P29678 (MP2K1_RABIT) Reviewed, UniProtKB/Swiss-Prot
Last modified November 13, 2013. Version 105. History...
Names and origin
|Protein names||Recommended name:|
Dual specificity mitogen-activated protein kinase kinase 1
Short name=MAP kinase kinase 1
Short name=MAPKK 1
ERK activator kinase 1
MAPK/ERK kinase 1
Short name=MEK 1
|Organism||Oryctolagus cuniculus (Rabbit) [Reference proteome]|
|Taxonomic identifier||9986 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Lagomorpha › Leporidae › Oryctolagus|
|Sequence length||393 AA.|
|Sequence processing||The displayed sequence is further processed into a mature form.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Binding of extracellular ligands such as growth factors, cytokines and hormones to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2 function specifically in the MAPK/ERK cascade, and catalyze the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and further transduction of the signal within the MAPK/ERK cascade. Depending on the cellular context, this pathway mediates diverse biological functions such as cell growth, adhesion, survival and differentiation, predominantly through the regulation of transcription, metabolism and cytoskeletal rearrangements. One target of the MAPK/ERK cascade is peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has been shown to export PPARG from the nucleus. The MAPK/ERK cascade is also involved in the regulation of endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC), as well as in the fragmentation of the Golgi apparatus during mitosis By similarity.
ATP + a protein = ADP + a phosphoprotein.
Ras proteins such as HRAS mediate the activation of RAF proteins such as RAF1 or BRAF which in turn activate extracellular signal-regulated kinases (ERK) through MAPK (mitogen-activated protein kinases) and ERK kinases MAP2K1/MEK1 and MAP2K2/MEK2. Activation occurs through phosphorylation of Ser-218 and Ser-222. MAP2K1/MEK1 is also the target of negative feed-back regulation by its substrate kinases, such as MAPK1/ERK2. These phosphorylate MAP2K1/MEK1 on Thr-292, thereby facilitating dephosphorylation of the activating residues Ser-218 and Ser-222. Inhibited by serine/threonine phosphatase 2A By similarity.
Found in a complex with at least BRAF, HRAS1, MAP2K1, MAPK3/ERK1 and RGS14 By similarity. Forms a heterodimer with MAP2K2/MEK2 By similarity. Forms heterodimers with KSR2 which further dimerize to form tetramers By similarity. Interacts with ARRB2, LAMTOR3, MAPK1/ERK2, MORG1, RAF1, PPARG and VRK2 By similarity. Interacts with SGK1 By similarity. Interacts with BIRC6/bruce By similarity.
Cytoplasm › cytoskeleton › microtubule organizing center › centrosome By similarity. Cytoplasm › cytoskeleton › microtubule organizing center › spindle pole body By similarity. Cytoplasm By similarity. Nucleus By similarity. Note: Localizes at centrosomes during prometaphase, midzone during anaphase and midbody during telophase/cytokinesis By similarity.
The proline-rich region localized between residues 270 and 307 is important for the binding to RAF1 and activation of MAP2K1/MEK1 By similarity.
Phosphorylation at Ser-218 and Ser-222 by MAP kinase kinase kinases (RAF or MEKK1) regulates positively the kinase activity By similarity. Also phosphorylated at Thr-292 by MAPK1/ERK2 and at Ser-298 by PAK By similarity. MAPK1/ERK2 phosphorylation of Thr-292 occurs in response to cellular adhesion and leads to inhibition of Ser-298 phosphorylation by PAK By similarity. Ref.1 Ref.5
Contains 1 protein kinase domain.
