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Mitogen-activated protein kinase kinase 7, also known as MAP2K7, is a human gene. The gene encodes a protein, MKK7. MKK7 is ubiquitously expressed in tissue. However, it displays a higher level of expression in skeletal muscle. This kinase specifically activates MAPK8/JNK1 and MAPK9/JNK2, and this kinase itself is phosphorylated and activated by MAP kinase kinase kinases including MAP3K1/MEKK1, MAP3K2/MEKK2,MAP3K3/MEKK5, and MAP4K2/GCK. This kinase is involved in the signal transduction mediating the cell responses to proinflammatory cytokines, and environmental stresses. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found, but only one transcript variant has been supported and defined

Nomenclature
- MAP2K7 is also known as:


 * MKK7


 * JNK-activated kinase 2


 * MAPK/ERK kinase 7 (MEK7)


 * Stress-activated protein kinase kinase 4 (SAPK kinase 4)


 * c-Jun N-terminal kinase kinase 2 (JNK kinase 2)

Structure and function
D-domains:

MKK7 has three conserved D-domains (docking domains) in the N-terminal. Characteristic for the D-domain is the cluster of positively charged aminoacids surrounded by hydrophobic aminoacids. These D-domains are needed for binding of MAPKK substrates, MAPK, such as JNK. MAPKK contain a common docking (CD) domain, which the D-domain recognizes. A single D domain has relatively low binding affinity, but through partly cooperative interaction of three such domains, it is suggested that the MKK7b (most abundant isoform in human) can bind JNK with full affinity. It has been shown that all three D-domains are necessary for correct JNK1:MKK7 complex formations, and for the phosphorylation and activation of JNK1 by MKK7.

DVD-domain:

The domain of versatile docking in the MKK7 protein is found at the C-termini of the catalytic core, and the consensus sequence of the domain is a helical 20 amino-acid motif. This domain is both required for the specific binding to, and activation of MKK7 by respective upstream MAPKKKs (e.g MEKK1). MKK7 and other mitogen activated protein kinase kinases also require a DVD domain to be able to discriminate against the various MAPKKK upstream. The MAPKK:MAPKKK interactions mediated by DVD domains facilitates the phosphorylation of MKK7. In addition to the activation of MKK7, binding via the DVD domain may also affect the MKK7 activation loop in such a way that the Ser and Thr of the S-K-A-K-T motif become accessible for phosphorylation.

Kinase domain:

The MKK7 contains one kinase domain. The MKK7:MAPKKK interactions, via the DVD domain, facilitates the phosphorylation of MKK7 by MAPKKKs on serine and threonine in a S-K-A-K-T motif in the catalytic domain (kinase domain).

Signaling and regulation
-- MKK7 play an important part in the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In collaboration with another mitogen-activated protein kinase kinase MKK4, MKK7 work as crucial transducers upstream of JNK signaling. Through joint efforts the two MKKs phosphorylate different JNK isoforms. As a result, MKK7 has a great impact on numerous physiological processes such as proliferation and differentiation, as well as pathological processes such as apoptosis and tumorigenesis. MKK7 are activated as a result of cellular stresses. They are activated by a number of MKKKs through phosphorylation at a S-K-A-K-T motif located in the MKK7s kinase domain. The MKKKs relate to MKK7 through its DVD site at the C-terminus and phosphorylate MKK7 at serine and threonine residues. Once activated, MKK4 and MKK7 directly phosphorylate specific tyrosine and threonine residues located in the conserved T-P-Y motif of the activation loop of the JNK protein. Although MKK7 act through dual specificity it tends to phosphorylate threonine on JNK protein, leaving MKK4 to phosphorylate tyrosine. Phosphorylated and activated JNKs activate substrates like transcription factors or pro-apoptotic protein. MKK7 and MKK4 seem to be regulating the expression of each other, thereby affecting the JNK signaling. The mono-phosphorylation of JNK on a threonine residue is adequate for the increase in JNK activity, which argues that MKK7 is an important constituent for JNK activity, while the additional phosphorylation of the tyrosine residue by MKK4 provide for a more favorable activation.

Active in sykdom
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Interactions
- MAP2K7 has been shown to interact with:


 * GADD45B
 * MAPK8
 * MAPK8IP3
 * MAPK8IP1
 * MAP3K12
 * MAP3K2
 * MAPK8IP2
 * DUSP19

- References: