Dual specificity kinase. Is activated by cytokines and environmental stress in vivo. Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in the MAP kinase p38. Part of a signaling cascade that begins with the activation of the adrenergic receptor ADRA1B and leads to the activation of MAPK14. (updated: Nov. 22, 2017)

Protein identification was indicated in the following studies:

Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.

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)

Total structural coverage: 97%

Model score: 0

(right-click above to access to more options from the contextual menu)

Variant	Description
	empty
	dbSNP:rs33911218
	dbSNP:rs36047035
	dbSNP:rs34105301
	dbSNP:rs2305873
	dbSNP:rs36076766
	dbSNP:rs56067280
	dbSNP:rs56216806
	colon cancer
	colon cancer
	dbSNP:rs35206134
	dbSNP:rs2363198

Biological Process

Activation of MAPK activity

Activation of protein kinase activity

Cardiac muscle contraction

Cellular response to vascular endothelial growth factor stimulus

Inflammatory response

Innate immune response

MyD88-dependent toll-like receptor signaling pathway

MyD88-independent toll-like receptor signaling pathway

Negative regulation of hippo signaling

P38MAPK cascade

Pathogenesis

Positive regulation of blood vessel endothelial cell migration

Positive regulation of protein kinase activity

Positive regulation of transcription, DNA-templated

Proteolysis in other organism

Regulation of apoptotic process

Regulation of cytokine biosynthetic process

Regulation of cytokine production

Regulation of mitotic cell cycle

Signal transduction

Signal transduction by protein phosphorylation

Stress-activated MAPK cascade

Stress-activated protein kinase signaling cascade

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

TRIF-dependent toll-like receptor signaling pathway

Cellular Component

Cytoplasm

Cytosol

Membrane

Nucleoplasm

Molecular Function

ATP binding

MAP kinase kinase activity

Obsolete signal transducer, downstream of receptor, with serine/threonine kinase activity

Protein kinase binding

Protein serine kinase activity

Protein serine/threonine kinase activity

Protein threonine kinase activity

Protein tyrosine kinase activity

Transmembrane receptor protein tyrosine kinase activity

The reference OMIM entry for this protein is 602315

Mitogen-activated protein kinase kinase 3; map2k3
Protein kinase, mitogen-activated, kinase 3; prkmk3
Mkk3; mapkk3
Mapk/erk kinase 3; mek3

DESCRIPTION

Mitogen-activated protein kinases (MAPKs) act in cellular signal transduction pathways in response to many extracellular signals. Activation of specific classes of MAPKs requires phosphorylation by specific MAPK kinases (MAP2Ks), also called MKKs or MEKs (see 601254), such as MAP2K3.

CLONING

PBS2, a yeast MKK, activates stress-activated protein kinases (SAPKs). Derijard et al. (1995) cloned 2 human homologs of PBS2 (MKK3 and MKK4), using primers based on distinct regions of the yeast gene to amplify cDNA clones from brain by PCR. The predicted 322-amino acid MKK3 protein is 40 to 42% identical to PBS2 and human MEK1 (176872) and MEK2 (601263), and 52% identical to MKK4 within the conserved region. Northern blot analysis showed that MKK3 is widely expressed, with highest expression in skeletal muscle. Han et al. (1997) cloned another form of MKK3, termed MKK3b, which has an additional 29 N-terminal amino acids. Northern blot analysis showed that MKK3b mRNA is much more abundant than MKK3, but has a similar expression pattern.

GENE FUNCTION

In vitro kinase assays and in vivo overexpression studies by Derijard et al. (1995) suggested that the SAPK p38 (MAPK14; 600289) is the substrate for MKK3. 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 pathways and inhibition of the nuclear factor kappa B (NF-kappa-B) 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 (601263), and MKK4/SEK1 (601335). YopJ was found to bind directly to MKKs in vitro, including MKK1, MKK3, 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. By yeast 2-hybrid analysis of a mouse T-cell cDNA library, Uhlik et al. (2003) showed that a C-terminal fragment of mouse Osm (CCM2; 607929) interacted with Mekk3 (MAP3K3; 602539), a p38 activator that responds to sorbitol-induced hyperosmotic conditions. Mekk3 and Osm colocalized in the cytoplasmic compartment of cotransfected cells, and the Mekk3-Osm complex was recruited to Rac1 (602048)- and cytoskeletal actin (see 102560)-containing membrane ruffles in response to sorbitol treatment. Protein interaction assays showed that Osm interacted directly with the Mekk3 substrate Mkk3, with actin, and with both GDP- and GTP-loaded Rac1. Uhlik et al. (2003) concluded that the RAC1-OSM-MEKK3-MKK3 complex is required for regulation of p38 activity in response to osmotic shock.

MAPPING

Using radiation hybrid mapping, Rampoldi et al. (1997) localized the MAP2K3 gene to 17q11.2.

ANIMAL MODEL

Lu et al. (1999) used homologous rec ... More on the omim web site

Subscribe to this protein entry history

Feb. 10, 2018: 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

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 602315 was added.

Dual specificity mitogen-activated protein kinase kinase 3 (MAP2K3)