Alternative Splicing of MAPKs in the Regulation of Signaling Specificity

The mitogen-activated protein kinase (MAPK) cascades transmit signals from extracellular stimuli to a variety of distinct cellular processes. The MAPKKs in each cascade specifically phosphorylate and activate their cognate MAPKs, indicating that this step funnels various signals into a seemingly linear pathway. Still, the effects of these cascades vary significantly, depending on the identity of the extracellular signals, which gives rise to proper outcomes. Therefore, it is clear that the specificity of the signals transmitted through the cascades is tightly regulated in order to secure the desired cell fate. Indeed, many regulatory components or processes that extend the specificity of the cascades have been identified. Here, we focus on a less discussed mechanism, that is, the role of distinct components in each tier of the cascade in extending the signaling specificity. We cover the role of distinct genes, and the alternatively spliced isoforms of MAPKKs and MAPKs, in the signaling specificity. The alternatively spliced MEK1b and ERK1c, which form an independent signaling route, are used as the main example. Unlike MEK1/2 and ERK1/2, this route’s functions are limited, including mainly the regulation of mitotic Golgi fragmentation. The unique roles of the alternatively spliced isoforms indicate that these components play an essential role in determining the proper cell fate in response to distinct stimulations.

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Mechanism of short-term ERK activation by electromagnetic fields at mobile phone frequencies

Biochemical Journal ◽

10.1042/bj20061653 ◽

2007 ◽

Vol 405 (3) ◽

pp. 559-568 ◽

Cited By ~ 151

Author(s):

Joseph Friedman ◽

Sarah Kraus ◽

Yirmi Hauptman ◽

Yoni Schiff ◽

Rony Seger

Keyword(s):

Mobile Phone ◽

Electromagnetic Fields ◽

Mobile Phones ◽

Egf Receptor ◽

Nadh Oxidase ◽

Mitogen Activated Protein Kinase ◽

Heparin Binding ◽

Cellular Processes ◽

Mapk Cascades ◽

Mitogen Activated Protein

The exposure to non-thermal microwave electromagnetic fields generated by mobile phones affects the expression of many proteins. This effect on transcription and protein stability can be mediated by the MAPK (mitogen-activated protein kinase) cascades, which serve as central signalling pathways and govern essentially all stimulated cellular processes. Indeed, long-term exposure of cells to mobile phone irradiation results in the activation of p38 as well as the ERK (extracellular-signal-regulated kinase) MAPKs. In the present study, we have studied the immediate effect of irradiation on the MAPK cascades, and found that ERKs, but not stress-related MAPKs, are rapidly activated in response to various frequencies and intensities. Using signalling inhibitors, we delineated the mechanism that is involved in this activation. We found that the first step is mediated in the plasma membrane by NADH oxidase, which rapidly generates ROS (reactive oxygen species). These ROS then directly stimulate MMPs (matrix metalloproteinases) and allow them to cleave and release Hb-EGF [heparin-binding EGF (epidermal growth factor)]. This secreted factor activates the EGF receptor, which in turn further activates the ERK cascade. Thus this study demonstrates for the first time a detailed molecular mechanism by which electromagnetic irradiation from mobile phones induces the activation of the ERK cascade and thereby induces transcription and other cellular processes.

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Leptin is involved in acrosome reaction by facilitating activation of MAPK cascades in the Chinese mitten crab, Eriocheir sinensis

Animal Biology ◽

10.1163/15707563-20191095 ◽

2020 ◽

Vol 70 (1) ◽

pp. 81-95

Author(s):

Qing Li ◽

Haitao Zhao ◽

Lin He ◽

Hongdan Yang ◽

Qun Wang

Keyword(s):

