Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

TPL2

  • Dimitra Virla
  • Christos Tsatsanis
  • Aristides G. Eliopoulos
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_626

Synonyms

Historical Background

The Tpl2 gene, also known as COT and MAP3K8 (Vougioukalaki et al. 2011), was independently discovered by three research teams in the early 1990s. COT (Cancer Osaka thyroid) was initially described by Miyoshi et al. as a putative human proto-oncogene, isolated from a human thyroid carcinoma cell line and discovered to have a rearranged 3′ end in the last coding exon (Miyoshi et al. 1991). The rat homologue of COT, named tumor progression locus (Tpl2), was identified by Tsichlis et al. as a proto-oncogene that is activated by provirus integration in Moloney murine leukemia virus (MoMuLV)-induced T-cell lymphomas and capable to transform NIH 3T3 fibroblasts in vitro (Patriotis et al. 1993). In mice, the Tpl2 gene locus is also targeted by provirus insertion in mouse mammary tumor virus (MMTV)-associated mammary carcinomas in mice (Erny et al. 1996). In all cases, provirus insertion occurs in the last intron of the gene and gives rise to a carboxy-terminally truncated TPL2 protein, termed TPL2-ΔC. In 1993, the normal cot analogue was cloned and found to encode for an ORF of 467 aa that generates two protein isoforms of 58 and 52 kDa through the utilization of alternative translation initiation sites at methionine 1 (M1-TPL2) and methionine 30 (M2-TPL2) (Fig. 1) (Aoki et al. 1993). Both isoforms of TPL2 are mainly localized in the cytoplasm; however, a pool of TPL2 is detected in the nuclear fraction (Choi et al. 2008; Kanellis et al. 2015; Khanal et al. 2009). In comparison to wild-type TPL2 (M1-TPL2), expression of TPL2-ΔC is associated with elevated transforming activity and signaling capacity indicating that removal of the C-terminal domain is required for its oncogenic potential (Ceci et al. 1997). Three mechanisms have been proposed to explain this phenomenon. First, the deletion abolishes the intermolecular interaction between the C-terminal tail and the kinase domain of TPL2, thus increasing its catalytic activity (Ceci et al. 1997). Second, the truncated protein lacks an amino acid sequence called “degron” (aa 435–457) that targets wild-type TPL2 for proteasomal degradation (Gandara et al. 2003). Finally, the C-terminus of TPL2 is important for the efficient interaction with other proteins that regulate its stability and kinase activity such as the p50 NF-κB precursor NF-κB1/p105, which functions to sequester TPL2 from its substrates (Fig. 1) (Beinke et al. 2003; Waterfield et al. 2003).
TPL2, Fig. 1

TPL2 primary structure and phosphorylation sites. The normal Tpl2 gene locus encodes two proteins with MW of 58 and 52 kDa through the utilization of alternative translation initiation sites at methionine 1 and methionine 30. The catalytic domain of TPL2 kinase activity is bordered by the N-terminus and C-terminus. Several phosphorylation sites have been identified within the kinase domain of TPL2, including Thr290 and Ser400. The inducible phosphorylation of TPL2 on Thr290 and Ser400 is essential for TPL2 activation. Ser62 becomes autophosphorylated and has been proposed to confer maximal TPL2 activation. The C-terminus carries a reported “degron” sequence (aa 435–457) that targets TPL2 for proteasomal degradation. NF-κB1 (p105) binds to and masks “degron,” thus regulating TPL2 stability

TPL2-Mediated Signal Transduction

The homology of TPL2 serine/threonine kinase domain to that of Saccharomyces cerevisae gene product STE11 which is a mitogen-activated protein kinase kinase kinase (MAP3K) was the first indication that TPL2 may act as a MAP3K. The mitogen-activated protein kinase (MAPK) cascades are evolutionarily conserved signaling pathways in eukaryotic cells. There are four major MAPKs in mammals: extracellular signal-regulated kinases (ERK1/2), extracellular signal-regulated kinase 5 (ERK5), c-Jun N-terminal kinases (JNK1/2/3), and p38 MAPKs (α, β, γ, δ). When overexpressed, TPL2 activates all MAPK pathways by directly phosphorylating their upstream kinases MEK1/2, MKK4, MKK6, and MEK5, respectively (Ceci et al. 1997; Chiariello et al. 2000; Salmeron et al. 1996). Overexpression of TPL2 also mediates NF-AT (nuclear factor of activated T cells) activation through MEK, PKCζ, and calcineurin-dependent mechanisms and induces NF-κB through the related MAP3 kinase NIK (Gomez-Casero et al. 2007; Lin et al. 1999; Tsatsanis et al. 1998a, b). In addition, DNA damage induced by ultraviolet B (UVB) has been reported to stimulate TPL2 phosphorylation and activation triggering its translocation to the nucleus where it phosphorylates histone H3 at Ser10 and induces c-Fos transcriptional activation (Choi et al. 2008). When overexpressed in EGF-stimulated cells, TPL2 mediates the interaction between PP2A (protein phosphatase 2A) and p53, thereby inhibiting the phosphorylation of p53 at Ser15 which is important for its stabilization (Khanal et al. 2009).

