Disease relevance of MAP2K6

• However, upon transient ischemia followed by reperfusion, the MKK6 TG mouse hearts exhibited significantly better functional recovery and less injury than NTG mouse hearts [1].
• In contrast, SB203580, a p38 MAPK-specific inhibitor, prevented MKK6-induced apoptosis in hepatoma cell lines [2].
• Rules generated using only ICAM1, MAP2K6 and KDR were comparably robust, with a single representative rule producing an accuracy of 90% when used by itself on the validation set, suggesting a crucial role for these genes in nodal metastasis [3].
• Immunohistochemistry demonstrated that MKK3 and MKK6 are expressed in RA and osteoarthritis (OA) synovium [4].
• CONCLUSIONS: These data demonstrate that different repertoires of downstream signaling proteins, particularly those of the MEK6-p38 MAPK-CK2 pathway and the PI3K pathway, are correlated with phenotypic manifestations of a cell culture model of OSE at progressive stages in the development of ovarian cancer [5].

Psychiatry related information on MAP2K6

• Immunoblot analysis demonstrated a significant increase of MKK6 level in Alzheimer's disease compared with age-matched controls [6].

High impact information on MAP2K6

• Conversely, inactivation of SWI-SNF enzymatic subunits abrogated MKK6-dependent induction of muscle gene expression [7].
• Dominant-negative MKK3 or MKK6 inhibited syncytial activation of p38, p53S46P, and apoptosis [8].
• We further reported that SMCs cotransfected with active forms of MEK1 and MKK6 secreted a nondialyzable, heat-labile protein factor(s) which induced de-differentiation of surrounding normal SMCs [9].
• Accordingly, a constitutively activated MKK6, a p38 activator, activated TGF-alpha shedding in the absence of exogenous stimuli [10].
• Activation of the novel stress-activated protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6); comparison of its substrate specificity with that of other SAP kinases [11].

Biological context of MAP2K6

• We tested different forms of c-Abl for their ability to induce apoptosis and found that apoptosis induction correlated with the activation of the MKK6-p38 kinase pathway [12].
• c-Abl-induced apoptosis, but not cell cycle arrest, requires mitogen-activated protein kinase kinase 6 activation [12].
• Constitutive activation of p38 by active MKK3 or MKK6 induces senescence [13].
• The murine and human SAPKK3 were 97% identical in their amino acid sequences [14].
• MEK6 regulates human involucrin gene expression via a p38alpha - and p38delta -dependent mechanism [15].

Anatomical context of MAP2K6

• SAPK4 was activated in vitro by SKK3 (also called MKK6) or when co-transfected with SKK3 into COS cells [11].
• However, under our assay conditions, SAPKK3 was the major activator of RK/p38 detected in extracts prepared from stress- or interleukin-1-stimulated epithelial (KB) cells, from bacterial lipopolysaccharide and tumour necrosis factor alpha-stimulated THP1 monocytes or from rabbit skeletal muscle [14].
• Purification and cDNA cloning of SAPKK3, the major activator of RK/p38 in stress- and cytokine-stimulated monocytes and epithelial cells [14].
• To investigate the effect of enhanced p38 MAPK activity on endothelial cell function, we expressed an activated mutant of MEK6 (MEK6E), an upstream regulator of p38 [16].
• MEK6 is highly expressed in skeletal muscle like many other members of this family, but in contrast to MKK3 its expression in leukocytes is very low [17].

Associations of MAP2K6 with chemical compounds

• The stress inducer arsenite activates mitogen-activated protein kinases extracellular signal-regulated kinases 1 and 2 via a MAPK kinase 6/p38-dependent pathway [18].
• Pretreatment of cells with SB203580, a specific inhibitor of p38, as well as expression of a dominant-negative mutant of MKK6, suppressed the transcriptional activation of the IL-2 promoter [19].
• MEK6 is strongly activated by UV, anisomycin, and osmotic shock but not by phorbol esters, nerve growth factor, and epidermal growth factor [17].
• In vitro kinase assays revealed that MKK6 was efficiently phosphorylated by PKR, and this could be inhibited by 2-aminopurine [20].
• These results suggest that MKK3, rather than MKK6, mediates alphav integrin-induced p38 MAPK activation [21].

Physical interactions of MAP2K6

• Mutants of full-length MTK1 were isolated that can interact with MKK6 in the absence of the activator GADD45 proteins [22].
• We also found that the preferential activation of p38alpha by MKK6 correlated with more efficient binding of MKK6 to p38alpha than to p38gamma [23].

Enzymatic interactions of MAP2K6

• Furthermore, MTK1 phosphorylated and activated MKK6 and SEK1 in vitro [24].

Regulatory relationships of MAP2K6

• Co-transfection with SAPKK3 induced SAPK3 activity and greatly enhanced activation in response to osmotic shock [25].
• SAPKK-4 and SAPKK-5 were also eluted from Mono S at higher NaC1 concentrations than SAPKK-3 and these enzymes activated SAP kinase-1 but not SAP kinase-2 [26].
• Protein kinase R (PKR) interacts with and activates mitogen-activated protein kinase kinase 6 (MKK6) in response to double-stranded RNA stimulation [20].
• In contrast, a constitutively active MKK6 mutant activated both p38 MAPK isoforms to similar extents [23].
• Moreover, stimulation of the endogenous stress pathways by adenovirus-mediated delivery of recombinant MAPK kinase 6 also activates VDR and sensitizes MCF-7 cells to vitamin D(3)-dependent growth inhibition [27].

Other interactions of MAP2K6

• These experiments indicate that SAPKK3 mediates the activation of SAPK3 in several mammalian cells [25].
• Activation of p21-activated kinase 6 by MAP kinase kinase 6 and p38 MAP kinase [28].
• PAK4 and PAK5 were similarly activated by MKK6, consistent with a conserved TPY motif in their activation domains [28].
• Furthermore, when co-expressed with TAK1 in cells in culture, both MAPKK6 and MKK3 were strongly activated [29].
• Cloning and characterization of MEK6, a novel member of the mitogen-activated protein kinase kinase cascade [17].

Analytical, diagnostic and therapeutic context of MAP2K6

• The surgically resected livers of 20 HCC patients were divided histologically into tumorous (T) and nontumorous (NT) lesions. p38 MAPK activity was analyzed using in vitro kinase assay and MKK6 activity was measured using Western blot analysis [2].
• Some were novel candidates, while others are involved in well-characterized mechanisms that could be relevant to cisplatin resistance, such as RECQL for DNA repair and MAP2K6 in the MAP pathway; all the genes were further validated by Real-time PCR [30].
• The mitogen-activated protein (MAP) kinase p38 and its upstream activator MAP kinase kinase 6 are involved in the activation of signal transducer and activator of transcription by hyperosmolarity [31].

References