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Molecular and Cellular Biology, November 2007, p. 7355-7364, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00301-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Phosphorylation of TPL-2 on Serine 400 Is Essential for Lipopolysaccharide Activation of Extracellular Signal-Regulated Kinase in Macrophages{triangledown}

M. J. Robinson ,1,{dagger},{ddagger} S. Beinke ,1,{dagger},§ A. Kouroumalis,1 P. N. Tsichlis,2 and S. C. Ley1*

Division of Immune Cell Biology, National Institute for Medical Research, London, United Kingdom,1 Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts2

Received 19 February 2007/ Returned for modification 27 March 2007/ Accepted 10 August 2007

Tumor progression locus 2 (TPL-2) kinase is essential for Toll-like receptor 4 activation of the mitogen-activated protein kinase extracellular signal-regulated kinase (ERK) and for upregulation of the inflammatory cytokine tumor necrosis factor (TNF) in lipopolysaccharide (LPS)-stimulated macrophages. LPS activation of ERK requires TPL-2 release from associated NF-{kappa}B1 p105, which blocks TPL-2 access to its substrate, the ERK kinase MEK. Here we demonstrate that TPL-2 activity is also regulated independently of p105, since LPS stimulation was still needed for TPL-2-dependent activation of ERK in Nfkb1–/– macrophages. In wild-type macrophages, LPS induced the rapid phosphorylation of serine (S) 400 in the TPL-2 C-terminal tail. Mutation of this conserved residue to alanine (A) blocked the ability of retrovirally expressed TPL-2 to induce the activation of ERK in LPS-stimulated Nfkb1–/– macrophages. TPL-2S400A expression also failed to reconstitute LPS activation of ERK and induction of TNF in Map3k8–/– macrophages, which lack endogenous TPL-2. Consistently, the S400A mutation was found to block LPS stimulation of TPL-2 MEK kinase activity. Thus, induction of TPL-2 MEK kinase activity by LPS stimulation of macrophages requires TPL-2 phosphorylation on S400, in addition to its release from NF-{kappa}B1 p105. Oncogenic C-terminal truncations of TPL-2 that remove S400 could promote its transforming potential by eliminating this critical control step.

* Corresponding author. Mailing address: Division of Immune Cell Biology, National Institute for Medical Research, 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

{triangledown} Published ahead of print on 20 August 2007.

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

{ddagger} Present address: London Research Institute, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.

§ Present address: University of California, San Francisco, Howard Hughes Medical Institute, 513 Parnassus Avenue, San Francisco, CA 94143-0795.

Molecular and Cellular Biology, November 2007, p. 7355-7364, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00301-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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