Acrosome Reaction ◽

Calcium Ionophore ◽

Eriocheir Sinensis ◽

Calcium Ionophore A23187 ◽

Mitogen Activated Protein Kinase ◽

Ionophore A23187 ◽

Mapk Cascades ◽

Mitten Crab ◽

Mitogen Activated Protein

Abstract The role of leptin has been documented in several studies, including activated threonine phosphorylation of extracellular signal-regulated kinase (ERK1/2) in the reproduction of rodents and humans. Our previous studies have demonstrated that mitogen-activated protein kinase (MAPK) cascades ERK, P38, and c-Jun N-terminal kinase (JNK) are involved in the spermatogenesis and acrosome reaction of Eriocheir sinensis. Therefore, the aim of this study was to investigate the expression of leptin and its receptor (LepR), and the effect of leptin on MAPK cascades during calcium ionophore A23187-induced spermatozoa acrosome reaction in crabs. Successful western blotting revealed a 16 kDa band for leptin, and 120 kDa and 90 kDa bands for the obese receptor (LepR), respectively, in the tested male reproductive tissues. Both leptin and LepR were localized at the pro-acrosomal vesicle and apical cap (AC) of spermatids, suggesting their role in the subsequent acrosome reaction. Moreover, acrosome reaction can be enhanced by leptin, and this effect decreased due to the anti-LepR antibody. Afterwards, we investigated the effects of leptin on MAPK cascades. The results showed that leptin mainly activated the phosphorylation of ERK, P38 and JNK proteins in the apical cap during the acrosome reaction in crab spermatozoa. This study addresses the role of leptin on spermatozoa, and suggests that leptin may induce molecular changes associated with spermatozoa during acrosome reaction.

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The Nuclear Translocation of Mitogen-Activated Protein Kinases: Molecular Mechanisms and Use as Novel Therapeutic Target

Neuroendocrinology ◽

10.1159/000494085 ◽

2018 ◽

Vol 108 (2) ◽

pp. 121-131 ◽

Cited By ~ 10

Author(s):

Karen Flores ◽

Suresh Singh Yadav ◽

Arieh A. Katz ◽

Rony Seger

Keyword(s):

Molecular Mechanisms ◽

Nuclear Translocation ◽

Mitogen Activated Protein Kinase ◽

Cellular Processes ◽

Development Of Resistance ◽

Mapk Cascades ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Importin Α ◽

Cancer And Inflammation

The mitogen-activated protein kinase (MAPK) cascades are central signaling pathways that play a central role in the regulation of most stimulated cellular processes including proliferation, differentiation, stress response and apoptosis. Currently 4 such cascades are known, each termed by its downstream MAPK components: the extracellular signal-regulated kinase 1/2 (ERK1/2), cJun-N-terminal kinase (JNK), p38 and ERK5. One of the hallmarks of these cascades is the stimulated nuclear translocation of their MAPK components using distinct mechanisms. ERK1/2 are shuttled into the nucleus by importin7, JNK and p38 by a dimer of importin3 with either importin9 or importin7, and ERK5 by importin-α/β. Dysregulation of these cascades often results in diseases, including cancer and inflammation, as well as developmental and neurological disorders. Much effort has been invested over the years in developing inhibitors to the MAPK cascades to combat these diseases. Although some inhibitors are already in clinical use or clinical trials, their effects are hampered by development of resistance or adverse side-effects. Recently, our group developed 2 myristoylated peptides: EPE peptide, which inhibits the interaction of ERK1/2 with importin7, and PERY peptide, which prevents JNK/p38 interaction with either importin7 or importin9. These peptides block the nuclear translocation of their corresponding kinases, resulting in prevention of several cancers, while the PERY peptide also inhibits inflammation-induced diseases. These peptides provide a proof of concept for the use of the nuclear translocation of MAPKs as therapeutic targets for cancer and/or inflammation.

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The MAPKKK CgMck1 Is Required for Cell Wall Integrity, Appressorium Development, and Pathogenicity in Colletotrichum gloeosporioides

Genes ◽

10.3390/genes9110543 ◽

2018 ◽

Vol 9 (11) ◽

pp. 543 ◽

Cited By ~ 4

Author(s):

Yu-Lan Fang ◽

Li-Ming Xia ◽

Ping Wang ◽

Li-Hua Zhu ◽

Jian-Ren Ye ◽

...

