MAP2K4 (mitogen-activated protein kinase kinase 4)

Gene

• Entrez ID: 6416
• Gene name: Mitogen-activated protein kinase kinase 4
• Gene symbol: MAP2K4
• Synonyms: JNKK, JNKK1, MAPKK4, MEK4, MKK4, PRKMK4, SAPKK-1, SAPKK1, SEK1, SERK1, SKK1
• Chromosome: 17
• Chromosome location: 17p12
• Summary: This gene encodes a member of the mitogen-activated protein kinase (MAPK) family. Members of this family act as an integration point for multiple biochemical signals and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation, and development. They form a three-tiered signaling module composed of MAPKKKs, MAPKKs, and MAPKs. This protein is phosphorylated at serine and threonine residues by MAPKKKs and subsequently phosphorylates downstream MAPK targets at threonine and tyrosine residues. A similar protein in mouse has been reported to play a role in liver organogenesis. A pseudogene of this gene is located on the long arm of chromosome X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT019756	hsa-miR-375	Microarray	20215506
MIRT023483	hsa-miR-15b-5p	CLASH	23622248
MIRT028937	hsa-miR-26b-5p	Microarray	19088304
MIRT030360	hsa-miR-25-3p	PAR-CLIP	21572407
MIRT030360	hsa-miR-25-3p	Western blot	27353001
MIRT053655	hsa-miR-145-5p	Microarray	22942087
MIRT053698	hsa-miR-188-5p	Microarray	22942087
MIRT054442	hsa-miR-27a-3p	Luciferase reporter assay, Western blot	24556602
MIRT054442	hsa-miR-27a-3p	Luciferase reporter assay, qRT-PCR, Western blot	27594411
MIRT437965	hsa-miR-92a-3p	PAR-CLIP	21572407
MIRT437965	hsa-miR-92a-3p	qRT-PCR, Luciferase reporter assay, Western blot	24705900
MIRT473851	hsa-miR-1185-2-3p	PAR-CLIP	23592263
MIRT473852	hsa-miR-1185-1-3p	PAR-CLIP	23592263
MIRT473853	hsa-let-7f-2-3p	PAR-CLIP	23592263
MIRT473854	hsa-miR-542-3p	PAR-CLIP	23592263
MIRT473855	hsa-miR-4261	PAR-CLIP	23592263
MIRT473856	hsa-miR-3134	PAR-CLIP	23592263
MIRT473857	hsa-miR-8082	PAR-CLIP	23592263
MIRT473858	hsa-miR-4534	PAR-CLIP	23592263
MIRT473859	hsa-miR-4433a-3p	PAR-CLIP	23592263
MIRT473860	hsa-miR-3688-3p	PAR-CLIP	23592263
MIRT556303	hsa-miR-6818-3p	PAR-CLIP	21572407
MIRT556304	hsa-miR-7855-5p	PAR-CLIP	21572407
MIRT556305	hsa-miR-4325	PAR-CLIP	21572407
MIRT556306	hsa-miR-7703	PAR-CLIP	21572407
MIRT556307	hsa-miR-6749-3p	PAR-CLIP	21572407
MIRT556308	hsa-miR-6792-3p	PAR-CLIP	21572407
MIRT556309	hsa-miR-4691-5p	PAR-CLIP	21572407
MIRT556310	hsa-miR-3185	PAR-CLIP	21572407
MIRT556311	hsa-miR-3121-5p	PAR-CLIP	21572407
MIRT556312	hsa-miR-660-3p	PAR-CLIP	21572407
MIRT556313	hsa-miR-5193	PAR-CLIP	21572407
MIRT556314	hsa-miR-3614-5p	PAR-CLIP	21572407
MIRT556315	hsa-miR-10a-3p	PAR-CLIP	21572407
MIRT556316	hsa-miR-559	PAR-CLIP	21572407
MIRT556317	hsa-miR-548y	PAR-CLIP	21572407
MIRT556318	hsa-miR-548w	PAR-CLIP	21572407
MIRT556319	hsa-miR-548o-5p	PAR-CLIP	21572407
MIRT556320	hsa-miR-548j-5p	PAR-CLIP	21572407
MIRT556321	hsa-miR-548i	PAR-CLIP	21572407
MIRT556322	hsa-miR-548h-5p	PAR-CLIP	21572407
MIRT556323	hsa-miR-548d-5p	PAR-CLIP	21572407
MIRT556324	hsa-miR-548c-5p	PAR-CLIP	21572407
MIRT556325	hsa-miR-548bb-5p	PAR-CLIP	21572407
MIRT556326	hsa-miR-548b-5p	PAR-CLIP	21572407
MIRT556327	hsa-miR-548ay-5p	PAR-CLIP	21572407
MIRT556328	hsa-miR-548au-5p	PAR-CLIP	21572407
MIRT556329	hsa-miR-548as-5p	PAR-CLIP	21572407
MIRT556330	hsa-miR-548ar-5p	PAR-CLIP	21572407
MIRT556331	hsa-miR-548aq-5p	PAR-CLIP	21572407
MIRT556332	hsa-miR-548ap-5p	PAR-CLIP	21572407
MIRT556333	hsa-miR-548am-5p	PAR-CLIP	21572407
MIRT556334	hsa-miR-548ak	PAR-CLIP	21572407
MIRT556335	hsa-miR-548ae-5p	PAR-CLIP	21572407
MIRT556336	hsa-miR-548ad-5p	PAR-CLIP	21572407
MIRT556337	hsa-miR-548ab	PAR-CLIP	21572407
MIRT556338	hsa-miR-548a-5p	PAR-CLIP	21572407
MIRT556339	hsa-miR-363-3p	PAR-CLIP	21572407
MIRT556340	hsa-miR-367-3p	PAR-CLIP	21572407
MIRT556341	hsa-miR-92b-3p	PAR-CLIP	21572407
MIRT556342	hsa-miR-32-5p	PAR-CLIP	21572407

