Cancer Letters

Cancer Letters

Volume 304, Issue 2, 28 May 2011, Pages 80-89
Cancer Letters

Mini-review
Tpl2 kinase signal transduction in inflammation and cancer

https://doi.org/10.1016/j.canlet.2011.02.004Get rights and content

Abstract

The activation of mitogen-activated protein kinases (MAPKs) is critically involved in inflammatory and oncogenic events. Tumor progression locus 2 (Tpl2), also known as COT and MAP3 kinase 8 (MAP3K8), is a serine-threonine kinase with an important physiological role in tumor necrosis factor, interleukin-1, CD40, Toll-like receptor and G protein-coupled receptor-mediated ERK MAPK signaling. Whilst the full characterization of the biochemical events that lead to the activation of Tpl2 still represent a major challenge, genetic and molecular evidence has highlighted interesting interactions with the NF-κB network. Here, we provide an overview of the multifaceted functions of Tpl2 and the molecular mechanisms that govern its regulation.

Introduction

Mitogen-activated protein kinases (MAPKs) are critically involved in the pathogenesis of a plethora of inflammatory and malignant diseases. There are three main families of MAPKs in mammals, the extracellular signal regulated kinases (ERKs), cJun N-terminal kinases (JNKs) and p38 MAPKs which function upstream of numerous kinases, transcription factors and other effector proteins and are important regulators of immune, oncogenic and cell death pathways. The highly conserved cascade that leads to MAPK activation involves a dual specificity MAPK kinase (MAP2K) that phosphorylates MAPK on Serine/Tyrosine residues and a MAP3K that acts upstream of MAP2K and phosphorylates it on Serine/Threonine residues. Activation of the limited number of MAPKs is controlled by an abundance of MAP3Ks which provide the stimulus and cell context specificity of signaling responses.

Tpl2 is a MAP3K with a major role in the activation of the ERK MAPK through direct phosphorylation of MEK, the ERK kinase. The Tpl2 gene locus encodes for two protein isoforms of 58 (Tpl2 long; Tpl2L) and 52 kDa (Tpl2 short; Tpl2S), generated by the utilization of alternative translation start sites at methionine 1 and methionine 30. The encoded proteins contain a serine/threonine kinase domain, an amino-terminal region with unknown function and a carboxy-terminal tail which carries sequences important for Tpl2 stability and regulation of catalytic activity (Fig. 1). There is 94% similarity in the amino-acid sequences of mouse and rat Tpl2 compared to human, allowing for the establishment of reliable models to dissect the impact of this kinase on immune and inflammatory responses and oncogenesis. Indeed, a plethora of recent studies reveal major roles for Tpl2 in inflammation and cancer. Here, we review the pleiotropic functions of Tpl2 and the molecular mechanisms involved in its regulation.

Section snippets

Tpl2 in innate immune responses

Innate immune responses, orchestrated by macrophages, dendritic cells, natural killer cells and neutrophils, represent the first line of defense against infections. Crucial to this process is the detection of pathogen-associated molecules by Toll-like receptors (TLRs), such as the recognition of the bacterial cell wall component lipopolysaccharide (LPS) by TLR4. In a seminal paper published in Cell in 2000, the team of Philip Tsichlis at Thomas Jefferson University (Philadelphia, USA) provided

Tpl2 is a potent kinase with broad range substrate specificity

Early studies aiming to define the biological role of Tpl2 revealed its wide range of substrate specificity. When overexpressed, Tpl2 as well as the oncogenic Tpl2ΔC mutant are able to engage a plethora of signaling pathways and to act in concert with other kinases and signaling molecules to influence cell survival and proliferation. The predominant pathway that is activated by ectopic expression of Tpl2 is the one leading to activation of ERK1 and ERK2 with MEK being its direct substrate [29],

Concluding remarks

Tpl2 is a MAP3 kinase at the crossroad of various pro-inflammatory and oncogenic signals. Whilst the mechanism of its activation is still unclear, an interesting interplay with positive (IKKβ) and negative (p105) regulators of the NF-κB pathway emerges which may explain some of the stimulus and cell-specific effects of Tpl2 ablation. It also generates important questions that are relevant to and bridge the NF-κB and MAPK research fields. With hindsight, it would be important to define the

Conflicts of interest

None declared.

Acknowledgments

This work was supported by the European Commission research program INFLA-CARE (EC contract number 223151) to A.G.E.

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