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 27-MAR-2024, entry version 161. 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). Interacts with MOS (By similarity). CC {ECO:0000250|UniProtKB:P31938, ECO:0000250|UniProtKB:Q01986, CC ECO:0000250|UniProtKB:Q02750, 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) positively regulates 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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.ENSOCUP00000029057; -. DR BindingDB; P29678; -. DR ChEMBL; CHEMBL5740; -. DR iPTMnet; P29678; -. DR PaxDb; 9986-ENSOCUP00000007582; -. DR GeneID; 100009316; -. DR KEGG; ocu:100009316; -. DR CTD; 5604; -. DR eggNOG; KOG0581; Eukaryota. DR InParanoid; P29678; -. DR OrthoDB; 2900742at2759; -. DR BRENDA; 2.7.12.2; 1749. DR PRO; PR:P29678; -. DR Proteomes; UP000001811; Unplaced. DR GO; GO:0005813; C:centrosome; IEA:UniProtKB-SubCell. DR GO; GO:0005769; C:early endosome; IEA:UniProt. DR GO; GO:0005925; C:focal adhesion; IEA:UniProt. DR GO; GO:0005770; C:late endosome; IEA:UniProt. DR GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005739; C:mitochondrion; IEA:UniProt. 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 GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW. DR GO; GO:2000641; P:regulation of early endosome to late endosome transport; IEA:UniProt. DR GO; GO:0090170; P:regulation of Golgi inheritance; IEA:UniProt. DR GO; GO:0032872; P:regulation of stress-activated MAPK cascade; IEA:UniProt. DR CDD; cd06650; PKc_MEK1; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. 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 PANTHER; PTHR47448; DUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE DSOR1-LIKE PROTEIN; 1. DR PANTHER; PTHR47448:SF2; MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1; 1. DR Pfam; PF00069; Pkinase; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 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 //