Transcription factors

Transcription factor	Regulation	Reference
HSF2	Repression	11557063

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000187	Process	Activation of MAPK activity	IBA	21873635
GO:0004672	Function	Protein kinase activity	TAS	7716521
GO:0004674	Function	Protein serine/threonine kinase activity	IEA
GO:0004708	Function	MAP kinase kinase activity	IBA	21873635
GO:0004713	Function	Protein tyrosine kinase activity	IEA
GO:0005515	Function	Protein binding	IPI	9808624
GO:0005524	Function	ATP binding	IEA
GO:0005634	Component	Nucleus	IEA
GO:0005829	Component	Cytosol	TAS
GO:0006915	Process	Apoptotic process	IEA
GO:0007165	Process	Signal transduction	TAS	7716521
GO:0007254	Process	JNK cascade	TAS
GO:0007257	Process	Activation of JUN kinase activity	IBA	21873635
GO:0008545	Function	JUN kinase kinase activity	IBA	21873635
GO:0009611	Process	Response to wounding	IEA
GO:0018108	Process	Peptidyl-tyrosine phosphorylation	IEA
GO:0030424	Component	Axon	IEA
GO:0031435	Function	Mitogen-activated protein kinase kinase kinase binding	IEA
GO:0032839	Component	Dendrite cytoplasm	IEA
GO:0034393	Process	Positive regulation of smooth muscle cell apoptotic process	IEA
GO:0038095	Process	Fc-epsilon receptor signaling pathway	TAS
GO:0043204	Component	Perikaryon	IEA
GO:0043525	Process	Positive regulation of neuron apoptotic process	IEA
GO:0045740	Process	Positive regulation of DNA replication	IEA
GO:0051770	Process	Positive regulation of nitric-oxide synthase biosynthetic process	IEA
GO:0061049	Process	Cell growth involved in cardiac muscle cell development	IEA
GO:0071260	Process	Cellular response to mechanical stimulus	IEP	19593445
GO:0072709	Process	Cellular response to sorbitol	IEA
GO:2000672	Process	Negative regulation of motor neuron apoptotic process	IEA

Other IDs

• MIM: 601335
• HGNC: 6844
• e!Ensembl: ENSG00000065559

Protein

• UniProt ID: P45985
• Protein name: Dual specificity mitogen-activated protein kinase kinase 4 (MAP kinase kinase 4) (MAPKK 4) (EC 2.7.12.2) (JNK-activating kinase 1) (MAPK/ERK kinase 4) (MEK 4) (SAPK/ERK kinase 1) (SEK1) (Stress-activated protein kinase kinase 1) (SAPK kinase 1) (SAPKK-1) (SAPKK1) (c-Jun N-terminal kinase kinase 1) (JNKK)
• Protein function: 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.
• PDB: 3ALN, 3ALO, 3VUT
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00069	Pkinase	102 → 367	Protein kinase domain	Domain

• Sequence:

  MAAPSPSGGGGSGGGSGSGTPGPVGSPAPGHPAVSSMQGKRKALKLNFANPPFKSTARFT
  LNPNPTGVQNPHIERLRTHSIESSGKLKISPEQHWDFTAEDLKDLGEIGRGAYGSVNKMV
  HKPSGQIMAVKRIRSTVDEKEQKQLLMDLDVVMRSSDCPYIVQFYGALFREGDCWICMEL
  MSTSFDKFYKYVYSVLDDVIPEEILGKITLATVKALNHLKENLKIIHRDIKPSNILLDRS
  GNIKLCDFGISGQLVDSIAKTRDAGCRPYMAPERIDPSASRQGYDVRSDVWSLGITLYEL
  ATGRFPYPKWNSVFDQLTQVVKGDPPQLSNSEEREFSPSFINFVNLCLTKDESKRPKYKE
  LLKHPFILMYEERAVEVACYVCKILDQMPATPSSPMYVD

• Sequence length: 399