MKK4 (MEK4, MAP2K4)

MKK4 is dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. MKK4 is the essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, MKK4 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. MKK4 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.

MKK4 (MEK4, MAP2K4) Related Areas

Enzyme>>Protein Kinase>>Intracellular Kinase>>Mitogen-Activated Protein Kinase (MAPK)>>MKK4/MEK4/MAP2K4

Signal Transduction>>Protein Kinase>>Intracellular Kinase>>Mitogen-Activated Protein Kinase (MAPK)>>MKK4/MEK4/MAP2K4

MKK4 (MEK4, MAP2K4) Alternative Names

MKK4, MEK4, MAP2K4, JNKK, JNKK1, MAPKK4, PRKMK4, SEK1, SERK1 [Homo sapiens]

MKK4, MEK4, Map2k4, RP23-340L19.1, JNKK1, PRKMK4, Sek1, Serk1 [Mus musculus]

Summaries for MKK4 (MEK4, MAP2K4)

Entrez Gene summary for MAP2K4:

This MAP2K4 gene encodes a dual specificity protein kinase that belongs to the Ser/Thr protein kinase family. MKK4 is a direct activator of MAP kinases in response to various environmental stresses or mitogenic stimuli. It has been shown to activate MAPK8/JNK1, MAPK9/JNK2, and MAPK14/p38, but not MAPK1/ERK2 or MAPK3/ERK3. MKK4 is phosphorylated, and thus activated by MAP3K1/MEKK. The knockout studies in mice suggested the roles of MKK4 in mediating survival signal in T cell development, as well as in the organogenesis of liver. [provided by RefSeq, Jul 2008]

OMIM - description for MKK4:

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. MKK4 is a MAPKK that directly activates the JNKs, as well as the related MAPK p38 (MAPK14; 600289) (Wu et al., 1997).

Wikipedia summary for MKK4:

Dual specificity mitogen-activated protein kinase kinase 4 is an enzyme that in humans is encoded by the MAP2K4 gene.

Human MKK4 (MEK4, MAP2K4) Protein General Information

 

• Protein names: Dual specificity mitogen-activated protein kinase kinase 4, Short name=MAPKK 4
• Sequence length: 399 AA.
• Domain: The DVD domain (redidues 364-387) contains a conserved docking site and is found in the mammalian MAP kinase kinases (MAP2Ks). The DVD sites bind to their specific upstream MAP kinase kinase kinases (MAP3Ks) and are essential for activation.
• Sequence similarities: MKK4 belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily. MKK4 contains 1 protein kinase domain.
• Post-translational modification: MKK4 is activated by phosphorylation on Ser-257 and Thr-261 by MAP kinase kinase kinases (MAP3Ks).
• Subunit structure: MKK4 interacts with SPAG9. MKK4 interacts (via its D domain) with its substrates MAPK8/JNK1, MAPK9/JNK2, MAPK10/JNK3, MAPK11 and MAPK14. Interacts (via its DVD domain) with MAP3Ks activators like MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with ARRB1, ARRB2 and MAPK8IP3/JIP3.
• Subcellular location: Cytoplasm. Nucleus
• Tissue specificity: Abundant expression is seen in the skeletal muscle. It is also widely expressed in other tissues.
• Catalytic activity: ATP + a protein = ADP + a phosphoprotein.
• Enzyme regulation: MKK4 is activated in response to a variety of cellular stresses, including UV and gamma-irradiation, heat shock, hyperosmolarity, T-cell receptor stimulation, peroxide and inflammatory cytokines. MKK4 is also activated by developmental cues. MAP2K4/MKK4 is activated by the majority of MKKKs, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K7/TAK1, MAP3K10/MLK2, MAP3K11/MLK3, MAP3K12/DLK and MAP3K13/LZK.

General information above from UniProt

Function for MKK4 (MEK4, MAP2K4) Protein

UniProtKB:

MKK4 is dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. MKK4 is the essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, MKK4 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. MKK4 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.

Genatlas:

• MKK4 may be involved in JNK cascade, protein amino acid phosphorylation, signal transduction
• MKK4 has serine/threonine kinase activity
• MKK4 plays a role in the suppression of metastatic colonization in ovarian cancer
• MKK4 and MAP2K7 are required for optimal activation of JNKs in a synergistic fashion but MAP2K4 can also affect the second stress kinase pathway MAPK14
• MKK4 antagonizes cardiomyocyte hypertrophy
• new role for MKK4 in regulating GJA1 expression and preventing hypertrophy-associated arrhythmogenesis
• MKK4 regulates GJA1 transcription most likely by virtue of two AP-1 binding sites in the GJA1 proximal promoter region
• MKK4 is critical cardiac protector preventing hypertrophy-associated ventricular arrhythmias through restriction of GJA1 remodeling

Homology for human MKK4 (MEK4, MAP2K4)

• homolog to murine Map2k4
• homolog to C.elegans R03g5.2
• homolog to yeast S.cerevisiae PBS2