Keyword(s):

Cell Wall ◽

Vegetative Growth ◽

Colletotrichum Gloeosporioides ◽

Mapk Signaling ◽

Cell Wall Integrity ◽

Mitogen Activated Protein Kinase ◽

Extracellular Signals ◽

Mapk Cascades ◽

Body Development ◽

Mitogen Activated Protein

Mitogen-activated protein kinase (MAPK) signaling pathway plays key roles in sensing extracellular signals and transmitting them from the cell membrane to the nucleus in response to various environmental stimuli. A MAPKKK protein CgMck1 in Colletotrichum gloeosporioides was characterized. Phenotypic analyses of the ∆Cgmck1 mutant showed that the CgMck1 was required for vegetative growth, fruiting body development, and sporulation. Additionally, the CgMCK1 deletion mutant showed significant defects in cell wall integrity, and responses to osmotic stresses. The mutant abolished the ability to develop appressorium, and lost pathogenicity to host plants. The ∆Cgmck1 mutant also exhibited a higher sensitivity to antifungal bacterium agent Bacillus velezensis. The deletion mutants of downstream MAPK cascades components CgMkk1 and CgMps1 showed similar defects to the ∆Cgmck1 mutant. In conclusion, CgMck1 is involved in the regulation of vegetative growth, asexual development, cell wall integrity, stresses resistance, and infection morphogenesis in C. gloeosporioides.

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Mitogen-Activated Protein Kinases (MAPKs) and Cholangiocarcinoma: The Missing Link

Cells ◽

10.3390/cells8101172 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1172 ◽

Cited By ~ 3

Author(s):

Chen ◽

Nelson ◽

Ávila ◽

Cubero

Keyword(s):

Mapk Pathway ◽

Mitogen Activated Protein Kinase ◽

Tract Cancer ◽

Response Differentiation ◽

Wide Range ◽

Pathophysiological Role ◽

Mitogen Activated Protein ◽

Extracellular Stimuli ◽

Signaling Components

In recent years, the incidence of both liver and biliary tract cancer has increased. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the two most common types of hepatic malignancies. Whereas HCC is the fifth most common malignant tumor in Western countries, the prevalence of CCA has taken an alarming increase from 0.3 to 2.1 cases per 100,000 people. The lack of specific biomarkers makes diagnosis very difficult in the early stages of this fatal cancer. Thus, the prognosis of CCA is dismal and surgery is the only effective treatment, whilst recurrence after resection is common. Even though chemotherapy and radiotherapy may prolong survival in patients with CCA, the 5-year survival rate is still very low—a significant global problem in clinical diagnosis and therapy. The mitogen-activated protein kinase (MAPK) pathway plays an important role in signal transduction by converting extracellular stimuli into a wide range of cellular responses including inflammatory response, stress response, differentiation, survival, and tumorigenesis. Dysregulation of the MAPK cascade involves key signaling components and phosphorylation events that play an important role in tumorigenesis. In this review, we discuss the pathophysiological role of MAPK, current therapeutic options, and the current situation of MAPK-targeted therapies in CCA.

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Systems analysis of MAPK signal transduction

Essays in Biochemistry ◽

10.1042/bse045095 ◽

2008 ◽

Vol 45 ◽

pp. 95-108 ◽

Cited By ~ 19

Author(s):

Nils Blüthgen ◽

Stefan Legewie

Keyword(s):

