Phosphorylation of TPL-2 on Serine 400 is Essential for Lipopolysaccharide Activation of Extracellular Signal-regulated Kinase in Macrophages

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2007 Aug 22

PMID 17709378

Citations 25

Authors

M J Robinson

S Beinke

A Kouroumalis

P N Tsichlis

S C Ley

Affiliations

Soon will be listed here.

Abstract

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-kappaB1 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-2(S400A) 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-kappaB1 p105. Oncogenic C-terminal truncations of TPL-2 that remove S400 could promote its transforming potential by eliminating this critical control step.

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References

Chiariello M, Marinissen M, Gutkind J . Multiple mitogen-activated protein kinase signaling pathways connect the cot oncoprotein to the c-jun promoter and to cellular transformation. Mol Cell Biol. 2000; 20(5):1747-58. PMC: 85357. DOI: 10.1128/MCB.20.5.1747-1758.2000. View

Papoutsopoulou S, Symons A, Tharmalingham T, Belich M, Kaiser F, Kioussis D . ABIN-2 is required for optimal activation of Erk MAP kinase in innate immune responses. Nat Immunol. 2006; 7(6):606-15. DOI: 10.1038/ni1334. View

Karin M, Ben-Neriah Y . Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol. 2000; 18:621-63. DOI: 10.1146/annurev.immunol.18.1.621. View

Morita S, Kojima T, Kitamura T . Plat-E: an efficient and stable system for transient packaging of retroviruses. Gene Ther. 2000; 7(12):1063-6. DOI: 10.1038/sj.gt.3301206. View

Dumitru C, Ceci J, Tsatsanis C, Kontoyiannis D, Stamatakis K, Lin J . TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell. 2001; 103(7):1071-83. DOI: 10.1016/s0092-8674(00)00210-5. View

Beinke S, Belich M, Ley S . The death domain of NF-kappa B1 p105 is essential for signal-induced p105 proteolysis. J Biol Chem. 2002; 277(27):24162-8. DOI: 10.1074/jbc.M201576200. View

Kane L, Mollenauer M, Xu Z, Turck C, Weiss A . Akt-dependent phosphorylation specifically regulates Cot induction of NF-kappa B-dependent transcription. Mol Cell Biol. 2002; 22(16):5962-74. PMC: 133991. DOI: 10.1128/MCB.22.16.5962-5974.2002. View

Guha M, Mackman N . The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells. J Biol Chem. 2002; 277(35):32124-32. DOI: 10.1074/jbc.M203298200. View

Mikkers H, Allen J, Knipscheer P, Romeijn L, Hart A, Vink E . High-throughput retroviral tagging to identify components of specific signaling pathways in cancer. Nat Genet. 2002; 32(1):153-9. DOI: 10.1038/ng950. View

10.

Lund A, Turner G, Trubetskoy A, Verhoeven E, Wientjens E, Hulsman D . Genome-wide retroviral insertional tagging of genes involved in cancer in Cdkn2a-deficient mice. Nat Genet. 2002; 32(1):160-5. DOI: 10.1038/ng956. View

11.

Eliopoulos A, Dumitru C, Wang C, Cho J, Tsichlis P . Induction of COX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signals. EMBO J. 2002; 21(18):4831-40. PMC: 126277. DOI: 10.1093/emboj/cdf478. View

12.

Lang V, Janzen J, Fischer G, Soneji Y, Beinke S, Salmeron A . betaTrCP-mediated proteolysis of NF-kappaB1 p105 requires phosphorylation of p105 serines 927 and 932. Mol Cell Biol. 2002; 23(1):402-13. PMC: 140687. DOI: 10.1128/MCB.23.1.402-413.2003. View

13.

Ojaniemi M, Glumoff V, Harju K, Liljeroos M, Vuori K, Hallman M . Phosphatidylinositol 3-kinase is involved in Toll-like receptor 4-mediated cytokine expression in mouse macrophages. Eur J Immunol. 2003; 33(3):597-605. DOI: 10.1002/eji.200323376. View

14.

Waterfield M, Zhang M, Norman L, Sun S . NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase. Mol Cell. 2003; 11(3):685-94. DOI: 10.1016/s1097-2765(03)00070-4. View

15.

Beinke S, Deka J, Lang V, Belich M, Walker P, Howell S . NF-kappaB1 p105 negatively regulates TPL-2 MEK kinase activity. Mol Cell Biol. 2003; 23(14):4739-52. PMC: 162207. DOI: 10.1128/MCB.23.14.4739-4752.2003. View

16.

Eliopoulos A, Wang C, Dumitru C, Tsichlis P . Tpl2 transduces CD40 and TNF signals that activate ERK and regulates IgE induction by CD40. EMBO J. 2003; 22(15):3855-64. PMC: 169059. DOI: 10.1093/emboj/cdg386. View

17.

Gandara M, Lopez P, Hernando R, Castano J, Alemany S . The COOH-terminal domain of wild-type Cot regulates its stability and kinase specific activity. Mol Cell Biol. 2003; 23(20):7377-90. PMC: 230324. DOI: 10.1128/MCB.23.20.7377-7390.2003. View

18.

Lang V, Symons A, Watton S, Janzen J, Soneji Y, Beinke S . 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; 24(12):5235-48. PMC: 419892. DOI: 10.1128/MCB.24.12.5235-5248.2004. View

19.

Waterfield M, Jin W, Reiley W, Zhang M, Sun S . IkappaB kinase is an essential component of the Tpl2 signaling pathway. Mol Cell Biol. 2004; 24(13):6040-8. PMC: 480897. DOI: 10.1128/MCB.24.13.6040-6048.2004. View

20.

Nolen B, Taylor S, Ghosh G . Regulation of protein kinases; controlling activity through activation segment conformation. Mol Cell. 2004; 15(5):661-75. DOI: 10.1016/j.molcel.2004.08.024. View