Loss of MAPK-activated protein kinase 2 enables potent dendritic cell-driven anti-tumour T cell response

Soukup, Klara; Halfmann, Angela; Dillinger, Barbara; Poyer, Fiona; Martin, Katharina; Blauensteiner, Bernadette; Kauer, Maximilian; Kuttke, Mario; Schabbauer, Gernot; Dohnal, Alexander

doi:10.1038/s41598-017-12208-7

Cited by 10 publications

(10 citation statements)

References 50 publications

(80 reference statements)

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“…Our results postulated that MK2 KD tends to stabilize the MKP-1 transcripts, thus, confirming the hypothesis that mRNA stabilization of this negative regulator possibly inhibits the progression of HNSCC. Our findings are in agreement with the latest report showing that systemic MK2 deletion reduced tumor burden by immunomodulatory cancer therapies in mice [35].…”

Section: Discussionsupporting

confidence: 94%

MAPKAPK2 plays a crucial role in the progression of head and neck squamous cell carcinoma by regulating transcript stability

Soni

Saroch

Chander

et al. 2019

J Exp Clin Cancer Res

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Background Head and neck squamous-cell carcinoma (HNSCC) ranks sixth among cancers worldwide. Though several molecular mechanisms of tumor initiation and progression of HNSCC are known, others remain unclear. Significance of p38/MAPKAPK2 (Mitogen-activated protein kinase-activated protein kinase-2) pathway in cell stress and inflammation is well established and its role in tumor development is being widely studied. Methods We have elucidated the role of MAPKAPK2 (MK2) in HNSCC pathogenesis using clinical tissue samples, MK2-knockdown (MK2 KD ) cells and heterotropic xenograft mice model. Results In patient-derived tissue samples, we observed that MK2 is reproducibly overexpressed. Increased stability of cyclin-dependent kinase inhibitor 1B (p27), mitogen-activated protein kinase phosphatase-1 (MKP-1) transcripts and decreased half-life of tumor necrosis factor-alpha (TNF-α) and vascular endothelial growth factor (VEGF) transcripts in MK2 KD cells suggests that MK2 regulates their transcript stability. In vivo xenograft experiments established that knockdown of MK2 attenuates course of tumor progression in immunocompromised mice. Conclusion Altogether, MK2 is responsible for regulating the transcript stability and is functionally important to modulate HNSCC pathogenesis. Electronic supplementary material The online version of this article (10.1186/s13046-019-1167-2) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 94%

MAPKAPK2 plays a crucial role in the progression of head and neck squamous cell carcinoma by regulating transcript stability

Soni

Saroch

Chander

et al. 2019

J Exp Clin Cancer Res

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“…The stimuli tested in the above experiments are harmful for cells and eventually result in cell death. However, p38α and MK2 are known to be activated also in physiological situations that do not necessarily lead to cell death, such as cytokine production in immune cells or during cell differentiation (7,27,28). To analyze the behavior of MK2 in these scenarios, we stimulated bone marrow-derived macrophages (BMDM) with lipopolysaccharide (LPS).…”

Section: Resultsmentioning

confidence: 99%

MK2 degradation as a sensor of signal intensity that controls stress-induced cell fate

Gutierrez-Prat

Cubillos-Rojas

Cánovas

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Cell survival in response to stress is determined by the coordination of various signaling pathways. The kinase p38α is activated by many stresses, but the intensity and duration of the signal depends on the stimuli. How different p38α-activation dynamics may impact cell life/death decisions is unclear. Here, we show that the p38α-signaling output in response to stress is modulated by the expression levels of the downstream kinase MK2. We demonstrate that p38α forms a complex with MK2 in nonstimulated mammalian cells. Upon pathway activation, p38α phosphorylates MK2, the complex dissociates, and MK2 is degraded. Interestingly, transient p38α activation allows MK2 reexpression, reassembly of the p38α–MK2 complex, and cell survival. In contrast, sustained p38α activation induced by severe stress interferes with p38α–MK2 interaction, resulting in irreversible MK2 loss and cell death. MK2 degradation is mediated by the E3 ubiquitin ligase MDM2, and we identify four lysine residues in MK2 that are directly ubiquitinated by MDM2. Expression of an MK2 mutant that cannot be ubiquitinated by MDM2 enhances the survival of stressed cells. Our results indicate that MK2 reexpression and binding to p38α is critical for cell viability in response to stress and illustrate how particular p38α-activation patterns induced by different signals shape the stress-induced cell fate.

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“…MK2, a key effector kinase of the p38MAPK pathway, regulates multiple critical aspects of the innate immune system cells, including neutrophils ( 50 – 52 ), dendritic cells ( 53 – 55 ) and macrophages ( 56 , 57 ). There is growing evidence that p38/MK2 pathway significantly contributes to inflammation-driven tumorigenesis at multiple levels, since elegant studies from the Nebreda lab have shown that epithelial p38α activity is required for tumor maintenance while myeloid p38α regulates both inflammatory cell recruitment to tumors and chemokine production ( 58 , 59 ).…”

Section: Discussionmentioning

confidence: 99%

MAPKAP Kinase-2 Drives Expression of Angiogenic Factors by Tumor-Associated Macrophages in a Model of Inflammation-Induced Colon Cancer

et al. 2021

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Chronic inflammation increases the risk for colorectal cancer through a variety of mechanisms involving the tumor microenvironment. MAPK-activated protein kinase 2 (MK2), a major effector of the p38 MAPK stress and DNA damage response signaling pathway, and a critical regulator of pro-inflammatory cytokine production, has been identified as a key contributor to colon tumorigenesis under conditions of chronic inflammation. We have previously described how genetic inactivation of MK2 in an inflammatory model of colon cancer results in delayed tumor progression, decreased tumor angiogenesis, and impaired macrophage differentiation into a pro-tumorigenic M2-like state. The molecular mechanism responsible for the impaired angiogenesis and tumor progression, however, has remained contentious and poorly defined. Here, using RNA expression analysis, assays of angiogenesis factors, genetic models, in vivo macrophage depletion and reconstitution of macrophage MK2 function using adoptive cell transfer, we demonstrate that MK2 activity in macrophages is necessary and sufficient for tumor angiogenesis during inflammation-induced cancer progression. We identify a critical and previously unappreciated role for MK2-dependent regulation of the well-known pro-angiogenesis factor CXCL-12/SDF-1 secreted by tumor associated-macrophages, in addition to MK2-dependent regulation of Serpin-E1/PAI-1 by several cell types within the tumor microenvironment.

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Loss of MAPK-activated protein kinase 2 enables potent dendritic cell-driven anti-tumour T cell response

Cited by 10 publications

References 50 publications

MAPKAPK2 plays a crucial role in the progression of head and neck squamous cell carcinoma by regulating transcript stability

MAPKAPK2 plays a crucial role in the progression of head and neck squamous cell carcinoma by regulating transcript stability

MK2 degradation as a sensor of signal intensity that controls stress-induced cell fate

MAPKAP Kinase-2 Drives Expression of Angiogenic Factors by Tumor-Associated Macrophages in a Model of Inflammation-Induced Colon Cancer

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