MAPK-induced Ser727 phosphorylation promotes SUMOylation of STAT1

2007 ◽  
Vol 409 (1) ◽  
pp. 179-185 ◽  
Author(s):  
Sari Vanhatupa ◽  
Daniela Ungureanu ◽  
Maija Paakkunainen ◽  
Olli Silvennoinen
Keyword(s):  
Interferon Γ ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Microbial Infections ◽  
Mitogen Activated Protein ◽  
P38mapk Pathway ◽  
Ifn Γ

STAT1 (signal transducer and activator of transcription 1) is a critical mediator of IFN-γ (interferon-γ)-induced gene responses, and its function is regulated through phosphorylation of Tyr701 and Ser727. MAPK (mitogen-activated protein kinase) pathways mediate phosphorylation of Ser727 in response to microbial infections, stress stimuli and growth factors. Recently, STAT1 was found to become modified by PIAS (protein inhibitor of activated STAT)-mediated SUMO-1 (small ubiquitin-related modifier-1) conjugation at Lys703, but the regulation of this modification is largely unknown. Here, we have investigated the role of MAPK-induced Ser727 phosphorylation in regulation of STAT1 SUMOylation. Activation of the p38MAPK pathway by upstream activating kinase, MKK6 (MAPK kinase-6) or osmotic stress enhanced the SUMOylation of STAT1, which was counteracted by the p38MAPK inhibitor SB202190 or by dominant-negative p38MAPK. Activation of the ERK1/2 (extracellular-signal-regulated kinase 1/2) pathway by Raf-1 also enhanced Ser727 phosphorylation and SUMOylation of STAT1, and this induction was counteracted by PD98059 inhibitor. Mutation of Ser727 to alanine abolished the p38MAPK-induced SUMOylation. Furthermore, S727D and S727E mutations, which mimic the phosphorylation of Ser727, enhanced the basal SUMOylation of STAT1 and interaction between PIAS1 and STAT1. Taken together, these results identify Ser727 phosphorylation as a regulator of STAT1 SUMOylation and highlight the central role of Ser727 in co-ordination of STAT1 functions in cellular responses.

ERK5 and its role in tumour development

2012 ◽  
Vol 40 (1) ◽  
pp. 251-256 ◽  
Author(s):  
Pamela A. Lochhead ◽  
Rebecca Gilley ◽  
Simon J. Cook
Keyword(s):  
Mitogen Activated Protein Kinase ◽  
Invasion And Migration ◽  
Extracellular Signal Regulated Kinase ◽  
Protein Levels ◽  
Extracellular Signal ◽  
Mapk Signalling ◽  
Mitogen Activated Protein ◽  
Tumour Cell Invasion ◽  
And Migration

The MEK5 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 5]/ERK5 pathway is the least well studied MAPK signalling module. It has been proposed to play a role in the pathology of cancer. In the present paper, we review the role of the MEK5/ERK5 pathway using the ‘hallmarks of cancer’ as a framework and consider how this pathway is deregulated. As well as playing a key role in endothelial cell survival and tubular morphogenesis during tumour neovascularization, ERK5 is also emerging as a regulator of tumour cell invasion and migration. Several oncogenes can stimulate ERK5 activity, and protein levels are increased by a novel amplification at chromosome locus 17p11 and by down-regulation of the microRNAs miR-143 and miR-145. Together, these finding underscore the case for further investigation into understanding the role of ERK5 in cancer.

scholarly journals Impact of ERK5 on the Hallmarks of Cancer

2019 ◽  
Vol 20 (6) ◽  
pp. 1426 ◽  
Author(s):  
Barbara Stecca ◽  
Elisabetta Rovida
Keyword(s):  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Biological Features ◽  
Promising Strategy ◽  
Biological Responses ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Relevant Role ◽  
Almost All

Extracellular signal-regulated kinase 5 (ERK5) belongs to the mitogen-activated protein kinase (MAPK) family that consists of highly conserved enzymes expressed in all eukaryotic cells and elicits several biological responses, including cell survival, proliferation, migration, and differentiation. In recent years, accumulating lines of evidence point to a relevant role of ERK5 in the onset and progression of several types of cancer. In particular, it has been reported that ERK5 is a key signaling molecule involved in almost all the biological features of cancer cells so that its targeting is emerging as a promising strategy to suppress tumor growth and spreading. Based on that, in this review, we pinpoint the hallmark-specific role of ERK5 in cancer in order to identify biological features that will potentially benefit from ERK5 targeting.

scholarly journals Phloretin alleviates dinitrochlorobenzene-induced dermatitis in BALB/c mice

2020 ◽  
Vol 34 ◽  
pp. 205873842092944
Author(s):  
Chieh-Shan Wu ◽  
Shih-Chao Lin ◽  
Shiming Li ◽  
Yu-Chih Chiang ◽  
Nicole Bracci ◽  
...  
Keyword(s):  
Mouse Model ◽  
Serum Levels ◽  
Interferon Γ ◽  
Chronic Inflammatory Disease ◽  
Mitogen Activated Protein Kinase ◽  
Normal Ranges ◽  
Mitogen Activated Protein ◽  
Ifn Γ ◽  
Allergic Contact

