ERK5 Activates NF-κB in Leukemic T Cells and Is Essential for Their Growth In Vivo

Garaude, Johan; Cherni, S.; Kaminski, Sandra; Delépine, Etienne; Chable‐Bessia, Christine; Benkirane, Monsef; Borges, Joana; Pandiella, Atanasio; Íñiguez, Miguel A.; Fresno, Manuel; Hipskind, Robert A.; Villalba, Martín

doi:10.4049/jimmunol.177.11.7607

Cited by 58 publications

(81 citation statements)

References 64 publications

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“…Previous reports have indicated that ERK5 activation reduces cellular inflammatory responses by inhibiting the NF‐κB pathway 14, 32. In contrast, in the setting of leukemic T lymphocytes33 or acute inflammation induced by Toll‐like receptor ligands or ischemia‐reperfusion injury,34 ERK5 activation enhances NF‐κB signaling. In this study, we showed that anagliptin treatment impaired the activation of the NF‐κB pathway in macrophages in an ERK5‐dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation

Ikedo

Minami

Kataoka

et al. 2017

JAHA

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BackgroundChronic inflammation plays a key role in the pathogenesis of intracranial aneurysms (IAs). DPP‐4 (dipeptidyl peptidase‐4) inhibitors have anti‐inflammatory effects, including suppressing macrophage infiltration, in various inflammatory models. We examined whether a DPP‐4 inhibitor, anagliptin, could suppress the growth of IAs in a rodent aneurysm model.Methods and Results IAs were surgically induced in 7‐week‐old male Sprague Dawley rats, followed by oral administration of 300 mg/kg anagliptin. We measured the morphologic parameters of aneurysms over time and their local inflammatory responses. To investigate the molecular mechanisms, we used lipopolysaccharide‐treated RAW264.7 macrophages. In the anagliptin‐treated group, aneurysms were significantly smaller 2 to 4 weeks after IA induction. Anagliptin inhibited the accumulation of macrophages in IAs, reduced the expression of MCP‐1 (monocyte chemotactic protein 1), and suppressed the phosphorylation of p65. In lipopolysaccharide‐stimulated RAW264.7 cells, anagliptin treatment significantly reduced the production of tumor necrosis factor α, MCP‐1, and IL‐6 (interleukin 6) independent of GLP‐1 (glucagon‐like peptide 1), the key mediator in the antidiabetic effects of DPP‐4 inhibitors. Notably, anagliptin activated ERK5 (extracellular signal–regulated kinase 5), which mediates the anti‐inflammatory effects of statins, in RAW264.7 macrophages. Preadministration with an ERK5 inhibitor blocked the inhibitory effect of anagliptin on MCP‐1 and IL‐6 expression. Accordingly, the ERK5 inhibitor also counteracted the suppression of p65 phosphorylation in vitro.ConclusionsA DPP‐4 inhibitor, anagliptin, prevents the growth of IAs via its anti‐inflammatory effects on macrophages.

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Section: Discussionmentioning

confidence: 99%

Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation

Ikedo

Minami

Kataoka

et al. 2017

JAHA

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“…Similarly, we observed that Src and Abl kinases regulate ERK5 activity (Figure 6c). Since no specific inhibitor is currently available, the role for ERK5 was evaluated by downregulating the kinase with a RNA interference approach (Figure 6d) (Garaude et al, 2006). Cells were infected with retroviruses expressing shRNA specific to ERK5 that allows more than 50% reduction in both kinase activity and protein level.…”

Section: Abl Regulates Erk5 Activation For Src-induced Transformationmentioning

confidence: 99%

The tyrosine kinase Abl is required for Src-transforming activity in mouse fibroblasts and human breast cancer cells

et al. 2007

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The cytoplasmic tyrosine kinase Src has been implicated in signal transduction induced by growth factors and integrins. Src also shows oncogenic activity when deregulated. Accumulating evidence indicates that the tyrosine kinase Abl is an important substrate for Src signalling in normal cells. Here we show that Abl is also required for Src-induced transformation of mouse fibroblasts. Abl does not mediate tyrosine phosphorylation of Stat3 and Shc, two important regulators of Src oncogenic activity. In contrast, Abl controls the activation of the small GTPase Rac for oncogenic signalling and active Rac partly rescued Src transformation in cells with inactive Abl. Moreover, Abl mediates Src-induced extracellular regulated kinase 5 (ERK5) activation to drive cell transformation. Finally, we find that Abl/Rac and Abl/ERK5 pathways also operate in human MCF7 and BT549 breast cancer cells, where neoplastic transformation depends on Src-like activities. Therefore, Abl is an important regulator of Src oncogenic activity both in mouse fibroblasts and in human cancer cells. Targeting these Abl-dependent signalling cascades may be of therapeutic value in breast cancers where Src-like function is important.

