| Structural highlights
Function
[M3K8_HUMAN] Required for lipopolysaccharide (LPS)-induced, TLR4-mediated activation of the MAPK/ERK pathway in macrophages, thus being critical for production of the proinflammatory 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.[1] [2] [3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
Macrophages are important cellular effectors in innate immune responses and play a major role in autoimmune diseases such as rheumatoid arthritis (RA). Cancer Osaka Thyroid (COT) kinase, also known as mitogen-activated protein kinase kinase kinase 8 (MAP3K8) and tumor progression locus 2 (Tpl-2), is a Serine-Threonine (ST) kinase and is a key regulator in the production of pro-inflammatory cytokines in macrophages. Due to its pivotal role in immune biology, COT kinase has been identified as an attractive target for pharmaceutical research that is directed at the discovery of orally available, selective and potent inhibitors for the treatment of autoimmune disorders and cancer. The production of monomeric, recombinant COT kinase has proven to be very difficult and issues with solubility and stability of the enzyme have hampered the discovery and optimization of potent and selective inhibitors. We developed a protocol for the production of recombinant human COT kinase that yields pure and highly active enzyme in sufficient yields for biochemical and structural studies. The quality of the enzyme allowed us to establish a robust in vitro phosphorylation assay for the efficient biochemical characterization of COT kinase inhibitors and to determine the X-ray co-crystal structures of the COT kinase domain in complex with two ATP-binding site inhibitors. The structures presented in this publication reveal two distinct ligand binding modes and a unique kinase domain architecture that has not been observed previously. The structurally versatile active site significantly impacts the design of potent, low-molecular weight COT inhibitors.
The Crystal Structure of Cancer Osaka Thyroid Kinase Reveals an Unexpected Kinase Domain Fold.,Gutmann S, Hinniger A, Fendrich G, Drueckes P, Antz S, Mattes H, Moebitz H, Ofner S, Schmiedeberg N, Stojanovic A, Rieffel S, Strauss A, Troxler T, Glatthar R, Sparrer H J Biol Chem. 2015 Apr 27. pii: jbc.M115.648097. PMID:25918157[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Velasco-Sampayo A, Alemany S. 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. PMID:11342626
- ↑ Waterfield MR, Zhang M, Norman LP, Sun SC. 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. PMID:12667451
- ↑ Lang V, Symons A, Watton SJ, Janzen J, Soneji Y, Beinke S, Howell S, Ley SC. 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. PMID:15169888 doi:http://dx.doi.org/10.1128/MCB.24.12.5235-5248.2004
- ↑ Rodriguez C, Pozo M, Nieto E, Fernandez M, Alemany S. TRAF6 and Src kinase activity regulates Cot activation by IL-1. Cell Signal. 2006 Sep;18(9):1376-85. Epub 2005 Dec 20. PMID:16371247 doi:http://dx.doi.org/10.1016/j.cellsig.2005.10.016
- ↑ Aoki M, Akiyama T, Miyoshi J, Toyoshima K. Identification and characterization of protein products of the cot oncogene with serine kinase activity. Oncogene. 1991 Sep;6(9):1515-9. PMID:1833717
- ↑ Watford WT, Hissong BD, Durant LR, Yamane H, Muul LM, Kanno Y, Tato CM, Ramos HL, Berger AE, Mielke L, Pesu M, Solomon B, Frucht DM, Paul WE, Sher A, Jankovic D, Tsichlis PN, O'Shea JJ. Tpl2 kinase regulates T cell interferon-gamma production and host resistance to Toxoplasma gondii. J Exp Med. 2008 Nov 24;205(12):2803-12. doi: 10.1084/jem.20081461. Epub 2008 Nov , 10. PMID:19001140 doi:http://dx.doi.org/10.1084/jem.20081461
- ↑ Handoyo H, Stafford MJ, McManus E, Baltzis D, Peggie M, Cohen P. IRAK1-independent pathways required for the interleukin-1-stimulated activation of the Tpl2 catalytic subunit and its dissociation from ABIN2. Biochem J. 2009 Oct 23;424(1):109-18. doi: 10.1042/BJ20091271. PMID:19754427 doi:http://dx.doi.org/10.1042/BJ20091271
- ↑ Jager J, Gremeaux T, Gonzalez T, Bonnafous S, Debard C, Laville M, Vidal H, Tran A, Gual P, Le Marchand-Brustel Y, Cormont M, Tanti JF. 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. doi: 10.2337/db09-0470. Epub 2009 Oct 6. PMID:19808894 doi:http://dx.doi.org/10.2337/db09-0470
- ↑ Gutmann S, Hinniger A, Fendrich G, Drueckes P, Antz S, Mattes H, Moebitz H, Ofner S, Schmiedeberg N, Stojanovic A, Rieffel S, Strauss A, Troxler T, Glatthar R, Sparrer H. The Crystal Structure of Cancer Osaka Thyroid Kinase Reveals an Unexpected Kinase Domain Fold. J Biol Chem. 2015 Apr 27. pii: jbc.M115.648097. PMID:25918157 doi:http://dx.doi.org/10.1074/jbc.M115.648097
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