Systems analysis of MAPK signal transduction

2008 ◽  
Vol 45 ◽  
pp. 95-108 ◽  
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.

scholarly journals Graded Mitogen-Activated Protein Kinase Activity Precedes Switch-Like c-Fos Induction in Mammalian Cells

2005 ◽  
Vol 25 (11) ◽  
pp. 4676-4682 ◽  
Author(s):  
Jeffrey P. MacKeigan ◽  
Leon O. Murphy ◽  
Christopher A. Dimitri ◽  
John Blenis
Keyword(s):  
Protein Kinase ◽  
Cell Fate ◽  
Oocyte Maturation ◽  
Mammalian Cells ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Cell Fate Decisions ◽  
Graded Response ◽  
Mitogen Activated Protein

ABSTRACT The mitogen-activated protein kinase (MAPK) pathway is an evolutionarily conserved signaling module that controls important cell fate decisions in a variety of physiological contexts. During Xenopus oocyte maturation, the MAPK cascade converts an increasing progesterone stimulus into a switch-like, all-or-nothing response. While the importance of such switch-like behavior is widely discussed in the literature, it is not known whether the MAPK pathway in mammalian cells exhibits a switch-like or graded response. For this study, we used flow cytometry and immunofluorescence to generate single-cell measurements of MAPK signaling in Swiss 3T3 fibroblasts. In contrast to the case in Xenopus oocytes, we found that ERK activation in individual mammalian cells is not ultrasensitive and shows a graded response to changes in agonist concentration. Thus, the conserved MAPK signaling module exhibits different systems-level properties in different cellular contexts. Furthermore, the graded ERK response was converted into a more switch-like behavior at the level of immediate-early gene induction and cell cycle progression. Thus, while MAPK signaling is involved in all-or-nothing cell fate decisions for both Xenopus oocyte maturation and mammalian fibroblast proliferation, the underlying mechanisms responsible for the switch-like nature of the cellular responses are different in these two systems, with the mechanism appearing to lie downstream of the kinase cascade in mammalian fibroblasts.

Activation of the insulin receptor (IR) by insulin and a synthetic peptide has different effects on gene expression in IR-transfected L6 myoblasts

2008 ◽  
Vol 412 (3) ◽  
pp. 435-445 ◽  
Author(s):  
Maja Jensen ◽  
Jane Palsgaard ◽  
Rehannah Borup ◽  
Pierre de Meyts ◽  
Lauge Schäffer
Keyword(s):  
Gene Expression ◽  
Insulin Receptor ◽  
Mapk Pathway ◽  
Receptor Activation ◽  
Mitogen Activated Protein Kinase ◽  
Single Chain ◽  
Therapeutic Implications ◽  
Insulin Mimetic ◽  
Mitogen Activated Protein

Single-chain peptides have been recently produced that display either mimetic or antagonistic properties against the insulin and IGF-1 (insulin-like growth factor 1) receptors. We have shown previously that the insulin mimetic peptide S597 leads to significant differences in receptor activation and initiation of downstream signalling cascades despite similar binding affinity and in vivo hypoglycaemic potency. It is still unclear how two ligands can initiate different signalling responses through the IR (insulin receptor). To investigate further how the activation of the IR by insulin and S597 differentially activates post-receptor signalling, we studied the gene expression profile in response to IR activation by either insulin or S597 using microarray technology. We found striking differences between the patterns induced by these two ligands. Most remarkable was that almost half of the genes differentially regulated by insulin and S597 were involved in cell proliferation and growth. Insulin either selectively regulated the expression of these genes or was a more potent regulator. Furthermore, we found that half of the differentially regulated genes interact with the genes involved with the MAPK (mitogen-activated protein kinase) pathway. These findings support our signalling results obtained previously and confirm that the main difference between S597 and insulin stimulation resides in the activation of the MAPK pathway. In conclusion, we show that insulin and S597 acting via the same receptor differentially affect gene expression in cells, resulting in a different mitogenicity of the two ligands, a finding which has critical therapeutic implications.

scholarly journals Transcriptional Coregulation by the Cell Integrity Mitogen-Activated Protein Kinase Slt2 and the Cell Cycle Regulator Swi4

