Disease relevance of MAP2K7

• Cardiac hypertrophy induced by mitogen-activated protein kinase kinase 7, a specific activator for c-Jun NH2-terminal kinase in ventricular muscle cells [1].
• However, constitutive JNK activation alone did not replicate the effects of DBPT in DLD-1 cells, and excessive JNK activation by adenovirus encoding MKK7 had little influence on DBPT-induced apoptosis [2].
• Here we used overexpression of mitogen-activated protein kinase kinase 7 (MKK7) to activate selectively JNK in T lymphoma Jurkat cells [3].

High impact information on MAP2K7

• This stimuli-dependent interaction of c-FLIP(L) with MKK7 might selectively suppress the prolonged phase of JNK activation [4].
• However, FcepsilonRI-induced activation of the tumor necrosis factor-alpha (TNF-alpha) gene promoter is not affected by expression of kinase-inactive MKK7 [5].
• Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2-terminal kinase [6].
• No scaffold protein was required for the MEKK2-JNKK2-JNK1 tripartite-complex formation [7].
• In addition, the results demonstrate that Lyn activates SAPK by an MKK7-dependent, SEK1-independent mechanism [8].

Biological context of MAP2K7

• We generated inducible cell lines from the human embryonal kidney carcinoma cell line, HEK293, by stable transfection with a constitutively active mutant of MKK7, MKK7(3E), fused to green fluorescent protein (GFP), under the control of an ecdysone-inducible promoter [9].
• These data implicate active MKK7 in the negative regulation of cell proliferation and provide evidence for a new role for this kinase in the regulation of a distinct, hitherto unrecognized set of genes [9].
• Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7 [10].
• Furthermore, hJNKK2 alpha activated the JNK-dependent signal transduction pathway in vivo by induction of c-Jun- and ATF2-mediated gene transcription [11].
• MKK7 is ubiquitously expressed in all adult and embryonic organs but displays high expression in epithelial tissues at later stages of fetal development [12].

Anatomical context of MAP2K7

• Immunofluorescence analysis revealed that the JNKK2-JNK1 fusion protein was predominantly located in the nucleus of transfected HeLa cells [13].
• Moreover, a dominant-negative mutant of MKK7 abrogated the transcriptional activation of the distal nuclear factor of activated T cells response element in the IL-2 promoter [14].
• Immunofluorescence analysis demonstrates that these MKK7 isoforms are detected in both cytoplasmic and nuclear compartments of cultured cells [15].
• Subcellular fractionation experiments of cerebral cortex identified DLK and MKK7 in similar nuclear and extranuclear subcellular compartments [16].
• The MKK7-JNK fusion proteins, which exhibited constitutive activity in 293T cells, were stably expressed in Swiss 3T3 fibroblasts using retrovirus-mediated gene transfer [17].

Associations of MAP2K7 with chemical compounds

• Inducible expression of a constitutively active mutant of mitogen-activated protein kinase kinase 7 specifically activates c-JUN NH2-terminal protein kinase, alters expression of at least nine genes, and inhibits cell proliferation [9].
• We found that MKK4 had a preference for the tyrosine residue, and MKK7 for the threonine residue, within the Thr-X-Tyr motif [18].
• Transient transfection with a JNKK2-JNK1 plasmid expressing constitutive JNK1 partially restored the effect of gemcitabine in H1299/GR cells [19].

Physical interactions of MAP2K7

• IL-1beta-induced AP-1 binding activity and AP-1-driven gene expression were strictly MKK-7 dependent [20].
• Furthermore, MKK-4 coprecipitated with MKK-7 and vice versa, indicating that the 3 kinases form a stable complex in FLS [21].

Enzymatic interactions of MAP2K7

• MKK7 also phosphorylates JNK2 alpha 2 at Thr-404 and Ser-407 in vitro, Ser-407 being phosphorylated much more rapidly than Thr-183 in vitro [10].
• Immunoblotting analysis indicated that JNK1 was phosphorylated by JNKK2 in the fusion protein on both Thr(183) and Tyr(185) residues [13].

Co-localisations of MAP2K7

• A third JNK pool is colocalized with MKK7 in the nucleus, and specific activities of both increase during neuritogenesis, nuclear JNK activity increasing 10-fold, whereas c-Jun expression and activity decrease [22].

Regulatory relationships of MAP2K7

• MKK7 activates JNK via phosphorylation of a threonine and tyrosine residue in a Thr-Pro-Tyr motif within kinase subdomain VIII [23].
• Consistently, CYLD negatively regulates the activation of MKK7, an upstream kinase known to mediate JNK activation by immune stimuli [24].

Other interactions of MAP2K7

• Although the regulation of JNKK1 activities and that of JNKK2 activities could be very similar, the two kinases may play somewhat different regulatory roles in a cell-type-dependent manner [25].
• However, in contrast with Thr-183 and Tyr-185, the phosphorylation of Thr-404 and Ser-407 is not increased in response to other agonists that activate MKK7 and SAPK1/JNK, suggesting that phosphorylation of these residues is catalysed by another protein kinase, such as CK2, which also phosphorylates Thr-404 and Ser-407 in vitro [10].
• Transient transfection assays demonstrated that JNKK2 potentiated the stimulation of c-Jun transcriptional activity by MEKK1 [26].
• Finally, MMP-3 production only required MKK-7, and there was no effect of MKK-4 deficiency [20].
• In confirmatory experiments performed in vivo, DLK both associated with and activated MKK7 [16].
• These data provide a basis for Gadd45beta-mediated blockade of MKK7, and ultimately, TNFalpha-induced PCD [27].

Analytical, diagnostic and therapeutic context of MAP2K7

• The mRNA for MKK7 is widely expressed in humans and mice and encodes a 47-kDa protein (419 amino acids), as determined by immunoblotting endogenous MKK7 with an antibody raised against its N terminus [28].
• Here we report the molecular cloning of a new member of the mammalian MAP kinase kinase group (MKK7) that functions as an activator of JNK [6].
• Phosphospecific antibodies and immunohistochemistry were used to evaluate the activation state of synovial MKK-4 and MKK-7 [21].
• METHODS: Ad19- and mock-infected HCFs were solubilized at various time points after infection, and cell lysates were subjected to SDS-PAGE followed by immunoblot analysis with a panel of antibodies against components of the MKK7/JNK/c-Jun pathway or immunoprecipitated for JNK assay [29].

References