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PMID: 21135874 Published · ppublish English Journal Article Review

Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase.

Cell research ·Vol. 21 ·No. 1 ·2011-01-00 ·Pages 131-45

Gantke T, Sriskantharajah S, Ley SC

Abstract

The IκB kinase (IKK) complex plays a well-documented role in innate and adaptive immunity. This function has been widely attributed to its role as the central activator of the NF-κB family of transcription factors. However, another important consequence of IKK activation is the regulation of TPL-2, a MEK kinase that is required for activation of ERK-1/2 MAP kinases in myeloid cells following Toll-like receptor and TNF receptor stimulation. In unstimulated cells, TPL-2 is stoichiometrically complexed with the NF-κB inhibitory protein NF-κB1 p105, which blocks TPL-2 access to its substrate MEK, and the ubiquitin-binding protein ABIN-2 (A20-binding inhibitor of NF-κB 2), both of which are required to maintain TPL-2 protein stability. Following agonist stimulation, the IKK complex phosphorylates p105, triggering its K48-linked ubiquitination and degradation by the proteasome. This releases TPL-2 from p105-mediated inhibition, facilitating activation of MEK, in addition to modulating NF-κB activation by liberating associated Rel subunits for translocation into the nucleus. IKK-induced proteolysis of p105, therefore, can directly regulate both NF-κB and ERK MAP kinase activation via NF-κB1 p105. TPL-2 is critical for production of the proinflammatory cytokine TNF during inflammatory responses. Consequently, there has been considerable interest in the pharmaceutical industry to develop selective TPL-2 inhibitors as drugs for the treatment of TNF-dependent inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. This review summarizes our current understanding of the regulation of TPL-2 signaling function, and also the complex positive and negative roles of TPL-2 in immune and inflammatory responses.

MeSH Terms
Adaptor Proteins, Signal Transducing/metabolism Antigens, Nuclear/metabolism Chromosomal Proteins, Non-Histone/metabolism Humans I-kappa B Kinase/metabolism MAP Kinase Kinase Kinases/metabolism,physiology NF-kappa B/metabolism,physiology Proto-Oncogene Proteins/metabolism,physiology Signal Transduction
Chemicals
Adaptor Proteins, Signal Transducing Antigens, Nuclear Chromosomal Proteins, Non-Histone NF-kappa B P105 antigen, human Proto-Oncogene Proteins TNIP2 protein, human I-kappa B Kinase MAP Kinase Kinase Kinases MAP3K8 protein, human
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Gantke Thorsten
Division of Immune Cell Biology, National Institute for Medical Research, Mill Hill, London, NW7 1AA, UK.
Sriskantharajah Srividya
Ley Steven C
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Article Info
Journal
Cell research
Abbr.
Cell Res
ISSN
1748-7838
DOI
10.1038/cr.2010.173
Published
2011-01-00
Epub
2010-00-07
Pages
131-45
Language
English
Region
England
NLM ID
9425763
PMCID
PMC3193413
Subset
IM
Grants
Medical Research Council · MC_U117584209 · United Kingdom
Corrections
ErratumIn
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External Links
PubMed source DOI: 10.1038/cr.2010.173 PMC Full Text View journal details
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