Atopic dermatitis (AD) is a chronic inflammatory disease of the skin that substantially affects a patient’s quality of life. While steroids are the most common therapy used to temporally alleviate the symptoms of AD, effective and nontoxic alternatives are urgently needed. In this study, we utilized a natural, plant-derived phenolic compound, phloretin, to treat allergic contact dermatitis (ACD) on the dorsal skin of mice. In addition, the effectiveness of phloretin was evaluated using a mouse model of ACD triggered by 2,4-dinitrochlorobenzene (DNCB). In our experimental setting, phloretin was orally administered to BALB/c mice for 21 consecutive days, and then, the lesions were examined histologically. Our data revealed that phloretin reduced the process of epidermal thickening and decreased the infiltration of mast cells into the lesion regions, subsequently reducing the levels of histamine and the pro-inflammatory cytokines interleukin (IL)-6, IL-4, thymic stromal lymphopoietin (TSLP), interferon-γ (IFN-γ) and IL-17A in the serum. These changes were associated with lower serum levels after phloretin treatment. In addition, we observed that the mitogen-activated protein kinase (MAPK) and NF-κB pathways in the dermal tissues of the phloretin-treated rodents were suppressed compared to those in the AD-like skin regions. Furthermore, phloretin appeared to limit the overproliferation of splenocytes in response to DNCB stimulation, reducing the number of IFN-γ-, IL-4-, and IL-17A-producing CD4+ T cells in the spleen back to their normal ranges. Taken together, we discovered a new therapeutic role of phloretin using a mouse model of DNCB-induced ACD, as shown by the alleviated AD-like symptoms and the reversed immunopathological effects. Therefore, we believe that phloretin has the potential to be utilized as an alternative therapeutic agent for treating AD.

Phorbol ester-induced activation of mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase and extracellular-signal-regulated protein kinase decreases glucose-6-phosphatase gene expression

2001 ◽  
Vol 357 (3) ◽  
pp. 867-873 ◽  
Author(s):  
Dieter SCHMOLL ◽  
Rolf GREMPLER ◽  
Andreas BARTHEL ◽  
Hans-Georg JOOST ◽  
Reinhard WALTHER
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Phorbol Ester ◽  
Regulation Of Gene Expression ◽  
Insulin Response ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Glucose-6-phosphatase (G6Pase) plays a central role in blood glucose homoeostasis, and insulin suppresses G6Pase gene expression by the activation of phosphoinositide 3-kinase (PI 3-kinase). Here, we show that the phorbol ester PMA decreases both basal and dexamethasone/cAMP-induced expression of a luciferase gene under the control of the G6Pase promoter in transiently transfected H4IIE hepatoma cells. This regulation was suppressed by the inhibitors of the mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase (MEK), PD98059 and U0126, but not by the inhibitor of PI 3-kinase, LY294002. The co-expression of a constitutively active mutant of MEK mimicked the regulation of G6Pase promoter activity by PMA. The effect of PMA on both basal and induced G6Pase gene transcription was impaired by the overexpression of a dominant negative MEK construct, as well as by the expression of mitogen-activated protein kinase phosphatase-1. The mutation of the forkhead-binding sites within the insulin-response unit of the G6Pase promoter, which decreases the effect of insulin on G6Pase gene expression, did not alter the regulation of gene expression by PMA. The data show that PMA decreases G6Pase gene expression by the activation of MEK and extracellular-signal regulated protein kinase. With that, PMA mimics the effect of insulin on G6Pase gene expression by a different signalling pathway.

scholarly journals p38α Mitogen-activated Protein Kinase Sensitizes Cells to Apoptosis Induced by Different Stimuli

2004 ◽  
Vol 15 (2) ◽  
pp. 922-933 ◽  
Author(s):  
Almudena Porras ◽  
Susana Zuluaga ◽  
Emma Black ◽  
Amparo Valladares ◽  
Alberto M. Alvarez ◽  
...  
Keyword(s):  
Map Kinase ◽  
Cell Types ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Survival Pathways ◽  
Proapoptotic Protein ◽  
Extracellular Signal ◽  
Survival Pathway ◽  
Mitogen Activated Protein

p38α mitogen-activated protein (MAP) kinase is a broadly expressed signaling molecule that participates in the regulation of cellular responses to stress as well as in the control of proliferation and survival of many cell types. We have used cell lines derived from p38α knockout mice to study the role of this signaling pathway in the regulation of apoptosis. Here, we show that cardiomyocytes and fibroblasts lacking p38α are more resistant to apoptosis induced by different stimuli. The reduced apoptosis of p38α-deficient cells correlates with decreased expression of the mitochondrial proapoptotic protein Bax and the apoptosis-inducing receptor Fas/CD-95. Cells lacking p38α also have increased extracellular signal-regulated kinase (ERKs) MAP kinase activity, and the up-regulation of this survival pathway seems to be at least partially responsible for the reduced levels of apoptosis in the absence of p38α. Phosphorylation of the transcription factor STAT3 on Ser-727, mediated by the extracellular signal-regulated kinase MAP kinase pathway, may contribute to the decrease in both Bax and Fas expression in p38α-/- cells. Thus, p38α seems to sensitize cells to apoptosis via both up-regulation of proapoptotic proteins and down-regulation of survival pathways.

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