scholarly journals MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets

2008 ◽  
Vol 115 (7) ◽  
pp. 203-218 ◽  
Author(s):  
Anthony J. Muslin
Keyword(s):  
Molecular Mechanisms ◽  
Cardiovascular Health ◽  
Mapk Pathway ◽  
Science Research ◽  
Pharmacological Therapy ◽  
Model Systems ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Intracellular MAPK (mitogen-activated protein kinase) signalling cascades probably play an important role in the pathogenesis of cardiac and vascular disease. A substantial amount of basic science research has defined many of the details of MAPK pathway organization and activation, but the role of individual signalling proteins in the pathogenesis of various cardiovascular diseases is still being elucidated. In the present review, the role of the MAPKs ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 MAPK in cardiac hypertrophy, cardiac remodelling after myocardial infarction, atherosclerosis and vascular restenosis will be examined, with attention paid to genetically modified murine model systems and to the use of pharmacological inhibitors of protein kinases. Despite the complexities of this field of research, attractive targets for pharmacological therapy are emerging.

scholarly journals Molecular Mechanisms of Liver Injury and Hepatocarcinogenesis: Focusing on the Role of Stress-Activated MAPK

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Hayato Nakagawa ◽  
Shin Maeda
Keyword(s):  
Liver Injury ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Effects ◽  
Wide Range ◽  
Mitogen Activated Protein ◽  
Compensatory Proliferation

Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality. Short-term prognosis of patients with HCC has improved recently due to advances in early diagnosis and treatment, but long-term prognosis is still unsatisfactory. Therefore, obtaining a further understanding of the molecular carcinogenic mechanisms and the unique pathogenic biology of HCC is important. The most characteristic process in hepatocarcinogenesis is underlying chronic liver injury, which leads to repeated cycles of hepatocyte death, inflammation, and compensatory proliferation and subsequently provides a mitogenic and mutagenic environment leading to the development of HCC. Recent in vivo studies have shown that the stress-activated mitogen-activated protein kinase (MAPK) cascade converging on c-Jun NH2-terminal kinase (JNK) and p38 plays a central role in these processes, and it has attracted considerable attention as a therapeutic target. However, JNK and p38 have complex functions and a wide range of cellular effects. In addition, crosstalk with each other and the nuclear factor-kappaB pathway further complicate these functions. A full understanding is essential to bring these observations into clinical settings. In this paper, we discuss the latest findings regarding the mechanisms of liver injury and hepatocarcinogenesis focusing on the role of the stress-activated MAPK pathway.

scholarly journals Autophagy as a therapeutic target in pancreatic cancer

2020 ◽  
Author(s):  
Max Piffoux ◽  
Erwan Eriau ◽  
Philippe A. Cassier
Keyword(s):  
Targeted Therapy ◽  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Mitogen Activated Protein Kinase ◽  
Ductal Adenocarcinoma ◽  
Extracellular Signal ◽  
Anti Cancer ◽  
Mitogen Activated Protein ◽  
Cellular Components

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterised by early metastasis and resistance to anti-cancer therapy, leading to an overall poor prognosis. Despite continued research efforts, no targeted therapy has yet shown meaningful efficacy in PDAC; mutations in the oncogene KRAS and the tumour suppressor TP53, which are the most common genomic alterations in PDAC, have so far shown poor clinical actionability. Autophagy, a conserved process allowing cells to recycle altered or unused organelles and cellular components, has been shown to be upregulated in PDAC and is implicated in resistance to both cytotoxic chemotherapy and targeted therapy. Autophagy is thus regarded as a potential therapeutic target in PDAC and other cancers. Although the molecular mechanisms of autophagy activation in PDAC are only beginning to emerge, several groups have reported interesting results when combining inhibitors of the extracellular-signal-regulated kinase/mitogen-activated protein kinase pathway and inhibitors of autophagy in models of PDAC and other KRAS-driven cancers. In this article, we review the existing preclinical data regarding the role of autophagy in PDAC, as well as results of relevant clinical trials with agents that modulate autophagy in this cancer.