Endogenous TPL2 is inactive in the absence of extracellular signals, raising the question of whether overexpression of TPL2 can lead to artifactual target protein phosphorylation. Generation of a tpl2 −/− mouse strain by Tsichlis’ laboratory clarified these concerns. Studies in tpl2 −/− mice suggested that TPL2 has an important physiological role in ERK signaling downstream of a plethora of receptors involved in innate and adaptive immunity including TLRs, CD40, TNF, and IL-1 receptors (Banerjee et al. 2008; Das et al. 2005; Dumitru et al. 2000; Eliopoulos et al. 2003; Stafford et al. 2006). In addition to ERK, TPL2 has been shown to contribute to JNK activation in TNF-stimulated fibroblasts and to be required for NF-κB transactivation by mediating the MSK1-dependent phosphorylation of the RelA (p65) NF-κB subunit at Ser276 (Das et al. 2005). A recent study demonstrated that a nuclear fraction of TPL2 may serve as a physical and functional partner of nucleophosmin (NPM/B23). NPM is a major nucleolar phosphoprotein that influences p53 responses to DNA damage and nucleolar stress, cellular activities that are linked to malignancy. TPL2 mediates the phosphorylation of a fraction of NPM at Thr199, an event required for its proteasomal degradation and maintenance of steady-state NPM levels (Kanellis et al. 2015).

Regulation of TPL2 Signaling

The precise molecular mechanisms which regulate TPL2 activity are a subject of ongoing investigations. In steady-state conditions, the entire pool of TPL2 associates with p105 NF-κB1 (Beinke et al. 2003; Belich et al. 1999). Through this molecular interaction, NF-κB1 stabilizes TPL2 by masking the “degron” sequence but also inhibits its activity by preventing access to MEK1, the ERK. The signal-induced phosphorylation of NF-κB1 at Ser927 and Ser932 by IKKβ leads to K48-linked ubiquitination of p105 NF-κB1 by SCF-βTrCP and triggers its degradation by the 26S proteasome and release of TPL2 from the complex. Liberated TPL2 is active toward MEK1 but unstable and consequently undergoes rapid degradation via the proteasome, thus restricting prolonged activation of ERK signaling (Waterfield et al. 2003). In addition, the A20-binding inhibitor of NF-κB2 (ABIN-2) has been shown to interact directly with TPL2, forming a ternary complex that includes p105 NF-κΒ1. Studies with primary cells from ABIN2 −/− mice revealed that ABIN-2 is important for stabilizing TPL2 but is not required for its activation (Fig. 2) (Beinke et al. 2003; Papoutsopoulou et al. 2006).
TPL2, Fig. 2

Intracellular signaling cascade involved in TPL2 activation downstream of Toll-like receptors (TLRs). The main cell signaling events involved in TPL2 activation, from TLR engagement by pathogen-associated molecular patterns (PAMPs) to the activation of key transcription factors. At steady state, TPL2 forms a complex with the cytoplasmic NF-κB inhibitory protein p105 and ABIN-2. The p105-TPL2 complex is functionally inactive, and its activation involves signal-induced (PAMP) p105 degradation and the dissociation of TPL2 from the complex. The signal-induced TPL2 signaling requires IKKβ, which phosphorylates p105 at Ser927 and Ser932 triggering its proteolysis and TPL2 at Thr290and Ser400 required for kinase activation. Other TPL2 phosphorylation events (Ser443 or Ser62) also occur while in complex with NF-κB1/ABIN-2. In addition, TLR stimulation induces IKK phosphorylation of TPL2 at S400 and TPL2 at S443 autophosphorylation, which triggers the recruitment of 14-3-3 to the C-terminus of TPL2, enhancing its MEK activity, which is essential for TPL2 activation of ERK1/2. Liberated TPL2 is active toward MEK1 but unstable and undergoes rapid degradation via the proteasome, thereby restricting prolonged activation of MEK/ERK signaling. MEK in turn phosphorylates ERK resulting in activation of various transcription factors that may force the transcription of inflammation-related genes. ERK also mediates the phosphorylation of other kinases, such as MSK1, which contributes to the activation of the transcription factors RelA (p65 NF-κB) and CREB by MSK1-dependent phosphorylation at Ser276 and Ser133, respectively. In addition, ERK is responsible for the posttranscriptional regulation of TNF synthesis through the expression of mRNA export receptor Tip-associated protein (TAP) and phosphorylation of TNF-converting enzyme (TACE). The 14-3-3 binding to TPL2 is also crucial for subsequent TNF induction, which is regulated independently of ERK1/2 activation. Pro-inflammatory cytokines such as TNF and IL-1β activate TPL2 also through IKKβ-mediated signals

