Disease relevance of Map3k8

• Protein kinase Tpl2/Cot is encoded by a protooncogene that is cis-activated by retroviral insertion in murine T cell lymphomas [1].
• We have shown here that Tpl2/Cot is constitutively activated in human leukemia cell lines transformed by the human T cell leukemia virus type I (HTLV-I) [1].
• Tpl-2 transgenic mice expressing the wild-type protein from the proximal Lck promoter fail to show a biological phenotype, whereas mice expressing the truncated protein develop large-cell lymphoblastic lymphomas of T-cell origin [2].
• Tpl-2/Cot proto-oncogene encodes a serine threonine kinase and was initially cloned as a provirus insertion site in MoMuLV-induced T cell lymphomas in rats [3].
• Overexpression of the Tpl-2/Cot oncogene in human breast cancer [3].

High impact information on Map3k8

• Subcellular fractionation of LPS-stimulated macrophages revealed that LPS signals transduced by Tpl2 specifically promote the transport of TNF-alpha mRNA from the nucleus to the cytoplasm [4].
• Tpl2 knockout mice produce low levels of TNF-alpha when exposed to lipopolysaccharide (LPS) and they are resistant to LPS/D-Galactosamine-induced pathology [4].
• Provirus insertion in the last intron of the Tpl-2 gene in retrovirus-induced rat T-cell lymphomas results in the enhanced expression of a carboxy-terminally truncated Tpl-2 kinase [2].
• NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase [5].
• A serine/threonine kinase, Cot/Tpl2, modulates bacterial DNA-induced IL-12 production and Th cell differentiation [6].

Biological context of Map3k8

• Recent studies revealed that Tpl2 undergoes phosphorylation at Thr-290 and that phosphorylation at this site is required for activation [7].
• The serine-threonine protein kinase encoded by the Tpl2 protooncogene transduces Toll-like and death receptor signals in a variety of cell types and plays an important role in innate immunity and inflammation [7].
• Here, we show that overexpression of the cot proto-oncogene is sufficient to stimulate the expression of c-jun and that, in turn, the activity of c-Jun is required for Cot-induced transformation [8].
• In contrast, the contribution of NIK to the transactivation function of p65/RelA seems to be negligible and more importantly NIK-KD did not inhibit induction by Cot and PKCzeta [9].
• The oncoprotein kinase Tpl2 plays an essential role in macrophage activation by the bacterial component lipopolysaccharide (LPS) [10].

Anatomical context of Map3k8

• Macrophages and B-cells from Tpl2 knock-out mice exhibit a restricted defect in lipopolysaccharide and death receptor signaling that is limited to the activation of ERK [11].
• Cot/Tpl2 is essential for RANKL induction by lipid A in osteoblasts [12].
• Macrophages from Tpl2 knockout (Tpl2(-/-)) mice exhibit a defect in ERK activation by lipopolysaccharide (LPS) [13].
• Peritoneal macrophages and bone marrow-derived DCs from Cot/Tpl2-/- mice produced significantly more IL-12 in response to CpG-DNA than those from WT mice [6].
• Deregulated activation of oncoprotein kinase Tpl2/Cot in HTLV-I-transformed T cells [1].

Associations of Map3k8 with chemical compounds

• We also showed that Tpl2 activation by TNF-alpha depends on a tyrosine kinase activity that is detected in TNF-alpha-stimulated cells [14].
• The Cot sequence contains a conserved threonine at position 290 in the activation loop of the kinase domain [15].
• Considering these data, we propose that the inhibition of LPS-induced Cot activation is one mechanism by which 15-deoxy-Delta12,14-prostaglandin J2 acts as an anti-inflammatory [16].
• 15-Deoxy-Delta12,14-prostaglandin J2, but not rosiglitazone, blocks Cot activation by LPS [16].
• The core DNA population that contains satellite sequences was then purified from total core DNA by denaturation of the DNA, reassociation to a low Cot value and hydroxyapatite chromatography to separate the renatured satellite fraction [17].

Regulatory relationships of Map3k8

• Diverse Toll-like receptors utilize Tpl2 to activate extracellular signal-regulated kinase (ERK) in hemopoietic cells [18].
• These observations prompted us to explore the molecular events by which Cot regulates c-jun expression [8].
• We show here that Cot/Tpl2 is also activated by other Toll-like receptor (TLR) ligands [6].

Other interactions of Map3k8

• IkappaB kinase is an essential component of the Tpl2 signaling pathway [19].
• In addition, we show that the activation of Tpl2 by TNF-alpha depends on signals transduced by both TRAF2 and RIP1 [11].
• Differential translational initiation of the Tpl2 mRNA gives rise to 58-kDa (p58) and 52-kDa (p52) isoforms [7].
• Interestingly, a large pool of Tpl2/Cot is liberated from p105 and exhibits constitutive kinase activity in HTLV-I-transformed T cells [1].
• We conclude that Tpl2 phosphorylation at Thr(290) is induced by LPS, depends on IKKbeta, and is required for the physiological activation of Tpl2 by external signals [20].

Analytical, diagnostic and therapeutic context of Map3k8

• These results indicate that Cot/Tpl2 is an important negative regulator of Th1-type adaptive immunity, that it achieves this regulation by inhibiting IL-12 production from accessory cells, and that it might be a potential target molecule in CpG-DNA-guided vaccination [6].

References