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“…Relative to other tissues, ERK5 is highly expressed in both the thymus and the spleen [21]. In addition, three studies have shown that ERK5 can be activated in T cells downstream of TCR-mediated signalling [28][29][30]. It has also been reported that MEKK2, an activator of the ERK5 pathway, can interact with LAD/RIBP, an Lck-interacting adaptor protein, which is recruited to the TCR complex [18].…”

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confidence: 99%

ERK5 regulation in naïve T‐cell activation and survival

et al. 2008

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ERK5 has been implicated in regulating the MEF2-dependent genes Klf2 and nur77 downstream of the TCR and the maintenance of expression of CD62L on peripheral T cells. Based on this data, knockout of ERK5 would be predicted to compromise T-cell development and the maintenance of T cells in the periphery. Using an ERK5 conditional knockout, driven by CD4-CRE or Vav-CRE transgenes resulting in the loss of ERK5 in T cells, we have found that ERK5 is not required for T-cell development. In addition, normal numbers of T cells were found in the spleens and lymph nodes of these mice. We also find that TCR stimulation is not a strong signal for ERK5 activation in primary murine T cells. ERK5 was found to contribute to the induction of Klf2 but not nur77 mRNA following TCR activation. Despite the reduction in Klf2 mRNA, no effect was seen in ERK5 knockouts on either the mRNA levels for the Klf2 target genes CD62L, CCR7 and S1P, or the cell surface expression of CD62L. These results suggest that while ERK5 does contribute to Klf2 regulation in T cells, it is not essential for the expression of CD62L or T-cell survival. IntroductionMitogen-activated protein kinase (MAPK) cascades are important mediators of cellular responses to a variety of signals, including growth factors, cytokines and cellular stresses. Fourteen MAPK isoforms have been identified in mammalian cells, which can broadly be divided into four groups, the classical MAPK (ERK1 and ERK2), p38 MAPK, JNK and atypical MAPK, which include ERK5, ERK3 and ERK8 [1][2][3][4][5].ERK5 is an unusual MAPK, as it contains a large C-terminal domain in addition to the MAPK domain [2,6,7]. The precise role of the C-terminal domain is unclear; however, it has been shown to be involved in the regulation of ERK5 sub-cellular localisation [8]. The C-terminal domain has also been suggested to act as a transcriptional co-activator for the MEF2 transcription factors [9]. In cells, ERK5 is activated in response to specific growth factors including EGF, as well as by some stresses, such as sorbitol and hydrogen peroxide [10,11]. Like other MAPK, ERK5 is activated by phosphorylation on its TXY motif downstream of a MAPK kinase. MEK5 was originally proposed as the kinase responsible for ERK5 activation, based on its interaction with ERK5 in a yeast two-hybrid assay [12]. This finding was later confirmed by the observation that embryonic fibroblasts isolated from MEK5 knockout mice were unable to activate ERK5 [13]. MEK5 is activated downstream of a MAPK kinase kinase Ã These authors contributed equally to this study. 2534(MAP3 K), most probably MEKK2. ERK5 signalling has been reported to be deficient in EGF and FGF stimulated embryonic fibroblast cells from MEKK2 knockout mice suggesting that MEKK2 is the predominant MAP3 K for MEK5, downstream of these signals [14,15]. It is not clear, however, if MEKK2 is the only MAP3 K able to activate the ERK5 pathway. Mouse knockouts of either ERK5 or MEK5 are embryonic lethal, however knockouts of MEKK2 are viable and do not exhibit obvious phen...

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ERK5 Activates NF-κB in Leukemic T Cells and Is Essential for Their Growth In Vivo

Cited by 58 publications

References 64 publications

Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation

Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation

The tyrosine kinase Abl is required for Src-transforming activity in mouse fibroblasts and human breast cancer cells

ERK5 regulation in naïve T‐cell activation and survival

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