TPL2 is subject to phosphorylation at multiple sites including Thr290, Ser400, and Ser62 (Cho et al. 2005; Robinson et al. 2007; Stafford et al. 2006). Phosphorylation at Thr290 and Ser400 are stimulus induced and are necessary for TPL2 activation (Cho et al. 2005; Robinson et al. 2007). Both Thr290 and Ser400 phosphorylations take place prior to the dissociation of the catalytic subunit from NF-κB1/ABIN-2. The phosphorylation at Thr290 is required for its release from p105 NF-κB1 and has been proposed to be mediated by IKKβ-dependent signals (Cho et al. 2005) or that it is an autophosphorylation event (Rousseau et al. 2008). The phosphorylation of Ser400 is believed to contribute to kinase activation likely through the induction of a conformational change which releases the inhibitory intermolecular interaction between the C-terminal tail and the kinase domain of TPL2 and is mediated by IKKβ-dependent signals (Robinson et al. 2007). Ser62 becomes autophosphorylated following IL-1 stimulation and has been suggested to contribute to maximal TPL2 activation (Stafford et al. 2006). A recent study provided a novel mechanistic insight into the activation of TPL2 signaling by demonstrating that TPL2 Ser400 phosphorylation by IKKβ and TPL2 Ser443 autophosphorylation synergized to trigger TPL2 association with 14-3-3. Recruitment of 14-3-3 to the phosphorylated C-terminus stimulated TPL2 kinase activity toward MEK1, the ERK. The binding of 14-3-3 to TPL2 was also essential for LPS-induced production of TNFα by macrophages, which is regulated by TPL2 independently of ERK1/2 activation (Ben-Addi et al. 2014).

The Functional Role of TPL2 Kinase in Inflammation and Immunity

TPL2 kinase is widely expressed in the spleen, thymus, lungs, intestine, liver, brain, testis, skeletal muscles, and pancreas. The generation of TPL2 knockout mice (Dumitru et al. 2000) allowed the analysis of the physiological role of TPL2 kinase in inflammatory and immune responses. TPL2-deficient mice were found to be resistant to LPS-induced endotoxin shock because of a defect in ERK activation, resulting in lower TNFα and COX-2/prostaglandin E2 production by macrophages (Dumitru et al. 2000; Eliopoulos et al. 2002b). The TPL2/MEK/ERK signaling axis regulates TNF expression at a posttranscriptional level by promoting the export of Tnf mRNA from the nucleus through the expression of mRNA export receptor Tip-assοciated protein (TAP) and phosphorylation of TNFα-converting enzyme (TACE) on Thr735 which is required for the pre-TNFα appearance at the cell membrane and the processing of pre-TNFα to TNFα indicating the significance of TPL2 in the posttranscriptional regulation of TNFα in macrophages (Fig. 2) (Dumitru et al. 2000; Rousseau et al. 2008). TPL2 is also indispensable for mRNA and protein expression of IL-1β and IL-10 following stimulation of macrophages and dendritic cells with LPS or CpG (Kaiser et al. 2009; Mielke et al. 2009). In addition, TPL2 is involved in ERK activation in TLR4- or TLR9-stimulated hepatic Kupffer and stellate cells, leading to induction of the fibrogenic genes IL-1β and TIMP-1 with concomitant reduction in liver fibrosis in tpl2−/− mice (Perugorria et al. 2013). Additionally, genetic ablation or pharmacological inhibition of TPL2 protected mice from antiplatelet antibody-induced thrombocytopenia, a model of idiopathic thrombocytopenic purpura (Kyrmizi et al. 2013). Mechanistically, this phenotype is linked to the requirement for TPL2 as a transducer of FcγR-mediated MEK/ERK1/2 signals leading to cytoplasmic Ca2+ influx, induction of pro-inflammatory cytokine production (IL-6, TNFα), and phagocytosis (Kyrmizi et al. 2013). Moreover, TPL2-deficient mice have also been studied in the context of a TNF-induced Crohn’s-like inflammatory bowel disease (IBD) mouse model (TNFΔARE mice). These mice exhibited attenuated progression of the disease, ablated TNF-induced ERK activation in macrophages, and low numbers of memory CD4+ and peripheral CD8+ lymphocytes, showing that TPL2 kinase regulates the lymphocytic response during progression of IBD (Kontoyiannis et al. 2002). TPL2 negatively regulates TLR induction of IL-12 p70 and IFN-β (interferon-β), independently, at least in part, of any effects on IL-10 production (Kaiser et al. 2009). In contrast, tpl2−/− mice display increased susceptibility to infection with Listeria monocytogenes, a fact that correlates well with decreased production of IL-1β which is indispensable for optimal anti-listeria responses (Mielke et al. 2009). Likewise, the absence of TPL2 in macrophages (but not T cells) leads to elevated inflammation, TH2 cell responses, and exacerbated fibrosis in mice subjected to Schistosoma mansoni infection (Kannan et al. 2016). Collectively, TPL2 signaling appears to mediate both pro- and anti-inflammatory effects by regulating innate immune responses

