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Molecular and Cellular Biology, November 2004, p. 9658-9667, Vol. 24, No. 21
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.21.9658-9667.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Lipopolysaccharide Activation of the TPL-2/MEK/Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase Cascade Is Regulated by I{kappa}B Kinase-Induced Proteolysis of NF-{kappa}B1 p105{dagger}

S. Beinke,1,{ddagger} M. J. Robinson,1,{ddagger} M. Hugunin,2 and S. C. Ley1*

Division of Immune Cell Biology, National Institute for Medical Research, London, United Kingdom,1 Molecular and Cellular Biology, Abbott Bioresearch Center, Worcester, Massachusetts2

Received 27 January 2004/ Returned for modification 4 March 2004/ Accepted 3 August 2004

The MEK kinase TPL-2 (also known as Cot) is required for lipopolysaccharide (LPS) activation of the extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase cascade in macrophages and consequent upregulation of genes involved in innate immune responses. In resting cells, TPL-2 forms a stoichiometric complex with NF-{kappa}B1 p105, which negatively regulates its MEK kinase activity. Here, it is shown that lipopolysaccharide (LPS) stimulation of primary macrophages causes the release of both long and short forms of TPL-2 from p105 and that TPL-2 MEK kinase activity is restricted to this p105-free pool. Activation of TPL-2, MEK, and ERK by LPS is also demonstrated to require proteasome-mediated proteolysis. p105 is known to be proteolysed by the proteasome following stimulus-induced phosphorylation of two serines in its PEST region by the I{kappa}B kinase (IKK) complex. Expression of a p105 point mutant, which is not susceptible to signal-induced proteolysis, in RAW264.7 macrophages impairs LPS-induced release of TPL-2 from p105 and its subsequent activation of MEK. Furthermore, expression of wild-type but not mutant p105 reconstitutes LPS stimulation of MEK and ERK phosphorylation in primary NF-{kappa}B1-deficient macrophages. Consistently, pharmacological blockade of IKK inhibits LPS-induced release of TPL-2 from p105 and TPL-2 activation. These data show that IKK-induced p105 proteolysis is essential for LPS activation of TPL-2, thus revealing a novel function of IKK in the regulation of the ERK MAP kinase cascade.

* Corresponding author. Mailing address: National Institute for Medical Research, Division of Immune Cell Biology, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom. Phone: 44-20-8816-2463. Fax: 44-20-8906-4477. E-mail: sley{at}nimr.mrc.ac.uk.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org.

{ddagger} S.B. and M.J.R. contributed equally to this study.

Molecular and Cellular Biology, November 2004, p. 9658-9667, Vol. 24, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.21.9658-9667.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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