Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK activation at least in response to proinflammatory cytokines, while other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate JNKs. MAP2K4 is required for maintaining peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7 exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14. (updated: April 1, 2015)

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)

Total structural coverage: 81%

Model score: 100

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Variant	Description
	dbSNP:rs17855590
	a lung squamous cell carcinoma sample; somatic mutation
	a colorectal adenocarcinoma sample
	an ovarian serous carcinoma sample; somatic mutation
	a metastatic melanoma sample; somatic mutation
	a colorectal adenocarcinoma sample

Biological Process

Activation of JUN kinase activity

Activation of MAPK activity

Activation of protein kinase activity

Apoptotic process

Cell growth involved in cardiac muscle cell development

Cellular response to mechanical stimulus

Cellular response to sorbitol

Fc-epsilon receptor signaling pathway

Innate immune response

JNK cascade

MyD88-dependent toll-like receptor signaling pathway

MyD88-independent toll-like receptor signaling pathway

Negative regulation of motor neuron apoptotic process

Pathogenesis

Positive regulation of DNA replication

Positive regulation of neuron apoptotic process

Positive regulation of nitric-oxide synthase biosynthetic process

Positive regulation of smooth muscle cell apoptotic process

Proteolysis in other organism

Regulation of apoptotic process

Regulation of mitotic cell cycle

Response to wounding

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

Axon

Cytoplasm

Cytosol

Dendrite cytoplasm

Intracellular anatomical structure

Nucleus

Perikaryon

Molecular Function

ATP binding

JUN kinase kinase activity

MAP kinase kinase activity

Mitogen-activated protein kinase kinase kinase binding

Protein kinase activity

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 601335

Mitogen-activated protein kinase kinase 4; map2k4
Sapk/erk kinase 1; serk1; sek1
Protein kinase, mitogen-activated, kinase 4; prkmk4
Mkk4; mapkk4
Mapk/erk kinase 4; mek4
Jnk-activated kinase 1; jnkk1

DESCRIPTION

At least 3 mitogen-activated protein kinase (MAPK) cascades exist in mammals, each consisting of a 3-kinase module composed of a MAPK, a MAPK kinase (MAPKK), and a MAPKK kinase (MAPKKK). JUN N-terminal kinases (JNKs; see 601158) are MAPKs that stimulate transcriptional activity of JUN (165160) in response to growth factors, proinflammatory cytokines, and certain environmental stresses, such as ultraviolet light or osmotic shock. MAP2K4 is a MAPKK that directly activates the JNKs, as well as the related MAPK p38 (MAPK14; 600289) (Wu et al., 1997).

CLONING

By screening a human T-lymphocyte Jurkat cDNA library with a mouse cDNA encoding Mma1-Sek1, a potential MAPKK, Lin et al. (1995) identified a human homolog of Mma1-Sek1, which they named JNKK. The deduced 399-amino acid JNKK protein shares more than 95% sequence similarity with Mma1-Sek1 in the kinase domain. JNKK is also similar to S. cerevisiae Pbs2.

GENE FUNCTION

One Ras-dependent protein kinase cascade leading from growth factor receptors to the extracellular signal-regulated kinase (ERK) subgroup of MAPKs is dependent on the protein kinase RAF1 (164760), which activates the MAPK/ERK kinase (MEK) dual-specificity kinases. A second protein kinase cascade leading to activation of the JNKs is dependent on MEK kinase (MEKK). Lin et al. (1995) found that JNKK was a dual-specificity kinase that activated JNK and functioned between MEKK and JNK. JNKK activated the JNKs, but not the ERKs, and was unresponsive to RAF1 in transfected HeLa cells. It also activated another MAPK, p38, whose activity is regulated similarly to that of the JNKs. Lin et al. (1995) also showed that human JNKK could partially complement Pbs2 deficiency in yeast. The stress-activated protein kinase (SAPK) and MAPK pathways are signal transduction cascades with distinct functions in mammals. White et al. (1996) noted that they are structurally related in their phosphorylation activity but differ in the events leading to phosphorylation. MAPKs are rapidly phosphorylated and activated in response to various extracellular stimuli. MAPK is regulated by its own phosphorylation by MAPK kinases (MAP2Ks), e.g., MAP2K1 (176872) and MAP2K6 (601254). In the SAPK pathway, SAPKs are the dominant JNKs activated in response to a variety of cellular stresses, including treatment with interleukin-beta (147720) and tumor necrosis factor-alpha (TNFA, or TNF; 191160). MAP2K4, or SERK1, is a potent physiologic activator of SAPKs. Wu et al. (1997) showed that JNKK1 was a specific activator of JNK1 (601158), JNK2 (602896), and p38, but not of ERK2 (176948). Among MEKK1 (600982), MEKK2 (MAP3K2; 609487), GCK, and ASK (MEKK5), MEKK1 was the most potent activator of JNKK1, followed by MEKK2; GCK and ASK only slightly activated JNKK1. A virulence factor from Yersinia pseudotuberculosis, YopJ, is a 33-kD protein that perturbs a multiplicity of signaling pathways. These include inhibition of the ERK, JNK, and p38 MAPK 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. YopJ was found to bind directly to MKKs in vitr ... More on the omim web site

Subscribe to this protein entry history

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 601335 was added.

Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4)