Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. Activates the ERK1 and ERK2 MAP kinases (By similarity). 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). (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: 95%

Model score: 89

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Variant	Description
	CFC4
	CFC4
	CFC4
	CFC4

Biological Process

Activation of MAPK activity

Activation of MAPKK activity

Activation of protein kinase activity

Axon guidance

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

Heart development

Innate immune response

Insulin receptor signaling pathway

MAPK cascade

MyD88-dependent toll-like receptor signaling pathway

MyD88-independent toll-like receptor signaling pathway

Negative regulation of gene expression

Neurotrophin TRK receptor signaling pathway

Pathogenesis

Peptidyl-serine autophosphorylation

Positive regulation of axonogenesis

Positive regulation of cell motility

Positive regulation of ERK1 and ERK2 cascade

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

Positive regulation of protein serine/threonine kinase activity

Positive regulation of transcription, DNA-templated

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 protein heterodimerization activity

Regulation of stress-activated MAPK cascade

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

Cellular Component

Cell cortex

Cell-cell junction

Cytoplasm

Cytoplasmic side of plasma membrane

Cytosol

Early endosome

Endoplasmic reticulum

Extracellular region

Focal adhesion

Golgi apparatus

Late endosome

Microtubule

Mitochondrion

Nucleus

Perinuclear region of cytoplasm

Peroxisomal membrane

Plasma membrane

Molecular Function

ATP binding

MAP kinase kinase activity

MAP-kinase scaffold activity

Metal ion binding

Molecular adaptor activity

PDZ domain 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 601263

Mitogen-activated protein kinase kinase 2; map2k2
Protein kinase, mitogen-activated, kinase 2; prkmk2
Mkk2; mapkk2
Mapk/erk kinase 2; mek2

CLONING

Zheng and Guan (1993) isolated and sequenced 2 human cDNAs encoding members of the MAP kinase kinase (MAP2K) family, designated MEK1 (176872) and MEK2 by them. The MEK2 cDNA encodes a predicted 400-amino acid protein that shares 80% sequence identity with human MEK1. Brott et al. (1993) cloned the mouse Mek2 gene.

GENE FUNCTION

Zheng and Guan (1993) showed that recombinant MEK2 and MEK1 both could activate human ERK1 (601795) in vitro. They further characterized biochemically the 2 MAP2Ks. A virulence factor from Yersinia pseudotuberculosis, YopJ, is a 33-kD protein that perturbs a multiplicity of signaling pathways. These include inhibition of the extracellular signal-regulated kinase ERK, c-jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) pathways and inhibition of the nuclear factor kappa B (NF-kappa-B; see 164011) pathway. The expression of YopJ has been correlated with the induction of apoptosis by Yersinia. Using a yeast 2-hybrid screen based on a LexA-YopJ fusion protein and a HeLa cDNA library, Orth et al. (1999) identified mammalian binding partners of YopJ. These included the fusion proteins of the GAL4 activation domain with MAPK kinases MKK1 (176872), MKK2, and MKK4/SEK1 (601335). YopJ was found to bind directly to MKKs in vitro, including MKK1, MKK3 (602315), MKK4, and MKK5 (602448). Binding of YopJ to the MKK blocked both phosphorylation and subsequent activation of the MKKs. These results explain the diverse activities of YopJ in inhibiting the ERK, JNK, p38, and NF-kappa-B signaling pathways, preventing cytokine synthesis and promoting apoptosis. YopJ-related proteins that are found in a number of bacterial pathogens of animals and plants may function to block MKKs so that host signaling responses can be modulated upon infection. Mittal et al. (2006) found that the Yersinia YopJ virulence factor inhibited the host inflammatory response and induced apoptosis of immune cells by catalyzing acetylation of 2 ser residues in the activation loop of MEK2, thereby blocking MEK2 activation and signal propagation. YopJ also caused acetylation of a thr residue in the activation loop of both IKKA (CHUK; 600664) and IKKB (IKBKB; 603258). Mittal et al. (2006) concluded that ser/thr acetylation is a mode of action for bacterial toxins that may also occur under nonpathogenic conditions to regulate protein function. Influenza A viruses are significant causes of morbidity and mortality worldwide. Annually updated vaccines may prevent disease, and antivirals are effective treatment early in disease when symptoms are often nonspecific. Viral replication is supported by intracellular signaling events. Using U0126, a nontoxic inhibitor of MEK1 and MEK2, and thus an inhibitor of the RAF1 (164760)/MEK/ERK pathway (see Favata et al. (1998)), Pleschka et al. (2001) examined the cellular response to infection with influenza A. U0126 suppressed both the early and late ERK activation phases after virus infection. Inhibition of the signaling pathway occurred without impairing the synthesis of viral RNA or protein, or the import of viral ribonucleoprotein complexes (RNP) into the nucleus. Instead, U0126 inhibited RAF/MEK/ERK signaling and the export of viral RNP without affecting the cellular mRNA export pathway. Pleschka et al. (2001) proposed that ERK regulates a cellular factor involved in the viral nuclear export protein function. They suggested that local application of MEK inhibitors may ... 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 601263 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 2 (MAP2K2)