2001 ◽  
Vol 21 (19) ◽  
pp. 6515-6528 ◽  
Author(s):  
Kristin Baetz ◽  
Jason Moffat ◽  
Jennifer Haynes ◽  
Michael Chang ◽  
Brenda Andrews
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cell Wall ◽  
Transcription Factor ◽  
Protein Kinase ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Regulatory Subunit ◽  
Cell Integrity ◽  
Mitogen Activated Protein

ABSTRACT In Saccharomyces cerevisiae, the heterodimeric transcription factor SBF (for SCB binding factor) is composed of Swi4 and Swi6 and activates gene expression at the G1/S-phase transition of the mitotic cell cycle. Cell cycle commitment is associated not only with major alterations in gene expression but also with highly polarized cell growth; the mitogen-activated protein kinase (MAPK) Slt2 is required to maintain cell wall integrity during periods of polarized growth and cell wall stress. We describe experiments aimed at defining the regulatory pathway involving the cell cycle transcription factor SBF and Slt2-MAPK. Gene expression assays and chromatin immunoprecipitation experiments revealed Slt2-dependent recruitment of SBF to the promoters of the G1 cyclinsPCL1 and PCL2 after activation of the Slt2-MAPK pathway. We performed DNA microarray analysis and identified other genes whose expression was reduced in both SLT2and SWI4 deletion strains. Genes that are sensitive to both Slt2 and Swi4 appear to be uniquely regulated and reveal a role for Swi4, the DNA-binding component of SBF, which is independent of the regulatory subunit Swi6. Some of the Swi4- and Slt2-dependent genes do not require Swi6 for either their expression or for Swi4 localization to their promoters. Consistent with these results, we found a direct interaction between Swi4 and Slt2. Our results establish a new Slt2-dependent mode of Swi4 regulation and suggest roles for Swi4 beyond its prominent role in controlling cell cycle transcription.

Control of the expression of inflammatory response genes

2003 ◽  
Vol 70 ◽  
pp. 95-106 ◽  
Author(s):  
Jeremy Saklatvala ◽  
Jonathan Dean ◽  
Andrew Clark
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Inflammatory Response ◽  
Mapk Pathway ◽  
Interleukin 1 ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Matrix Metalloproteinase 1 ◽  
Inflammatory Stimuli ◽  
Mitogen Activated Protein

The expression of genes involved in the inflammatory response is controlled both transcriptionally and post-transcriptionally. Primary inflammatory stimuli, such as microbial products and the cytokines interleukin-1 (IL-1) and tumour necrosis factor α (TNFα), act through receptors of either the Toll and IL-1 receptor (TIR) family or the TNF receptor family. These cause changes in gene expression by activating four major intracellular signalling pathways that are cascades of protein kinases: namely the three mitogen-activated protein kinase (MAPK) pathways, and the pathway leading to activation of the transcription factor nuclear factor ϰB (NFϰB). The pathways directly activate and induce the expression of a limited set of transcription factors which promote the transcription of inflammatory response genes. Many of the mRNAs are unstable, and are stabilized by the p38 MAPK pathway. Instability is mediated by clusters of the AUUUA motif in the 3″ untranslated regions of the mRNAs. Control of mRNA stability provides a means of increasing the amplitude of a response and allows rapid adjustment of mRNA levels. Not all mRNAs stabilized by p38 contain AUUUA clusters; for example, matrix metalloproteinase-1 and -3 mRNAs lack these clusters, but are stabilized. Inflammatory gene expression is inhibited by glucocorticoids. These suppress MAPK signalling by inducing a MAPK phosphatase. This may be a significant mechanism additional to that by which the glucocorticoid receptor interferes with transcription factors.

scholarly journals The Repertoire of Fos and Jun Proteins Expressed during the G1 Phase of the Cell Cycle Is Determined by the Duration of Mitogen-Activated Protein Kinase Activation

1999 ◽  
Vol 19 (1) ◽  
pp. 330-341 ◽  
Author(s):  
Simon J. Cook ◽  
Natasha Aziz ◽  
Martin McMahon
Keyword(s):  
Protein Kinase ◽  
Cell Fate ◽  
Active Form ◽  
Mapk Cascade ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Activation ◽  
Cell Fate Decisions ◽  
Mitogen Activated Protein ◽  
Early Expression ◽  
Fos Expression