Similarly, TPL2 contributes either positively or negatively to adaptive immune responses. In particular, TPL2 is required for the transduction of ERK activation signals initiated by CD40 engagement and contributes to IgE synthesis in response to IL-4 and anti-CD40 mAb stimulation in B lymphocytes (Eliopoulos et al. 2003). In certain disease models, TPL2 deficiency exacerbates the inflammatory response. In this regard, in a mouse model of allergen (ovalbumin)-induced inflammation, tpl2 −/− mice produce considerably higher levels of both OVA-specific and total IgE compared to tpl2 +/+ mice. It was proposed that the upregulation of IgE is correlated with increased secretion of TH2 cytokines such as IL-4 and IL-5 and decreased secretion of IFN-γ by tpl2 −/− T cells exposed to ovalbumin (Watford et al. 2008). The shift toward TH2 polarization of the T-cell response to OVA in tpl2 −/− mice is in agreement with studies showing that the defense of TPL2 knockout mice to the intracellular parasite Toxoplasma gondii is impaired because of a T-cell autonomous TH2 shift of the T-cell response (Watford et al. 2008). Moreover, Sugimoto et al. showed that bone marrow-derived DCs from tpl2 −/− mice produce significantly more IL-12 in response to CpG-DNA than those from WT mice and showed TH1-skewed antigen-specific immune responses upon Leishmania major infection in vivo (Sugimoto et al. 2004). In addition, TPL2 does not only contribute to the differentiation of TH1 cell subset but also induces the production of TH17-promoting cytokine IL-23 indicating that TPL2 may positively regulate TH17 cell differentiation (Kakimoto et al. 2010). Indeed, the positive role of TPL2 in IL-17 signaling was demonstrated in experimental autoimmune encephalomyelitis (EAE) as it regulates both the onset and severity of disease, highlighting its therapeutic importance in TH1- and TH17-driven diseases such as multiple sclerosis and psoriasis and its function in stromal cells (Sriskantharajah et al. 2014). In this regard, it is also known that the instability of regulatory T (Treg) cells is implicated in the pathogenesis of autoimmune diseases. Of relevance, the TPL2/MEK/ERK signaling pathway downregulates the Foxp3 DNA-binding activity, thereby destabilizing the Treg lineage (Guo et al. 2014). A recent study uncovered a novel function of TPL2 as a key mediator of invariant natural killer T cell (iNKT cell) signal transduction and function in the liver. iNKT cells represent a major subset of innate-like T lymphocytes that bridge innate and adaptive immunity and operate as orchestrators of hepatic inflammation underpinning liver damage. Vyrla et al. reported that TPL2 ablation in the mouse ameliorates immune-mediated hepatitis and revealed ERK and Akt as the TPL2-regulated signaling pathways responsible for the production of the iNKT cell effector cytokines IL-4 and IFN-γ through the activation of the transcription factors JunB and NF-AT (Vyrla et al. 2016).

