT TURN 352..357
FT /evidence="ECO:0007829|PDB:7JUR"
FT HELIX 359..365
FT /evidence="ECO:0007829|PDB:7JUR"
FT HELIX 371..379
FT /evidence="ECO:0007829|PDB:7JUR"
SQ SEQUENCE 393 AA; 43453 MW; 0341B42FF9218D51 CRC64;
MPKKKPTPIQ LNPAPDGSAV NGTSSAETNL EALQKKLEEL ELDEQQRKRL EAFLTQKQKV
GELKDDDFEK ISELGAGNGG VVFKVSHKPS GLVMARKLIH LEIKPAIRNQ IIRELQVLHE
CNSPYIVGFY GAFYSDGEIS ICMEHMDGGS LDQVLKKAGR IPEQILGKVS IAVIKGLTYL
REKHKIMHRD VKPSNILVNS RGEIKLCDFG VSGQLIDSMA NSFVGTRSYM SPERLQGTHY
SVQSDIWSMG LSLVEMAVGR YPIPPPDAKE LELMFGCQVE GDAAETPPRP RTPGRPLSSY
GMDSRPPMAI FELLDYIVNE PPPKLPSAVF SLEFQDFVNK CLIKNPAERA DLKQLMVHAF
IKRSDAEEVD FAGWLCSTIG LNQPSTPTHA AGV
