Mitogen-activated protein kinase kinase kinase 8

UniProt P41279 Organism Homo sapiens Gene COT, ESTF, MAP3K8 EC 2.7.11.25

Also known as: COT, ESTF, MAP3K8

Function

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 (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.

Classification

Family (Pfam): PF00069 Pkinase
InterPro: Kinase-like_dom_sf, MAP_kinase_kinase_kinase, MAPKKK8, Prot_kinase_dom, Ser/Thr_kinase_AS
Functional cluster: Serine/Threonine Protein Kinases

Experimental structures · PDB · 3

4Y83 X-ray 2.89A
4Y85 X-ray 2.33A
5IU2 X-ray 2.70A

A predicted model is available from AlphaFold.

Gene Ontology · 11

Drugs targeting this protein · 1

TILPISERTIB inhibitor

Related proteins · sequence + function similarity

Co-cited proteins · studied together in the literature

Mitogen-activated protein kinase kinase kinase 8 3 shared papers
Kinase suppressor of Ras 2 1 shared papers
Mitogen-activated protein kinase kinase kinase 8 1 shared papers
Nuclear factor NF-kappa-B p105 subunit 2 shared papers
TNFAIP3-interacting protein 2 1 shared papers

Literature · 25 cited papers

Retraction. IRAK1-independent pathways required for the interleukin-1-stimulated activation of the Tpl2 catalytic subunit and its dissociation from ABIN2. Biochem. J. · 2014
An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J. Proteomics · 2014
Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
IkappaB kinase 2 regulates TPL-2 activation of extracellular signal-regulated kinases 1 and 2 by direct phosphorylation of TPL-2 serine 400. Mol. Cell. Biol. · 2012
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
IRAK1-independent pathways required for the interleukin-1-stimulated activation of the Tpl2 catalytic subunit and its dissociation from ABIN2. Biochem. J. · 2009
Tpl2 kinase regulates T cell interferon-gamma production and host resistance to Toxoplasma gondii. J. Exp. Med. · 2008
A quantitative atlas of mitotic phosphorylation. Proc. Natl. Acad. Sci. U.S.A. · 2008
Characterization of phosphorylation sites on Tpl2 using IMAC enrichment and a linear ion trap mass spectrometer. J. Proteome Res. · 2007
TRAF6 and Src kinase activity regulates Cot activation by IL-1. Cell. Signal. · 2006
Phosphorylation at Thr-290 regulates Tpl2 binding to NF-kappaB1/p105 and Tpl2 activation and degradation by lipopolysaccharide. Proc. Natl. Acad. Sci. U.S.A. · 2005
The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
… and 13 more in the literature graph

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