ABSTRACT In Rat-1 fibroblasts nonmitogenic doses of lysophosphatidic acid (LPA) stimulate a transient activation of mitogen-activated protein kinase (MAPK), whereas mitogenic doses elicit a sustained response. This sustained phase of MAPK activation regulates cell fate decisions such as proliferation or differentiation, presumably by inducing a program of gene expression which is not observed in response to transient MAPK activation. We have examined the expression of members of the AP-1 transcription factor complex in response to stimulation with different doses of LPA. c-Fos, c-Jun, and JunB are induced rapidly in response to LPA stimulation, whereas Fra-1 and Fra-2 are induced after a significant lag. The expression of c-Fos is transient, whereas the expression of c-Jun, JunB, Fra-1, and Fra-2 is sustained. The early expression of c-Fos can be reconstituted with nonmitogenic doses of LPA, but the response is transient compared to that observed with mitogenic doses. In contrast, expression of Fra-1, Fra-2, and JunB and optimal expression of c-Jun are observed only with doses of LPA which induce sustained MAPK activation and DNA synthesis. LPA-stimulated expression of c-Fos, Fra-1, Fra-2, c-Jun, and JunB is inhibited by the MEK1 inhibitor PD098059, indicating that the Raf-MEK-MAPK cascade is required for their expression. In cells expressing a conditionally active form of Raf-1 (ΔRaf-1:ER), we observed that selective, sustained activation of Raf-MEK-MAPK was sufficient to induce expression of Fra-1, Fra-2, and JunB but, interestingly, induced little or no c-Fos or c-Jun. The induction of c-Fos observed in response to LPA was strongly inhibited by buffering the intracellular [Ca2+]. Moreover, although Raf activation or calcium ionophores induced little c-Fos expression, we observed a synergistic induction in response to the combination of ΔRaf-1:ER and ionomycin. These results suggest that kinetically distinct phases of MAPK activation serve to regulate the expression of distinct AP-1 components such that sustained MAPK activation is required for the induced expression of Fra-1, Fra-2, c-Jun, and JunB. However, in contrast to the case for Fra-1, Fra-2, and JunB, activation of the MAPK cascade alone is not sufficient to induce c-Fos expression, which rather requires cooperation with other signals such as Ca2+mobilization. Finally, the identification of the Fra-1, Fra-2, c-Jun, and JunB genes as genes which are selectively regulated by sustained MAPK activation or in response to activated Raf suggests that they are candidates to mediate certain of the effects of Ras proteins in oncogenic transformation.

scholarly journals The TAK1-NLK Mitogen-Activated Protein Kinase Cascade Functions in the Wnt-5a/Ca2+ Pathway To Antagonize Wnt/β-Catenin Signaling

2003 ◽  
Vol 23 (1) ◽  
pp. 131-139 ◽  
Author(s):  
Tohru Ishitani ◽  
Satoshi Kishida ◽  
Junko Hyodo-Miura ◽  
Naoto Ueno ◽  
Jun Yasuda ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Transcriptional Activation ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Hek293 Cells ◽  
Transmembrane Segments ◽  
Mitogen Activated Protein ◽  
Kinase Cascade ◽  
Dependent Protein ◽  
Canonical Wnt

ABSTRACT Wnt signaling controls a variety of developmental processes. The canonical Wnt/β-catenin pathway functions to stabilize β-catenin, and the noncanonical Wnt/Ca2+ pathway activates Ca2+/calmodulin-dependent protein kinase II (CaMKII). In addition, the Wnt/Ca2+ pathway activated by Wnt-5a antagonizes the Wnt/β-catenin pathway via an unknown mechanism. The mitogen-activated protein kinase (MAPK) pathway composed of TAK1 MAPK kinase kinase and NLK MAPK also negatively regulates the canonical Wnt/β-catenin signaling pathway. Here we show that activation of CaMKII induces stimulation of the TAK1-NLK pathway. Overexpression of Wnt-5a in HEK293 cells activates NLK through TAK1. Furthermore, by using a chimeric receptor (β2AR-Rfz-2) containing the ligand-binding and transmembrane segments from the β2-adrenergic receptor (β2AR) and the cytoplasmic domains from rat Frizzled-2 (Rfz-2), stimulation with the β-adrenergic agonist isoproterenol activates activities of endogenous CaMKII, TAK1, and NLK and inhibits β-catenin-induced transcriptional activation. These results suggest that the TAK1-NLK MAPK cascade is activated by the noncanonical Wnt-5a/Ca2+ pathway and antagonizes canonical Wnt/β-catenin signaling.

