Disease relevance of Nr2c2

• The TAK1-mediated antiapoptotic effects were also observed in human lung adenocarcinoma A549 cells [1].
• The Yersinia enterocolitica effector YopP inhibits host cell signalling by inactivating the protein kinase TAK1 in the IL-1 signalling pathway [2].
• Here, we investigated the potential involvement of TAK1 in cardiac hypertrophy [3].
• In adult mouse myocardium, TAK1 kinase activity was upregulated 7 days after aortic banding, a mechanical load that induces hypertrophy and expression of transforming growth factor beta [3].
• To reveal the effects of blocking these pathways simultaneously, fibroblasts were infected with retroviruses encoding TAK1K63W, an inactive mutant of the protein kinase TAK1 [4].

High impact information on Nr2c2

• An activating mutation of TAK1 expressed in myocardium of transgenic mice was sufficient to produce p38 mitogen-activated protein kinase phosphorylation in vivo, cardiac hypertrophy, interstitial fibrosis, severe myocardial dysfunction, 'fetal' gene induction, apoptosis and early lethality [3].
• TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice [3].
• Thus, TAK1 activity is induced as a delayed response to mechanical stress, and can suffice to elicit myocardial hypertrophy and fulminant heart failure [3].
• The function of TAK1 in T cells is unclear, however [5].
• The kinase TAK1 is critical for innate and B cell immunity [5].

Biological context of Nr2c2

• The amino acid sequence of mouse TAK1 (mTAK1) is highly homologous to that of human TAK1, with an overall identity of 98% [6].
• Southern analysis using genomic DNA prepared from a panel of hamster/human and mouse/human hybrid cell lines indicated that the TAK1 gene is located on human chromosome 3 [6].
• We have cloned the gene encoding the mouse homologue of the orphan receptor, TAK1, a member of the nuclear receptor superfamily, from a mouse testis cDNA library [6].
• In conclusion, TAK1 is essential in the regulation of keratinocyte growth, differentiation, and apoptosis [7].
• Finally, expression of TAK1 and TAB1 in HeLa cells or treatment of cells with cytokines stimulated phosphorylation of Thr-172 of AMPK [8].

Anatomical context of Nr2c2

• Cloning of the gene encoding the murine orphan receptor TAK1 and cell-type-specific expression in testis [6].
• Here we have demonstrated that TAK1 is the major regulator of skin inflammation as well as keratinocyte death in vivo [9].
• In contrast, TAK1-deficient mouse embryonic fibroblasts are resistant to TRAIL-induced apoptosis, and treatment of control mouse embryonic fibroblasts with 5Z-7-oxozeaenol did not drastically promote the TRAIL-induced activation of a caspase cascade [1].
• We show here that T cell-specific deletion of the gene encoding TAK1 resulted in reduced development of thymocytes, especially of regulatory T cells expressing the transcription factor Foxp3 [5].
• In contrast, two TAK1-binding proteins, TAB1 and TAB2, which are involved in the activation of TAK1, were localized in the neurites and the nuclei of the differentiating cells, respectively [10].

Associations of Nr2c2 with chemical compounds

• Our results demonstrate that TAK1 is a master regulator of TNF signaling in skin and regulates skin inflammation and keratinocyte death [9].
• Recently, serine/threonine kinase TAK1 and TAK1 binding protein 1 and 2 (TAB1/2) have been identified as molecules involved in IL-1-induced TRAF6-mediated activation of AP-1 and NF-kappa B via mitogen-activated protein (MAP) kinases and I kappa B kinases, respectively [11].
• The inhibitory effect of cycloheximide was accompanied with down-regulation of Tak1 expression and TGF-beta1-induced PAI-1 expression [12].

Other interactions of Nr2c2

• These results suggest that TNF induces TAK1-deficient keratinocyte death because of the lack of NF-kappaB (and possibly JNK)-mediated cell survival signaling [9].
• Finally, we have shown that deletion of the TNF receptor can largely rescue keratinocyte death as well as inflammatory skin condition in epidermal-specific TAK1-deficient mice [9].
• Selection for a Snf+ growth phenotype yielded cDNA plasmids expressing LKB1, Ca2+/calmodulin-dependent protein kinase kinase, and transforming growth factor-beta-activated kinase (TAK1), a member of the mitogen-activated protein kinase kinase kinase family [8].

Analytical, diagnostic and therapeutic context of Nr2c2

• Flow cytometry showed that the binding of Annexin V to cell surface was also synergistically increased by TRAIL in combination with TAK1 siRNA [1].
• Immunoblotting was used to detect Tak1, p53, and Bax [12].

References