In addition to its function in hematopoietic cell lineages, TPL2 is also implicated in the regulation of nonmyeloid cells. Thus, in acute pancreatitis, nonmyeloid expression of TPL2 regulates inflammation by mediating pro-inflammatory gene expression and the generation of neutrophil chemoattracting factors (MCP-1, MIP-2, and IL-6). Furthermore, another study reported that genetic and pharmacologic inhibition of TPL2 is protective in a mouse model of ventilator-induced lung injury, ameliorating both high-permeability pulmonary edema and lung inflammation evidenced by decreased concentrations of proteins, IL-6, and MIP-2 in bronchoalveolar lavage fluid (BALF) (Kaniaris et al. 2014). The impact of TPL2 was also shown in ligature-induced periodontitis. Thus, TPL2 was shown to be involved in the regulation of RANKL, TNFα, COX-2, prostaglandin E2 (PGE2), and IL-1β affecting the progression of alveolar bone loss and osteoclastogenesis in periodontal tissue during experimental periodontitis (Ohnishi et al. 2010). In addition, following epithelial injury-induced colitis, intestinal myofibroblasts (IMFs) were reported to function as sensors of inflammatory signals and activate, through TPL2, the COX-2/PGE2 signaling pathway that regulates epithelial homeostatic responses (Roulis et al. 2014). TPL2 kinase is found upregulated in adipose tissue in obesity and therefore controls obesity-associated metabolic dysfunction as tpl2 −/− mice exhibited improved insulin sensitivity with enhanced glucose uptake in skeletal muscle and increased suppression of glucose and lipid output in the liver (Jager et al. 2009). Thus, TPL2 kinase may have a role in adipose tissue dysfunction in obesity and type 2 diabetes, as TPL2 was found to be expressed in INS-1E β-cells of mouse and human islets, to be activated and upregulated by inflammatory stimuli, and to mediate ERK1/2, JNK, and p38 MAPK signals (Varin et al. 2016).

The Impact of TPL2 Kinase on Cancer

TPL2 kinase plays contradictory roles in cancer with tumor-promoting or tumor-suppressing attributes. Early studies showed that transgenic mice expressing TPL2-ΔC under the control of a T-cell-specific promoter develop T-cell lymphoblastic lymphomas by the age of 3 months, whereas expression of wild-type TPL2 has no effect (Ceci et al. 1997). Elevated TPL2 expression has been reported in large granular T lymphocyte proliferative disorders (Christoforidou et al. 2004), gastric colon adenocarcinomas (Ohara et al. 1995), Epstein-Barr virus (EBV)-related nasopharyngeal carcinoma, and Hodgkin’s disease (Eliopoulos et al. 2002a), but C-terminal deletions in TPL2 have not been detected in human malignancies (Vougioukalaki et al. 2011). Intriguingly, the expression of TPL2 is reduced in other tumor types, including lung cancer and various lymphomas (Vougioukalaki et al. 2011) (Gkirtzimanaki et al. 2013), prompting the examination of the physiological role of TPL2 in carcinogenesis by utilizing global and tissue-specific knockout mice.

Tpl2−/− animals bred onto an MHC Class I-restricted T-cell antigen receptor transgenic (TCR2C) background were found to develop CD8+ T-cell lymphomas because of a defect in ERK-dependent CTLA4 induction that renders CD8+ T lymphocytes hyperproliferative in response to TCR signals (Tsatsanis et al. 2008). Genetic ablation of TPL2 has also been reported to result in accelerated chemical-induced skin carcinogenesis coupled with exaggerated edema and inflammatory cell infiltration (Decicco-Skinner et al. 2011). Similarly, the absence of TPL2 facilitated mutated Apc-driven colon tumorigenesis that was associated with downregulation of IL-10 levels and decreased numbers of regulatory T cells (Tregs) in the intestinal mucosa of tpl2−/− mice (Serebrennikova et al. 2012). In a mouse model mimicking colitis-propelled colorectal cancer, TPL2 ablation also led to increased number and size of tumors. This effect was attributed to upregulation of HGF production by intestinal myofibroblasts resulting in enhanced epithelial proliferation and decreased apoptosis (Koliaraki et al. 2012). Moreover, tpl2−/− mice displayed accelerated onset and multiplicity of urethane-induced lung tumors in mice, in line with reduced levels of TPL2 expression correlating with poor lung cancer patient survival (Gkirtzimanaki et al. 2013). Of relevance to these findings, TPL2 were reported to antagonize oncogene-induced cell transformation and survival in lung epithelial cells through JNK-dependent upregulation of nucleophosmin (NPM), which is required for the optimal p53 response to genotoxic stress (Kanellis et al. 2015). Collectively, the aforementioned reports point to a tumor suppressor role of TPL2 in vivo.

