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 (updated: Oct. 16, 2019)

Protein identification was indicated in the following studies:

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

Publication	Identification ¹	Uniprot mapping ²	Not mapped / Obsolete	TrEMBL	Swiss-Prot
Goodman (2013)	2289 (gene list)	2278	53	20599	2269
Lange (2014)	1234	1234	7	28	1224
Hegedus (2015)	2638	2622	0	235	2387
Wilson (2016)	1658	1528	170	291	1068
d'Alessandro (2017)	1826	1817	2	0	1815
Bryk (2017)	2090	2060	10	108	1942
Chu (2018)	1853	1804	55	362	1387

¹ as available in the article and/or in supplementary material
² uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.

Protein sequence (FASTA)

Protein coevolution profile (FreeContact)

Multiple Sequence Alignment (Muscle)

This protein is annotated as membranous in Gene Ontology.

Total structural coverage: 96%

Model score: 100

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Variant	Description
	CFC3
	CFC3
	CFC3
	MEL; somatic mutation
	MEL; somatic mutation
	MEL; somatic mutation; results in increased MAPK signal transduction

Biological Process

Activation of MAPK activity

Activation of MAPKK activity

Activation of protein kinase activity

Axon guidance

Bergmann glial cell differentiation

Cell cycle arrest

Cell motility

Cell population proliferation

Cellular senescence

Cerebellar cortex formation

Chemotaxis

Epidermal growth factor receptor signaling pathway

Epithelial cell proliferation involved in lung morphogenesis

ERK1 and ERK2 cascade

Face development

Fc-epsilon receptor signaling pathway

Fibroblast growth factor receptor signaling pathway

Golgi inheritance

Heart development

Innate immune response

Insulin receptor signaling pathway

Keratinocyte differentiation

Labyrinthine layer development

MAPK cascade

Melanosome transport

Mitotic nuclear division

Movement of cell or subcellular component

MyD88-dependent toll-like receptor signaling pathway

MyD88-independent toll-like receptor signaling pathway

Negative regulation of cell population proliferation

Negative regulation of gene expression

Negative regulation of homotypic cell-cell adhesion

Neuron differentiation

Neurotrophin TRK receptor signaling pathway

Pathogenesis

Peptidyl-threonine phosphorylation

Placenta blood vessel development

Positive regulation of axonogenesis

Positive regulation of cell differentiation

Positive regulation of cell migration

Positive regulation of ERK1 and ERK2 cascade

Positive regulation of gene expression

Positive regulation of production of miRNAs involved in gene silencing by miRNA

Positive regulation of protein serine/threonine kinase activity

Positive regulation of Ras protein signal transduction

Positive regulation of transcription elongation from RNA polymerase II promoter

Positive regulation of transcription, DNA-templated

Protein heterooligomerization

Protein phosphorylation

Proteolysis in other organism

Ras protein signal transduction

Regulation of apoptotic process

Regulation of axon regeneration

Regulation of early endosome to late endosome transport

Regulation of Golgi inheritance

Regulation of mitotic cell cycle

Regulation of stress-activated MAPK cascade

Regulation of vascular associated smooth muscle contraction

Response to axon injury

Response to glucocorticoid

Response to oxidative stress

Signal transduction

Signal transduction by protein phosphorylation

Small GTPase mediated signal transduction

Stress-activated MAPK cascade

Stress-activated protein kinase signaling cascade

Thymus development

Thyroid gland development

Toll-like receptor 10 signaling pathway

Toll-like receptor 2 signaling pathway

Toll-like receptor 3 signaling pathway

Toll-like receptor 4 signaling pathway

Toll-like receptor 5 signaling pathway

Toll-like receptor 9 signaling pathway

Toll-like receptor signaling pathway

Toll-like receptor TLR1:TLR2 signaling pathway

Toll-like receptor TLR6:TLR2 signaling pathway

Trachea formation

TRIF-dependent toll-like receptor signaling pathway

Vascular endothelial growth factor receptor signaling pathway

Vesicle transport along microtubule

Cellular Component

Axon

Cell cortex

Cytoplasm

Cytosol

Dendrite cytoplasm

Early endosome

Endoplasmic reticulum

Extracellular exosome

Focal adhesion

Golgi apparatus

Late endosome

Microtubule

Microtubule organizing center

Mitochondrion

Nucleus

Perikaryon

Perinuclear region of cytoplasm

Plasma membrane

Spindle pole body

Molecular Function

ATP binding

MAP kinase kinase activity

MAP-kinase scaffold activity

Obsolete signal transducer, downstream of receptor, with protein tyrosine phosphatase activity

