MAP2K1
entrez
5604
canonical
uniprot
Q02750
canonical
ensembl
ENSG00000169032
resolver
ensp
ENSP00000302486
resolver
ensp
ENSP00000508437
resolver
ensp
ENSP00000510309
resolver
ensp
ENSP00000571590
resolver
enst
ENST00000692683
resolver
enst
ENST00000693150
resolver
genesymbol
MAP2K1
resolver
genesymbol_syn
MEK1
resolver
genesymbol_syn
PRKMK1
resolver
hgnc
HGNC:6840
resolver
uniprot
A0A8I5KYS7
resolver
uniprot
A0A8I5QJ47
resolver
uniprot
A4QPA9
resolver
uniprot
B4DFY5
resolver
uniprot_entry
A0A8I5KYS7_HUMAN
resolver
uniprot_entry
A0A8I5QJ47_HUMAN
resolver
uniprot_entry
A4QPA9_HUMAN
resolver
uniprot_entry
B4DFY5_HUMAN
resolver
uniprot_entry
MP2K1_HUMAN
resolver
activity_regulation
ACTIVITY REGULATION: 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 (PubMed:29433126). Activation occurs through phosphorylation of Ser-218 and Ser-222 (By similarity). MAP2K1/MEK1 binds KSR1 or KSR2 releasing the inhibitory intramolecular interaction between KSR1 or KSR2 protein kinase and N-terminal domains (PubMed:29433126). This allows KSR1 or KSR2 dimerization with BRAF leading to BRAF activation and phosphorylation of MAP2K1 (PubMed:29433126). 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). Many inhibitors have been identified including pyrrole derivatives, TAK-733 (one of a series of 8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione derivatives), CH4987655 and RDEA119/BAY 869766 (PubMed:15543157, PubMed:17880056, PubMed:18951019, PubMed:19019675, PubMed:19161339, PubMed:19706763, PubMed:20621728, PubMed:21310613). {ECO:0000250|UniProtKB:Q01986, ECO:0000269|PubMed:15543157, ECO:0000269|PubMed:17880056, ECO:0000269|PubMed:18951019, ECO:0000269|PubMed:19019675, ECO:0000269|PubMed:19161339, ECO:0000269|PubMed:19706763, ECO:0000269|PubMed:20621728, ECO:0000269|PubMed:21310613, ECO:0000269|PubMed:29433126}.
uniprot
proteins
amino_acid_sequence
MPKKKPTPIQLNPAPDGSAVNGTSSAETNLEALQKKLEELELDEQQRKRLEAFLTQKQKVGELKDDDFEKISELGAGNGGVVFKVSHKPSGLVMARKLIHLEIKPAIRNQIIRELQVLHECNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQVLKKAGRIPEQILGKVSIAVIKGLTYLREKHKIMHRDVKPSNILVNSRGEIKLCDFGVSGQLIDSMANSFVGTRSYMSPERLQGTHYSVQSDIWSMGLSLVEMAVGRYPIPPPDAKELELMFGCQVEGDAAETPPRPRTPGRPLSSYGMDSRPPMAIFELLDYIVNEPPPKLPSGVFSLEFQDFVNKCLIKNPAERADLKQLMVHAFIKRSDAEEVDFAGWLCSTIGLNQPSTPTHAAGV
uniprot
proteins
disease_involvement
DISEASE: Cardiofaciocutaneous syndrome 3 (CFC3) [MIM:615279]: A form of cardiofaciocutaneous syndrome, a multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects and intellectual disability. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. Distinctive features of CFC3 include macrostomia and horizontal shape of palpebral fissures. {ECO:0000269|PubMed:16439621, ECO:0000269|PubMed:18042262}. Note=The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Melorheostosis, isolated (MEL) [MIM:155950]: A sclerosing bone disorder characterized by hyperostosis of the cortex of tubular bones, frequently involving one limb. The lesions may be accompanied by abnormalities of adjacent soft tissue, joint contractures, sclerodermatous skin lesions, muscle atrophy, or hemangioma. {ECO:0000269|PubMed:29643386}. Note=The disease is caused by variants affecting the gene represented in this entry.
uniprot
proteins
ec_number
2.7.12.2
uniprot
proteins
function
FUNCTION: 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. Activates BRAF in a KSR1 or KSR2-dependent manner; by binding to KSR1 or KSR2 releases the inhibitory intramolecular interaction between KSR1 or KSR2 protein kinase and N-terminal domains which promotes KSR1 or KSR2-BRAF dimerization and BRAF activation (PubMed:29433126). 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. {ECO:0000269|PubMed:14737111, ECO:0000269|PubMed:17101779, ECO:0000269|PubMed:29433126}.