In contrast, however, other studies indicate that TPL2 may promote tumor growth. Thus, Gruosso et al. reported that TPL2 is accumulated in high-grade serous ovarian carcinomas (HGSC) and confers pro-tumorigenic effects that are mainly mediated by the MEK/ERK/p90RSK pathway. Thus, TPL2 may serve as a predictive marker for the efficiency of MEK inhibitors, which represents a promising new therapeutic alternative for HGSC patients (Gruosso et al. 2015). Along the same line, mutated BRaf-bearing human melanomas that develop resistance to Raf inhibitors were found to possess higher TPL2 copy numbers (Johannessen et al. 2010). In this context, suppression of TPL2 expression or activity may resensitize melanoma cells to Raf inhibitors. Increased expression and catalytic activity of TPL2 has also been reported to promote androgen depletion-independent (ADI) prostate cancer growth through the activation of the MEK/ERK and NF-κB signaling pathways (Jeong et al. 2011). In another study, a TLR2/6-dependent TPL2 pathway was found to positively regulate the inflammatory milieu of myeloma niche by promoting the “inflammatory switch” of macrophages to myeloma-associated monocytes/macrophages (Hope et al. 2014).

There is also evidence supporting a role for TPL2 in tumor metastasis-related processes. Thus, IL-33 activates the MEK/ERK, JNK-c-Jun, and STAT3 signaling pathways via TPL2, followed by increased AP-1 and STAT3 transcriptional activities which direct IL-33-induced EMT and support tumor-associated inflammation in the microenvironment of breast tumors (Kim et al. 2015). TPL2 also transduces proteinase-activated receptor 1 (PAR1) signals to regulate the expression of MMPs and other secreted molecules both in fibroblasts and tumor cells, promoting cell transformation, tumor metastasis, and angiogenesis (Hatziapostolou et al. 2008). In this regard, TPL2 is indispensable for PAR1 to engage a Rac1 and focal adhesion kinase (FAK)-dependent pathway, to activate ERK and JNK1, and to promote reorganization of the actin cytoskeleton and cell migration (Hatziapostolou et al. 2011). The in vivo relevance of these findings is supported by the elevated levels of TPL2 in metastatic castration-resistant prostate cancers compared to localized disease in humans and by the increased metastatic potential of ADI prostate cancer cells engineered to overexpress TPL2 that were orthotopically implanted in mice (Lee et al. 2015).

Summary

TPL2 is a serine/threonine protein kinase with an obligatory role in the transduction of Toll-like receptor, death receptor, and G-protein-coupled receptor-mediated ERK/MAPK signaling. TPL2 catalytic activity and stability are closely intertwined and regulated through the interaction of TPL2 with p105 NF-κB1 and ABIN-2. The phosphorylation of TPL2 depends on active IKKβ, an obligatory component of the canonical NF-κF pathway. The generation of TPL2 knockout mice has contributed considerably to the delineation of the physiological role of TPL2 in innate and adaptive immune responses. Genetic and pharmacological studies have described both positive and negative effects of TPL2 in inflammatory pathologies and malignancies that warrant further analyses of the molecular mechanisms that govern its regulation and function. Along these lines, several pharmaceutical companies including Wyeth/Pfizer, Abbott, and Novartis are developing small-molecule TPL2 inhibitors with some of them showing relative specificity in vitro and promising anti-inflammatory efficacy in vivo (Gutmann et al. 2015; Hall et al. 2007).

Notes

Acknowledgments

Dimitra Vyrla was supported through the action “Funding of Postdoctoral Researchers” of the Operational Program “Development of Human Resources, Education and Lifelong Learning,” 2014–2020, implemented by State Schlolarships Foundation (IKY) and cofinanced by the European Social Fund and the Greek State.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Dimitra Virla
    • 1
  • Christos Tsatsanis
    • 3
  • Aristides G. Eliopoulos
    • 1
    • 2
  1. 1.Molecular and Cellular Biology Laboratory, Division of Basic SciencesUniversity of Crete Medical SchoolHeraklionGreece
  2. 2.Institute for Molecular Biology and Biotechnology, Foundation of Research and Technology Hellas (FORTH)HeraklionGreece
  3. 3.Department of Clinical ChemistryUniversity of Crete Medical SchoolHeraklionGreece