Protein C-terminus binding

Protein kinase activity

Protein N-terminus binding

Protein serine kinase activity

Protein serine/threonine kinase activator activity

Protein serine/threonine kinase activity

Protein serine/threonine/tyrosine kinase activity

Protein threonine kinase activity

Protein tyrosine kinase activity

Scaffold protein binding

Transmembrane receptor protein tyrosine kinase activity

The reference OMIM entry for this protein is 176872

Mitogen-activated protein kinase kinase 1; map2k1
Protein kinase, mitogen-activated, kinase 1; prkmk1
Mkk1; mapkk1
Mapk/erk kinase 1; mek1

CLONING

Mitogen-activated protein (MAP) kinases, also known as extracellular signal-regulated kinases (ERKs) (see ERK2, or MAPK1; 176948), are thought to act as an integration point for multiple biochemical signals because they are activated by a wide variety of extracellular signals, are rapidly phosphorylated on threonine and tyrosine residues, and are highly conserved in evolution (Crews et al., 1992). A critical protein kinase lies upstream of MAP kinase and stimulates the enzymatic activity of MAP kinase. Crews et al. (1992) cloned a mouse cDNA, denoted Mek1 (for Map/Erk kinase-1) by them, that encodes a member of this protein kinase family. The 393-amino acid, 43.5-kD protein is most closely related in size and sequence to the product encoded by the byr1 gene of S. pombe. The Mek1 gene was highly expressed in murine brain. Seger et al. (1992) cloned a cDNA encoding the human homolog of Mek1, symbolized MKK1 by them, from a human T-cell cDNA library. The predicted protein has a calculated molecular mass of 43 kD. They also isolated a related cDNA, called MKK1b, that appears to be an alternatively spliced form of MKK1. Seger et al. (1992) detected a 2.6-kb MKK1 transcript by Northern blot analysis in all tissues examined. Zheng and Guan (1993) also cloned a human cDNA corresponding to MEK1. They noted that the 393-amino acid protein shares 99% amino acid identity with murine Mek1 and 80% homology with human MEK2 (601263). The authors characterized biochemically the human MEK1 and MEK2 gene products. The gene is also symbolized MAP2K1, or PRKMK1.

MAPPING

Using radiation hybrid mapping, Rampoldi et al. (1997) localized the MAP2K1 gene to 15q22.1-q22.33. By somatic cell hybrid analysis and FISH, Meloche et al. (2000) mapped MAP2K1 to 15q21 and a pseudogene, MAP2K1P1, to 8p21. Brott et al. (1993) mapped the mouse Mek1 gene to chromosome 9.

GENE FUNCTION

Crews et al. (1992) found that the mouse Mek1 protein expressed in bacteria phosphorylated the Erk gene product in vitro. Seger et al. (1992) found that overexpression of MKK1 in COS cells led to increased phorbol ester-stimulated MAP kinase kinase activity. Seger and Krebs (1995) reviewed the MAP kinase signaling cascade. Ryan et al. (2000) showed that inhibition of MEK1 blocks p53 (191170)-induced NF-kappa-B activation and apoptosis but not cell cycle arrest. They demonstrated that p53 activates NF-kappa-B through the RAF/MEK1/p90(rsk) (see 601684) pathway rather than the TNFR1 (191190)/TRAF2 (601895)/IKK (e.g., 600664) pathway used by TNFA (191160). To elucidate the mechanism through which MAPK signaling regulates the MYOD (159970) family of transcription factors, Perry et al. (2001) investigated the role of the signaling intermediate MEK1 in myogenesis. Transfection of activated MEK1 strongly repressed gene activation and myogenic conversion by the MYOD family. This repression was not mediated by direct phosphorylation of MYOD or by changes in MYOD stability or subcellular distribution. Deletion mapping revealed that MEK1-mediated repression required the MYOD N-terminal transactivation domain. Moreover, activated MEK1 was nuclearly localized and bound a complex containing MYOD in a manner that was dependent on the presence of the MYOD N terminus. These data demonstrated that MEK1 signaling has a strong negative effect on MYOD activity via a mechanism involving binding of MEK1 to the nuclear MYOD transcriptional complex. Takekawa et al. (2005) identifi ... More on the omim web site

Subscribe to this protein entry history

Oct. 27, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated

June 20, 2017: Protein entry updated
Automatic update: comparative model was added.

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 176872 was added.

Jan. 28, 2016: Protein entry updated
Automatic update: model status changed

Jan. 24, 2016: Protein entry updated
Automatic update: model status changed

Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1)