Convergence of the SUMO and MAPK pathways on the ETS-domain transcription factor Elk-1

2006 ◽  
Vol 73 ◽  
pp. 121-129 ◽  
Author(s):  
Shen-Hsi Yang ◽  
Andrew D. Sharrocks
Keyword(s):  
Transcription Factor ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Highly Active ◽  
Molecular Events ◽  
Extracellular Signal ◽  
Activated State ◽  
Mitogen Activated Protein ◽  
Ets Domain

The ETS-domain transcription factor Elk-1 is regulated by phosphorylation in response to activation of the MAPK (mitogen-activated protein kinase) pathways. This phosphorylation triggers a series of molecular events that convert Elk-1 from a transcriptionally silent state into a highly active state and then back to a basal level. At the same time, activation of the ERK (extracellular-signal-regulated kinase) MAPK pathway leads to loss of modification of Elk-1 by SUMO (small ubiquitin-related modifier). As SUMO imparts repressive properties on Elk-1, ERK-mediated SUMO loss leads to de-repression at the same time as the ERK pathway promotes activation of Elk-1. Thus a two-step mechanism is employed to convert Elk-1 into its fully activated state. Here, the molecular events underlying these changes in Elk-1 status, and the role of PIASxα [protein inhibitor of activated STAT (signal transducer and activator of transcription) xα] as a co-activator that facilitates this process, are discussed.

The role of Raf kinases in malignant transformation

2002 ◽  
Vol 4 (8) ◽  
pp. 1-18 ◽  
Author(s):  
Walter Kolch ◽  
Ashwin Kotwaliwale ◽  
Keith Vass ◽  
Petra Janosch
Keyword(s):  
Molecular Mechanisms ◽  
Mitogen Activated Protein Kinase ◽  
Ras Proteins ◽  
Surface Receptors ◽  
Extracellular Signal Regulated Kinase ◽  
Raf Kinase ◽  
Growth Inhibitory ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

The Raf kinases are proto-oncogenes that work at the entry point of the mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) pathway, a signalling module that connects cell-surface receptors and Ras proteins to nuclear transcription factors. The pathway impinges on all the functional hallmarks of cancer cells: immortalisation, growth-factor-independent proliferation, insensitivity to growth-inhibitory signals, ability to invade and metastasise, ability to attract blood vessels, and evasion of apoptosis. Indeed, the pathway is hyperactivated in 30% of all human tumours including prevalent cancers of the colon and lung. The molecular mechanisms underlying the role of Raf kinase in tumourigenesis and the opportunities for therapeutic intervention are reviewed in this article.

scholarly journals Regulation of ERK2 activity by dynamic S-acylation

2021 ◽  
Author(s):  
Saara-Anne Azizi ◽  
Tian Qiu ◽  
Noah Brookes ◽  
Bryan C Dickinson
Keyword(s):  
Mapk Pathway ◽  
Effector Proteins ◽  
Mitogen Activated Protein Kinase ◽  
Post Translational Modifications ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Epidermal Growth ◽  
Key Sites ◽  
Egf Signaling

The extracellular signal-regulated kinases (ERK1/2) are key effector proteins of the mitogen activated protein kinase pathway, choreographing essential processes of cellular physiology. Critical in regulating these regulators are a patchwork of mechanisms, including post-translational modifications (PTMs) such as MEK-mediated phosphorylation. Here, we discover that ERK1/2 are subject to S-palmitoylation, a reversible lipid modification of cysteine residues, at C271/C254. Moreover, the levels of ERK1/2 S-acylation are modulated by epidermal growth factor (EGF) signaling, mirroring its phosphorylation dynamics, and palmitoylation-deficient ERK2 displays altered phosphorylation patterns at key sites. We find that chemical inhibition of either lipid addition or removal significantly alters ERK1/2's EGF-triggered transcriptional program. We also identify a subset of "writer" protein acyl transferases (PATs) and an "eraser" acyl protein thioesterase (APT) that drive ERK1/2's cycle of palmitoylation and depalmitoylation. Finally, we examine ERK1/2 S-acylation in a mouse model of metabolic syndrome, correlating changes in its lipidation levels with alterations in writer/eraser expression and solidifying the link between ERK1/2 activity, ERK1/2 lipidation, and organismal health. This study not only presents a previously undescribed mode of ERK1/2 regulation and a node to modulate MAPK pathway signaling in pathophysiological conditions, it also offers insight into the role of dynamic S29 palmitoylation in cell signaling more generally.

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.

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