Gene Expression ◽

Cell Fate ◽

Mapk Pathway ◽

Experimental Studies ◽

Mitogen Activated Protein Kinase ◽

Cell Fate Decisions ◽

Biological Responses ◽

Mitogen Activated Protein ◽

Kinase Cascade ◽

Extracellular Stimuli

For more than a decade, the MAPK (mitogen-activated protein kinase) cascade has been studied using mathematical modelling and quantitative experimentation [1]. The MAPK cascade relays the presence of extracellular stimuli such as growth hormones to the nucleus and controls the expression of hundreds of genes. MAPKs control major cell fate decisions such as proliferation, differentiation and apoptosis, mainly by inducing alterations in gene expression. In this chapter, we discuss how systems biology analysis provides insights into the functioning of this cascade. We show how this pathway assists the cell in responding properly to extracellular cues by filtering out sub-threshold stimuli, while efficiently transmitting physiologically relevant inputs. Several different receptors signal through the MAPK pathway even though they elicit opposite biological responses, thus raising the question of how specificity is achieved in MAPK signalling. Experimental studies revealed that specific biological responses are encoded by quantitative aspects of the MAPK signal such as amplitude or duration. We discuss mechanisms that enable the pathway to generate quantitatively different signals, and also explain how different signals are interpreted by the downstream gene expression machinery.

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PPARγand MEK Interactions in Cancer

PPAR Research ◽

10.1155/2008/309469 ◽

2008 ◽

Vol 2008 ◽

pp. 1-16 ◽

Cited By ~ 38

Author(s):

Elke Burgermeister ◽

Rony Seger

Keyword(s):

Cell Fate ◽

Molecular Mechanisms ◽

Inflammatory Diseases ◽

Mitogen Activated Protein Kinase ◽

Peroxisome Proliferator ◽

Signaling Crosstalk ◽

Peroxisome Proliferator Activated Receptor ◽

Mapk Cascades ◽

Extracellular Signal ◽

Mitogen Activated Protein

Peroxisome proliferator-activated receptor-gamma (PPARγ) exerts multiple functions in determination of cell fate, tissue metabolism, and host immunity. Two synthetic PPARγligands (rosiglitazone and pioglitazone) were approved for the therapy of type-2 diabetes mellitus and are expected to serve as novel cures for inflammatory diseases and cancer. However, PPARγand its ligands exhibit a janus-face behaviour as tumor modulators in various systems, resulting in either tumor suppression or tumor promotion. This may be in part due to signaling crosstalk to the mitogen-activated protein kinase (MAPK) cascades. The genomic activity of PPARγis modulated, in addition to ligand binding, by phosphorylation of a serine residue by MAPKs, such as extracellular signal-regulated protein kinases-1/2 (ERK-1/2), or by nucleocytoplasmic compartmentalization through the ERK activators MAPK kinases-1/2 (MEK-1/2). PPARγligands themselves activate the ERK cascade through nongenomic and often PPARγ-independent signaling. In the current review, we discuss the molecular mechanisms and physiological implications of the crosstalk of PPARγwith MEK-ERK signaling and its potential as a novel drug target for cancer therapy in patients.

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Alternative splicing results in RET isoforms with distinct trafficking properties

Molecular Biology of the Cell ◽

10.1091/mbc.e12-02-0114 ◽

2012 ◽

Vol 23 (19) ◽

pp. 3838-3850 ◽

Cited By ~ 33

Author(s):

Douglas S. Richardson ◽

David M. Rodrigues ◽

Brandy D. Hyndman ◽

Mathieu J. F. Crupi ◽

Adrian C. Nicolescu ◽

...

Keyword(s):

Plasma Membrane ◽

Expression Patterns ◽

Adaptor Proteins ◽

Mitogen Activated Protein Kinase ◽

Functional Differences ◽

Midbrain Dopaminergic Neurons ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Alternatively Spliced

