Mitogen-activated protein kinase kinase kinase 8

Definition

Required for lipopolysaccharide (LPS)-induced, TLR4-mediated activation of the MAPK/ERK pathway in macrophages, thus being critical for production of the pro-inflammatory cytokine TNF-alpha (TNF) during immune responses. Involved in the regulation of T-helper cell differentiation and IFNG expression in T-cells. Involved in mediating host resistance to bacterial infection through negative regulation of type I interferon (IFN) production. In vitro, activates MAPK/ERK pathway in response to IL1 in an IRAK1-independent manner, leading to up-regulation of IL8 and CCL4. Transduces CD40 and TNFRSF1A signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production. May also play a role in the transduction of TNF signals that activate JNK and NF-kappa-B in some cell types. In adipocytes, activates MAPK/ERK pathway in an IKBKB-dependent manner in response to IL1B and TNF, but not insulin, leading to induction of lipolysis. Plays a role in the cell cycle. Isoform 1 shows some transforming activity, although it is much weaker than that of the activated oncogenic variant.

References:

[1]. Cristina Rodríguez, et al. TRAF6 and Src kinase activity regulates Cot activation by IL-1. Cell Signal. 2006 Sep;18(9):1376-85. [Content Brief]

[2]. M Aoki, et al. Identification and characterization of protein products of the cot oncogene with serine kinase activity. Oncogene. 1991 Sep;6(9):1515-9. [Content Brief]

[3]. Wendy T Watford, et al. Tpl2 kinase regulates T cell interferon-gamma production and host resistance to Toxoplasma gondii. J Exp Med. 2008 Nov 24;205(12):2803-12. [Content Brief]

[4]. V Lang, et al. ABIN-2 forms a ternary complex with TPL-2 and NF-kappa B1 p105 and is essential for TPL-2 protein stability. Mol Cell Biol. 2004 Jun;24(12):5235-48. [Content Brief]

[5]. A Velasco-Sampayo, et al. p27kip protein levels and E2F activity are targets of Cot kinase during G1 phase progression in T cells. J Immunol. 2001 May 15;166(10):6084-90. [Content Brief]

[6]. Michael R Waterfield, et al. NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase. Mol Cell. 2003 Mar;11(3):685-94. [Content Brief]

[7]. Jennifer Jager, et al. Tpl2 kinase is upregulated in adipose tissue in obesity and may mediate interleukin-1beta and tumor necrosis factor-{alpha} effects on extracellular signal-regulated kinase activation and lipolysis. Diabetes. 2010 Jan;59(1):61-70. [Content Brief]

生物医学辞典

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