Direct protein sequencing
|Gene Ontology (GO)|
Inferred from electronic annotation. Source: UniProtKB-SubCellnucleus
Inferred from electronic annotation. Source: UniProtKB-SubCellspindle pole body
Inferred from electronic annotation. Source: UniProtKB-SubCell
Inferred from electronic annotation. Source: UniProtKB-KWprotein serine/threonine kinase activity
Inferred from electronic annotation. Source: UniProtKB-KWprotein tyrosine kinase activity
Inferred from electronic annotation. Source: UniProtKB-KW
|Complete GO annotation...|
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Initiator methionine||1||1||Removed Ref.3|
|Chain||2 – 393||392||Dual specificity mitogen-activated protein kinase kinase 1||PRO_0000086368|
|Domain||68 – 361||294||Protein kinase|
|Nucleotide binding||74 – 82||9||ATP By similarity|
|Region||270 – 307||38||RAF1-binding By similarity|
|Compositional bias||262 – 307||46||Pro-rich|
|Active site||190||1||Proton acceptor By similarity|
|Binding site||97||1||ATP By similarity|
|Site||8 – 9||2||Cleavage; by anthrax lethal factor By similarity|
Amino acid modifications
|Modified residue||218||1||Phosphoserine; by RAF Ref.1|
|Modified residue||222||1||Phosphoserine; by RAF Ref.1|
|Modified residue||286||1||Phosphothreonine By similarity|
|Modified residue||292||1||Phosphothreonine; by MAPK1 By similarity|
|Modified residue||298||1||Phosphoserine; by PAK By similarity|
Helix Strand Turn
|Helix||44 – 55||12|
|Turn||56 – 59||4|
|Turn||65 – 67||3|
|Beta strand||73 – 75||3|
|Turn||88 – 91||4|
|Beta strand||95 – 100||6|
|Helix||105 – 115||11|
|Helix||116 – 120||5|
|Beta strand||129 – 133||5|
|Beta strand||136 – 143||8|
|Helix||151 – 156||6|
|Helix||163 – 184||22|
|Helix||193 – 195||3|
|Beta strand||196 – 198||3|
|Beta strand||204 – 206||3|
|Helix||213 – 218||6|
|Helix||232 – 236||5|
|Helix||242 – 258||17|
|Helix||271 – 273||3|
|Helix||310 – 319||10|
|Turn||327 – 329||3|
|Helix||332 – 341||10|
|Turn||346 – 348||3|
|Helix||352 – 356||5|
|Helix||359 – 366||8|
|Helix||371 – 375||5|
|Turn||376 – 378||3|
|||"Identification of the sites in MAP kinase kinase-1 phosphorylated by p74raf-1."|
Alessi D.R., Saito Y., Campbell D.G., Cohen P., Sithanadam G., Rapp U., Ashworth A., Marshall C.J., Cowley S.
EMBO J. 13:1610-1619(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], PHOSPHORYLATION AT SER-218 AND SER-222 BY RAF.
|||"The amino acid sequence of a mammalian MAP kinase kinase."|
Ashworth A., Nakielny S., Cohen P., Marshall C.
Oncogene 7:2555-2556(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 16-393, PARTIAL PROTEIN SEQUENCE.
Tissue: Brain and Skeletal muscle.
|||"MAP kinase kinase from rabbit skeletal muscle. A novel dual specificity enzyme showing homology to yeast protein kinases involved in pheromone-dependent signal transduction."|
Nakielny S., Campbell D.G., Cohen P.
FEBS Lett. 308:183-189(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 2-16; 85-96 AND 190-201.
Tissue: Skeletal muscle.
|||"Renaturation and partial peptide sequencing of mitogen-activated protein kinase (MAP kinase) activator from rabbit skeletal muscle."|
Wu J., Michel H., Rossomando A., Haystead T., Shabanowitz J., Hunt D.F., Sturgill T.W.
Biochem. J. 285:701-705(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 85-96 AND 190-201.
Tissue: Skeletal muscle.
|||"A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK."|
Brennan D.F., Dar A.C., Hertz N.T., Chao W.C., Burlingame A.L., Shokat K.M., Barford D.
Nature 472:366-369(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (3.46 ANGSTROMS) IN COMPLEX WITH ATP AND HUMAN KSR2, PHOSPHORYLATION.
|Z30163 mRNA. Translation: CAA82912.1.|
|RefSeq||NP_001076098.1. NM_001082629.1. |
3D structure databases
|SMR||P29678. Positions 62-382. |
Protein-protein interaction databases
|IntAct||P29678. 1 interaction.|
Protocols and materials databases
Genome annotation databases
Enzyme and pathway databases
|BRENDA||220.127.116.11. 1749. |
Family and domain databases
|InterPro||IPR011009. Kinase-like_dom. |
|Pfam||PF00069. Pkinase. 1 hit. |
|SMART||SM00220. S_TKc. 1 hit. |
|SUPFAM||SSF56112. SSF56112. 1 hit. |
|PROSITE||PS00107. PROTEIN_KINASE_ATP. 1 hit. |
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
|Accession||Primary (citable) accession number: P29678|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|