Disease relevance of MAP2K4

• These data seem to re-establish a rather consistent rate of genetic inactivation of MAP2K4 among most tumor types, including breast cancer [1].
• Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene [2].
• These findings suggest that MKK4 may function as a suppressor of tumorigenesis or metastasis in certain types of cells [3].
• A recent report on the deletion and mutation of the MKK4 gene in human pancreatic, lung, breast, testicle, and colorectal cancer cell lines suggests an additional role for MKK4 in tumor suppression [2].
• Evidence that phosphatidylinositol 3-kinase- and mitogen-activated protein kinase kinase-4/c-Jun NH2-terminal kinase-dependent Pathways cooperate to maintain lung cancer cell survival [4].

Psychiatry related information on MAP2K4

• JKK1, an upstream activator of JNK/SAPK, is activated in Alzheimer's disease [5].

High impact information on MAP2K4

• JNKK activated the JNKs but did not activate the ERKs and was unresponsive to Raf-1 in transfected HeLa cells [6].
• Mutations in this region interfere with the ability of JNKK1 to respond to TNF but do not affect its activation by physical stressors [7].
• A conserved docking site, termed DVD, is found in the mammalian MAP kinase kinases (MAPKKs) belonging to the three major subfamilies, namely MEK1, MKK4/7, and MKK3/6 [8].
• Arsenic trioxide inhibits nuclear receptor function via SEK1/JNK-mediated RXRalpha phosphorylation [9].
• We provide a novel scenario of the proapoptotic role of IkappaB kinase beta (IKKbeta)-NF-kappaB, which can act as the activator of the JNK pathway through the induction of GADD45alpha for triggering MKK4/JNK activation, in response to the stimulation of arsenite, a cancer therapeutic reagent [10].

Chemical compound and disease context of MAP2K4

• Loss of expression of receptor tyrosine kinase family genes PTK7 and SEK in metastatic melanoma [11].
• Blockage of NF-kappaB induces serine 15 phosphorylation of mutant p53 by JNK kinase in prostate cancer cells [12].
• No differences in MKK4/SEK1 gene expression or in the 41 other metastasis and tumor suppressor genes were found in A375 melanoma cells cultured in Tyr- and Phe-deprived media [13].

Biological context of MAP2K4

• The MKK4 protein has been implicated in activation of JNK1 and p38 MAPK on phosphorylation by conserved kinase pathways [2].
• In addition, in a panel of 45 pancreatic carcinomas prescreened for loss of heterozygosity, one somatic missense mutation of MKK4 is observed and confirmed in the primary tumor (2%) [2].
• Finally, activated Akt inhibited SEK1-mediated apoptosis, and this effect of Akt was prevented by overexpression of SEK(S78A) [14].
• This docking site conforms to the consensus sequence for known D-sites in other MKKs and contains the first of the two cleavage sites for anthrax lethal factor protease that have been found in the N terminus of MKK4 [15].
• Staurosporine inhibited GST-MKK4 with an IC50 of 70 nM [16].

Anatomical context of MAP2K4

• The exception is breast cancer, where genetic inactivation in 3 of 22 (15%) cell lines had suggested that the mutational involvement of MAP2K4 might be accentuated in this tumor type [1].
• Here, we report that two human tumor cell lines, derived from pancreatic carcinoma and lung carcinoma, harbor homozygous deletions that eliminate coding portions of the MKK4 locus at 17p, located approximately 10 cM centromeric of p53 [3].
• Furthermore, LY294002 induced apoptosis of MKK4-null but not wild-type mouse embryo fibroblasts [4].
• SEK-AL, a dominant-negative mutant of SEK1, was transfected into HL-60 cells (HL-60/SEK-AL) to assess the role of JNK/SAPK activity in apoptosis [17].
• Expression of a dominant negative mutant of Ras blocked the anisomycin-induced activation of SAPK and SEK1, but did not affect markedly the arsenite-induced or heat shock-induced activation in PC12 cells [18].

Associations of MAP2K4 with chemical compounds

• In vitro and in vivo (32)P labeling indicated that Akt phosphorylated SEK1 on serine 78 [14].
• We found that MKK4 had a preference for the tyrosine residue, and MKK7 for the threonine residue, within the Thr-X-Tyr motif [19].
• The level of Jun-NH2-terminal kinase (JNK) activity and the phosphorylation of the JNK kinase, SEK1, were unchanged by chronic high glucose concentrations [20].
• Nitric oxide modulates the c-Jun N-terminal kinase/stress-activated protein kinase activity through activating c-Jun N-terminal kinase kinase [21].
• Furthermore, exposure of cells to sodium nitroprusside resulted in the stimulation of JNK kinase (JNKK1/SEK1) [21].

Physical interactions of MAP2K4

• A docking site in MKK4 mediates high affinity binding to JNK MAPKs and competes with similar docking sites in JNK substrates [15].
• It binds the upstream kinases ASK1 and MKK4 and couples stimulation of the angiotensin II receptor AT1aR to activation of a cytoplasmic pool of JNK3 [22].
• Furthermore, MKK-4 coprecipitated with MKK-7 and vice versa, indicating that the 3 kinases form a stable complex in FLS [23].

Enzymatic interactions of MAP2K4

• Transiently expressed SEK1 isolated from palytoxin-treated cells can phosphorylate and activate JNK, which, in turn, can phosphorylate c-Jun [24].

Regulatory relationships of MAP2K4

• In contrast SEK can activate SAPK when present in substoichiometric amounts, but this activation is slow, consistent with the rate-limiting step in activation being the dissociation of an inactive SEK:SAPK complex [25].
• Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation [14].
• Consistent with these observations, immunoprecipitated MEKK2 directly activated recombinant MKK4 in vitro but failed to activate MKK3 [26].
• In contrast, MKK4-activated JNK3 alpha 1 had no increase in Vmax compared to nonactivated levels and had no phosphorylation on the basis of mass spectrometry [27].
• Cotransfection of dominant-negative JNK kinase inhibits phosphorylation of kinase-negative MLK2 by anisomycin-activated JNK [28].

Other interactions of MAP2K4

• 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 [29].
• The inhibitory action of insulin on SEK1 or JNK1 activation was prevented by the phosphatidylinositol 3-kinase inhibitor LY294002 [14].
• Ser/Thr protein phosphatase 5 inactivates hypoxia-induced activation of an apoptosis signal-regulating kinase 1/MKK-4/JNK signaling cascade [30].
• Impaired activity of these stress kinases by PED correlated with inhibition of stress-induced Cdc-42, MKK4, and MKK6 activation [31].
• Co-expressed MAP kinase kinase (MKK)-1, MKK-4, MKK-3 and MKK-6 were activated in vivo by DeltaMAPKKK4 [32].

Analytical, diagnostic and therapeutic context of MAP2K4

• To address this question, we studied an independent panel of 20 breast cancer cell lines and xenografts for MAP2K4 alterations [1].
• Co-immunoprecipitation analysis revealed that endogenous Akt physically interacted with endogenous SEK1 in cells and that this interaction was promoted by insulin [14].
• Phosphospecific antibodies and immunohistochemistry were used to evaluate the activation state of synovial MKK-4 and MKK-7 [23].
• METHODS: FLS were transfected with MKK-4 and/or MKK-7 small interfering RNA, and protein levels were determined by immunoblotting [33].
• Inhibition of JNK activity, by transfecting cells with a dominant-negative JNKK- MKK4 construct, led to a strong reduction of apoptosis after MHC-I ligation [34].

References