Mini-reviewTpl2 kinase signal transduction in inflammation and cancer
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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2021, Cell ReportsCitation Excerpt :It is critical for the production of inflammatory mediators, such as IL-1, Cox2, PGE2, TNF, and IL-6 (Das et al., 2005; Dumitru et al., 2000; Eliopoulos et al., 2002; McNab et al., 2013; Pattison et al., 2016), and it regulates IL-10, IL-12, type I interferon (IFN), and hepatocyte growth factor (HGF) production in different models of inflammation (Kaiser et al., 2009; Koliaraki et al., 2012; Papoutsopoulou et al., 2006; Tomczak et al., 2006). Although Tpl2 mutations in human cancers are considered rare events (Clark et al., 2004; Newman et al., 2019), it has been reported to be overexpressed or constitutively active in various cancer types and inflammatory disorders (Vougioukalaki et al., 2011). It has been widely suggested that Tpl2 is an attractive target to promote anti-cancer and anti-inflammatory strategies for specific cancer types and inflammatory conditions, due to its broad regulation of immune responses (Gantke et al., 2012; Lee et al., 2015).
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These authors contributed equally to the work.