uniprot
proteins
mass_dalton
43439
uniprot
proteins
mutagenesis
MUTAGEN 97; /note="K->A: Loss of catalytic activity. Strongly reduces phosphorylation upon UV irradiation."; /evidence="ECO:0000269|PubMed:20956560"; MUTAGEN 97; /note="K->R: Loss of catalytic activity. No effect on BRAF-KSR1 or BRAF-KSR2 dimerization."; /evidence="ECO:0000269|PubMed:29433126, ECO:0000269|PubMed:8131746"; MUTAGEN 150; /note="S->A: No loss of activity."; /evidence="ECO:0000269|PubMed:8131746"; MUTAGEN 212; /note="S->A: No loss of activity."; /evidence="ECO:0000269|PubMed:8131746"; MUTAGEN 218; /note="S->A: Loss of catalytic activity. No effect on BRAF-KSR1 dimerization; when associated with A-222."; /evidence="ECO:0000269|PubMed:29433126, ECO:0000269|PubMed:8131746"; MUTAGEN 218; /note="S->D: No effect on BRAF-KSR1 dimerization; when associated with D-222."; /evidence="ECO:0000269|PubMed:29433126"; MUTAGEN 219; /note="M->V: Increases interaction with KSR1 and BRAF."; /evidence="ECO:0000269|PubMed:29433126"; MUTAGEN 219; /note="M->W: Increases interaction with KSR1 and BRAF; when associated with L-220."; /evidence="ECO:0000269|PubMed:29433126"; MUTAGEN 220; /note="A->L: Increases interaction with KSR1 and BRAF; when associated with w-219."; /evidence="ECO:0000269|PubMed:29433126"; MUTAGEN 221; /note="N->Y: Increases interaction with KSR1 and BRAF."; /evidence="ECO:0000269|PubMed:29433126"; MUTAGEN 222; /note="S->A: Loss of catalytic activity. No effect on BRAF-KSR1 dimerization; when associated with A-218."; /evidence="ECO:0000269|PubMed:29433126, ECO:0000269|PubMed:8131746"; MUTAGEN 222; /note="S->D: No effect on BRAF-KSR1 dimerization; when associated with D-218."; /evidence="ECO:0000269|PubMed:29433126"; MUTAGEN 311; /note="F->S: Loss of interaction with BRAF and KSR1. Loss of BRAF-KSR1 dimerization."; /evidence="ECO:0000269|PubMed:29433126
uniprot
proteins
post_translational_modification
PTM: Phosphorylation at Ser-218 and Ser-222 by MAP kinase kinase kinases (BRAF or MEKK1) positively regulates kinase activity (PubMed:29433126, PubMed:8131746). Also phosphorylated at Thr-292 by MAPK1/ERK2 and at Ser-298 by PAK (PubMed:16129686). MAPK1/ERK2 phosphorylation of Thr-292 occurs in response to cellular adhesion and leads to inhibition of Ser-298 phosphorylation by PAK (PubMed:16129686). Autophosphorylated at Ser-218 and Ser-222, autophosphosphorylation is promoted by NEK10 following UV irradiation (PubMed:20956560). {ECO:0000269|PubMed:16129686, ECO:0000269|PubMed:20956560, ECO:0000269|PubMed:29433126, ECO:0000269|PubMed:8131746}.; PTM: (Microbial infection) Acetylation by Yersinia YopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway. {ECO:0000269|PubMed:16728640}.
uniprot
proteins
protein_family
MAP kinase kinase subfamily
uniprot
proteins
protein_family
Protein kinase superfamily
uniprot
proteins
protein_family
STE Ser/Thr protein kinase family
uniprot
proteins
pubmed
10409742
uniprot
proteins
pubmed
11104681
uniprot
proteins
pubmed
1281467
uniprot
proteins
pubmed
14737111
uniprot
proteins
pubmed
15520807
uniprot
proteins
pubmed
15543157
uniprot
proteins
pubmed
16129686
uniprot
proteins
pubmed
16439621
uniprot
proteins
pubmed
16728640
uniprot
proteins
pubmed
17101779
uniprot
proteins
pubmed
17880056
uniprot
proteins
pubmed
18042262
uniprot
proteins
pubmed
18329369
uniprot
proteins
pubmed
18691976
uniprot
proteins
pubmed
18951019
uniprot
proteins
pubmed
19019675
uniprot
proteins
pubmed
19161339
uniprot
proteins
pubmed
19369195
uniprot
proteins
pubmed
19447520
uniprot
proteins
pubmed
19565474
uniprot
proteins
pubmed
19706763
uniprot
proteins
pubmed
20621728
uniprot
proteins
pubmed
20679487
uniprot
proteins
pubmed
20956560
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
21310613
uniprot
proteins
pubmed
21316218
uniprot
proteins
pubmed
21779493
uniprot
proteins
pubmed
24275569
uniprot
proteins
pubmed
26195727
uniprot
proteins
pubmed
29433126
uniprot
proteins
pubmed
29643386
uniprot
proteins
pubmed
32721402
uniprot
proteins
pubmed
34779126
uniprot
proteins
pubmed
35670744
uniprot
proteins
pubmed
8131746
uniprot
proteins
pubmed
8388392
uniprot
proteins
pubmed
9563949
uniprot
proteins
pubmed
9779990
uniprot
proteins
sequence_length
393
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000269|PubMed:14737111}. Cytoplasm, cytoskeleton, microtubule organizing center, spindle pole body {ECO:0000269|PubMed:14737111}. Cytoplasm {ECO:0000269|PubMed:10409742, ECO:0000269|PubMed:17101779}. Nucleus {ECO:0000269|PubMed:17101779}. Membrane {ECO:0000269|PubMed:10409742}; Peripheral membrane protein {ECO:0000269|PubMed:10409742}. Note=Localizes at centrosomes during prometaphase, midzone during anaphase and midbody during telophase/cytokinesis (PubMed:14737111). Membrane localization is probably regulated by its interaction with KSR1 (PubMed:10409742). {ECO:0000269|PubMed:10409742, ECO:0000269|PubMed:14737111}.
uniprot
proteins