MAP2K7

Template:PBB Dual specificity mitogen-activated protein kinase kinase 7, also known as MAP kinase kinase 7 or MKK7, is an enzyme that in humans is encoded by the MAP2K7 gene.

MKK7 is involved in signal transduction mediating the cell responses to proinflammatory cytokines, and environmental stresses. 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.

MKK7 is ubiquitously expressed in all tissue. However, it displays a higher level of expression in skeletal muscle. 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)

Isoforms

The murine MKK7 protein is encoded by 14 exons which can be alternatively spliced to yield a group of protein kinases. This results in six isoforms with three possible N-termini (α, β, and γ isoforms) and two possible C-termini (1 and 2 isoforms). The molecular mass of the isoforms spans from 38 to 52 kDa, with between 345 and 467 amino acids.

The physiological relevance of the different MKK7 isoforms is still unclear. Evidence shows that the MKK7α, which lacks an NH2-termini extension, shows a lower basal activity in binding JNK compared to the MKKβ and γ isoforms. The increased basal activity in the β and γ isoforms can be due to three D-domains present in the N-terminus of these isoforms.

Structure and function

The domains of MKK7: More text is coming.

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. MAPK 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.

Scaffold proteins

Scaffold protein:Model showing how a scaffold protein binds a MAPKKK, MAPKK (MKK4 or MKK7) and a JNK in a multienzyme complex.

In addition to the direct interactions between JNK, MKK7 and other upstream protein kinases, various scaffold proteins function to ensure specificity between the components of the MAPK signaling cascade. Different JNK isoforms, MAPK, and MAPKKs (e.g., MKK7 or MKK4) bind specifically to the scaffold proteins, forming multienzyme complexes. Several mammalian scaffold proteins have been identified, such as JNK-interacting protein (JIP) 1, JIP2, JNK/SAPK associated protein 1 (JSAP1)/JIP3, JNK associated leucine-zipper protein 1 (JLP), and plenty of Src homology 3 (POSH) and their various splice variants.

Interactions

MAP2K7 has been shown to interact with:

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

Role in disease

MKK7 is involved in the development of epithelial tissues such as skin and lungs, and also the developing teeth, during early embryogenesis in mice. Experiments also indicate that MKK7 in addition to MKK4 are required for mammalian body plan organization during embryogenesis. MKK7 has also been suggested to function as a Metastase Suppressor Gene (MSG) by promoting tumor dormancy at the metastatic site.

Further reading

• Lu X, Nemoto S, Lin A (1997). "Identification of c-Jun NH2-terminal protein kinase (JNK)-activating kinase 2 as an activator of JNK but not p38". J. Biol. Chem. 272 (40): 24751–4. doi:10.1074/jbc.272.40.24751. PMID 9312068.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
• Wu Z, Wu J, Jacinto E, Karin M (1997). "Molecular cloning and characterization of human JNKK2, a novel Jun NH2-terminal kinase-specific kinase". Mol. Cell. Biol. 17 (12): 7407–16. PMC 232596. PMID 9372971.{{cite journal}}: CS1 maint: multiple names: authors list (link)
• Wang Y, Su B, Sah VP; et al. (1998). "Cardiac hypertrophy induced by mitogen-activated protein kinase kinase 7, a specific activator for c-Jun NH2-terminal kinase in ventricular muscle cells". J. Biol. Chem. 273 (10): 5423–6. doi:10.1074/jbc.273.10.5423. PMID 9488659. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
• Yang J, New L, Jiang Y; et al. (1998). "Molecular cloning and characterization of a human protein kinase that specifically activates c-Jun N-terminal kinase". Gene. 212 (1): 95–102. doi:10.1016/S0378-1119(98)00158-9. PMID 9661668. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
• Deacon K, Blank JL (1999). "MEK kinase 3 directly activates MKK6 and MKK7, specific activators of the p38 and c-Jun NH2-terminal kinases". J. Biol. Chem. 274 (23): 16604–10. doi:10.1074/jbc.274.23.16604. PMID 10347227.{{cite journal}}: CS1 maint: unflagged free DOI (link)
• Karandikar M, Xu S, Cobb MH (2001). "MEKK1 binds raf-1 and the ERK2 cascade components". J. Biol. Chem. 275 (51): 40120–7. doi:10.1074/jbc.M005926200. PMID 10969079.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
• Fleming Y, Armstrong CG, Morrice N; et al. (2001). "Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7". Biochem. J. 352 Pt 1: 145–54. PMC 1221441. PMID 11062067. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
• Vitale G, Bernardi L, Napolitani G; et al. (2001). "Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor". Biochem. J. 352 Pt 3: 739–45. PMC 1221512. PMID 11104681. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
• Chayama K, Papst PJ, Garrington TP; et al. (2001). "Role of MEKK2-MEK5 in the regulation of TNF-alpha gene expression and MEKK2-MKK7 in the activation of c-Jun N-terminal kinase in mast cells". Proc. Natl. Acad. Sci. U.S.A. 98 (8): 4599–604. doi:10.1073/pnas.081021898. PMC 31880. PMID 11274363. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
• Acierno JS, Kennedy JC, Falardeau JL; et al. (2001). "A physical and transcript map of the MCOLN1 gene region on human chromosome 19p13.3-p13.2". Genomics. 73 (2): 203–10. doi:10.1006/geno.2001.6526. PMID 11318610. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
• Tournier C, Dong C, Turner TK; et al. (2001). "MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines". Genes Dev. 15 (11): 1419–26. doi:10.1101/gad.888501. PMC 312702. PMID 11390361. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
• Gross EA, Callow MG, Waldbaum L; et al. (2002). "MRK, a mixed lineage kinase-related molecule that plays a role in gamma-radiation-induced cell cycle arrest". J. Biol. Chem. 277 (16): 13873–82. doi:10.1074/jbc.M111994200. PMID 11836244. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
• Kawaguchi M, Onuchic LF, Huang SK (2002). "Activation of extracellular signal-regulated kinase (ERK)1/2, but not p38 and c-Jun N-terminal kinase, is involved in signaling of a novel cytokine, ML-1". J. Biol. Chem. 277 (18): 15229–32. doi:10.1074/jbc.C100641200. PMID 11891214.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)