Disease relevance of MAP3K4

• Unlike most mouse models of NTDs, MEKK4 mutant embryos display genetically co-segregated exencephaly and spina bifida, recapitulating the phenotypes observed in human patients [1].
• However, a clear differential toxicity pattern was observed in favor of animals treated with Adcox-2 MTK when compared with controls [2].
• A series of deletion mutants within the 5' flanking region of the hMT-IIA gene was constructed and fused to the structural sequences of the Herpes simplex thymidine kinase (TK) gene to generate hMTK chimeric genes [3].

High impact information on MAP3K4

• MEKK4 sequesters RIP2 to dictate NOD2 signal specificity. [4]
• A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK [5].
• MEKK4 Signaling Regulates Filamin Expression and Neuronal Migration [6].
• RNA interference (RNAi) targeting MEKK4 also impaired neuronal migration [6].
• Expression of Fln was elevated in MEKK4(-/-) forebrain, most notably near sites of failed neuronal migration [6].
• CD4 T cells from MEKK4-/- mice have reduced p38 activity and defective IFNgamma synthesis [7].

Biological context of MAP3K4

• The MEKK4 carboxyl-terminal catalytic domain is approximately 55% homologous to the catalytic domains of MEKKs 1, 2, and 3 [8].
• Together, these data demonstrate MEKK4 regulation of p38 and that substrates downstream of p38 control cellular homeostasis [9].
• Targeted mutation of the active site lysine of MEK kinase 4 (MEKK4) produces a kinase-inactive MEKK4 protein (MEKK4(K1361R)) [9].
• MEKK4 is tyrosine-phosphorylated and the IFNgamma-dependent phosphorylation requires intracellular calcium [10].
• Loss of mitogen-activated protein kinase kinase kinase 4 (MEKK4) results in enhanced apoptosis and defective neural tube development [1].

Anatomical context of MAP3K4

• Immunoprecipitation of endogenous MAPKKK4 by specific antibodies showed that MAPKKK4 was activated after the treatment of K562 cells with various stress conditions [11].
• A calcium-dependent interaction between MEKK4 and annexin II was observed when MEKK4 was immunoprecipitated from rat aortic smooth muscle cells that were treated with angiotensin II [12].
• In the present paper, we report IFNgamma-dependent activation of the MEKK4 (MAPK/extracellular-signal-regulated kinase kinase kinase 4) pathway in HaCaT human keratinocytes [10].
• In contrast, proliferation of MEKK4-deficient neuroepithelial cells appeared to be largely unaffected [1].
• Using MTK1, 31 leukemia cell lines and 76 leukemia blasts from pediatric patients were analyzed for expression of the c-kit receptor by flow cytometry [13].

Associations of MAP3K4 with chemical compounds

• Of the four MEKKs tested, only MEKK3 and MEKK4 are involved in arsenate-mediated activation of JNK [14].
• Prior studies indicated that MEKK4 was phosphorylated on tyrosine in vivo, and in fact, Pyk2 interacts with MEKK4 in an angiotensin II dependent manner in rat aortic smooth muscle cells [12].
• Mice deficient in MEKK4 develop highly penetrant NTDs that cannot be rescued by supplementation with folic acid or inositol [1].

Physical interactions of MAP3K4

• GADD45 proteins bind a site in MTK1 near the inhibitory domain and relieve autoinhibition [15].
• Mutants of full-length MTK1 were isolated that can interact with MKK6 in the absence of the activator GADD45 proteins [15].
• Additional studies demonstrate that the SH2 (Src homology 2)-domain-containing tyrosine phosphatase SHP2 co-immunoprecipitates with MEKK4 in an IFNgamma-dependent manner and co-localizes with MEKK4 after IFNgamma stimulation in the perinuclear region in HaCaT cells [10].
• Furthermore, Ccd1 physically interacted with MEKK4 in their physiological concentrations and prevented MEKK4 from binding to Axin [16].

Enzymatic interactions of MAP3K4

• Furthermore, MTK1 phosphorylated and activated MKK6 and SEK1 in vitro [17].

Regulatory relationships of MAP3K4

• CIN85 was also shown to regulate the activation of MEKK4 by GADD45 proteins and promote multi-ubiquitination of MEKK4 [18].

Other interactions of MAP3K4

• We report the identification of a human MAPK kinase kinase, MAPKKK4, via sequence similarity with other MAPKKKs [11].
• When truncated MAPKKK4 (DeltaMAPKKK4) was overexpressed in HEK293 cells, it was constitutively active and induced the activation of endogenous p38alpha, c-Jun N-terminal kinase (JNK)1/2 and extracellular signal-regulated kinase (ERK)2 in vivo [11].
• A human homolog of the yeast Ssk2/Ssk22 MAP kinase kinase kinases, MTK1, mediates stress-induced activation of the p38 and JNK pathways [17].
• In the autoinhibited conformation, the MTK1 kinase domain cannot interact with its substrate, MKK6 [15].
• The MKKKs, MEKK3 and MEKK4, are upstream regulators of p38 in many cells [19].

Analytical, diagnostic and therapeutic context of MAP3K4

• Furthermore, the calcium-binding protein, annexin II, and the calcium-regulated kinase, Pyk2, co-immunoprecipitate with MEKK4 after treatment with IFNgamma [10].

References