RET encodes a receptor tyrosine kinase that is essential for spermatogenesis, development of the sensory, sympathetic, parasympathetic, and enteric nervous systems and the kidneys, as well as for maintenance of adult midbrain dopaminergic neurons. RET is alternatively spliced to encode multiple isoforms that differ in their C-terminal amino acids. The RET9 and RET51 isoforms display unique levels of autophosphorylation and have differential interactions with adaptor proteins. They induce distinct gene expression patterns, promote different levels of cell differentiation and transformation, and play unique roles in development. Here we present a comprehensive study of the subcellular localization and trafficking of RET isoforms. We show that immature RET9 accumulates intracellularly in the Golgi, whereas RET51 is efficiently matured and present in relatively higher amounts on the plasma membrane. RET51 is internalized faster after ligand binding and undergoes recycling back to the plasma membrane. This differential trafficking of RET isoforms produces a more rapid and longer duration of signaling through the extracellular-signal regulated kinase/mitogen-activated protein kinase pathway downstream of RET51 relative to RET9. Together these differences in trafficking properties contribute to some of the functional differences previously observed between RET9 and RET51 and establish the important role of intracellular trafficking in modulating and maintaining RET signaling.

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Selective Regulation of c-jun Gene Expression by Mitogen-Activated Protein Kinases via the 12-O-Tetradecanoylphorbol-13-Acetate- Responsive Element and Myocyte Enhancer Factor 2 Binding Sites

Molecular and Cellular Biology ◽

10.1128/mcb.25.9.3784-3792.2005 ◽

2005 ◽

Vol 25 (9) ◽

pp. 3784-3792 ◽

Cited By ~ 46

Author(s):

Midori Kayahara ◽

Xin Wang ◽

Cathy Tournier

Keyword(s):

Gene Expression ◽

Protein Kinase ◽

Cell Fate ◽

P38 Mapk ◽

Physiological Role ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Mapk Cascades ◽

Mitogen Activated Protein

ABSTRACT To further understand how the mitogen-activated protein kinase (MAPK) signaling pathways regulate AP-1 activity, we have elucidated the physiological role of these cascades in the regulation of c-jun gene expression. c-Jun is a crucial component of AP-1 complexes and has been shown in vitro to be a point of integration of numerous signals that can differentially affect its expression as well as its transcriptional activity. Our strategy was based on the use of (i) genetically modified fibroblasts deficient in components of the MAPK cascades and (ii) pharmacological reagents. The results demonstrate that c-Jun NH2-terminal protein kinase (JNK) is essential for a basal level of c-Jun expression and for c-Jun phosphorylation in response to stress. In addition to JNK, p38 MAPK or ERK1/2 and ERK5 are required for mediating UV radiation- or epidermal growth factor (EGF)-induced c-Jun expression, respectively. Further studies indicate that p38 MAPK inhibits the activation of JNK in response to EGF, causing a down-regulation of c-Jun. Overall, these data provide important insights into the mechanisms that ultimately determine the function of c-Jun as a regulator of cell fate.

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Role of p90RSK in Kidney and Other Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms20040972 ◽

2019 ◽

Vol 20 (4) ◽

pp. 972 ◽

Cited By ~ 4

Author(s):

Ling Lin ◽

Samantha White ◽

Kebin Hu

Keyword(s):

Kidney Diseases ◽

Critical Role ◽

Mitogen Activated Protein Kinase ◽

Cellular Processes ◽

Downstream Effector ◽

Extracellular Signal ◽

Mapk Signalling ◽

Mitogen Activated Protein ◽

Selection Of

The 90 kDa ribosomal s6 kinases (RSKs) are a group of serine/threonine kinases consisting of 4 RSK isoforms (RSK1-4), of which RSK1 is also designated as p90RSK. p90RSK plays an important role in the Ras-mitogen-activated protein kinase (MAPK) signalling cascade and is the direct downstream effector of Ras-extracellular signal-regulated kinase (ERK1/2) signalling. ERK1/2 activation directly phosphorylates and activates p90RSK, which, in turn, activates various signalling events through selection of different phosphorylation substrates. Upregulation of p90RSK has been reported in numerous human diseases. p90RSK plays an important role in the regulation of diverse cellular processes. Thus, aberrant activation of p90RSK plays a critical role in the pathogenesis of organ dysfunction and damage. In this review, we focus on the current understanding of p90RSK functions and roles in the development and progression of kidney diseases. Roles of p90RSK, as well as other RSKs, in cardiovascular disorders and cancers are also discussed.

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