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

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1172 ◽  
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.

scholarly journals Activation of Srk1 by the Mitogen-activated Protein Kinase Sty1/Spc1 Precedes Its Dissociation from the Kinase and Signals Its Degradation

2008 ◽  
Vol 19 (4) ◽  
pp. 1670-1679 ◽  
Author(s):  
Sandra López-Avilés ◽  
Eva Lambea ◽  
Alberto Moldón ◽  
Maribel Grande ◽  
Alba Fajardo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Mitogen Activated Protein Kinase ◽  
Regulatory Domain ◽  
Cycle Progression ◽  
Mitogen Activated Protein ◽  
Extracellular Stimuli ◽  
Response To Stress ◽  
Cytotoxic Stress

Control of cell cycle progression by stress-activated protein kinases (SAPKs) is essential for cell adaptation to extracellular stimuli. The Schizosaccharomyces pombe SAPK Sty1/Spc1 orchestrates general changes in gene expression in response to diverse forms of cytotoxic stress. Here we show that Sty1/Spc1 is bound to its target, the Srk1 kinase, when the signaling pathway is inactive. In response to stress, Sty1/Spc1 phosphorylates Srk1 at threonine 463 of the regulatory domain, inducing both activation of Srk1 kinase, which negatively regulates cell cycle progression by inhibiting Cdc25, and dissociation of Srk1 from the SAPK, which leads to Srk1 degradation by the proteasome.

scholarly journals Cooperative Regulation of DOG2, Encoding 2-Deoxyglucose-6-Phosphate Phosphatase, by Snf1 Kinase and the High-Osmolarity Glycerol–Mitogen-Activated Protein Kinase Cascade in Stress Responses of Saccharomyces cerevisiae

2000 ◽  
Vol 182 (18) ◽  
pp. 5121-5126 ◽  
Author(s):  
Yoshiyuki Tsujimoto ◽  
Shingo Izawa ◽  
Yoshiharu Inoue
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Saccharomyces Cerevisiae ◽  
Osmotic Stress ◽  
Mitogen Activated Protein Kinase ◽  
High Osmolarity ◽  
High Osmolarity Glycerol ◽  
Mitogen Activated Protein ◽  
Kinase Cascade ◽  
Protein Kinase Cascade

ABSTRACT We screened the genome of Saccharomyces cerevisiae for the genes responsive to oxidative stress by using the lacZtransposon-insertion library. As a result, we found that expression of the DOG2 gene coding for 2-deoxyglucose-6-phosphate phosphatase was induced by oxidative stress. The expression ofDOG2 was also induced by osmotic stress. We found a putative cis element (STRE, a stress response element) in the DOG2 promoter adjacent to a consensus sequence to which the Mig1p repressor is known to bind. The basal levels ofDOG2 gene expression were increased in amig1Δ mutant, while the derepression of DOG2was not observed in a snf1Δ mutant under glucose-deprived conditions. Induction of the DOG2 gene expression by osmotic stress was observed in any of the three disruptantspbs2Δ, hog1Δ, and snf1Δ. However, the osmotic induction was completely abolished in both thesnf1Δ pbs2Δ mutant and the snf1Δ hog1Δ mutant. Additionally, these single mutants as well as double mutants failed to induce DOG2 expression by oxidative stress. These results suggest that Snf1p kinase and the high-osmolarity glycerol–mitogen-activated protein kinase cascade are likely to be involved in the signaling pathway of oxidative stress and osmotic stress in regulation of DOG2.

scholarly journals Proteasome inhibitors up-regulate haem oxygenase-1 gene expression: requirement of p38 MAPK (mitogen-activated protein kinase) activation but not of NF-kappaB (nuclear factor kappaB) inhibition

2004 ◽  
Vol 379 (3) ◽  
pp. 587-593 ◽  
Author(s):  
Wen-Tung WU ◽  
Kwan-Hwa CHI ◽  
Feng-Ming HO ◽  
Wei-Chia TSAO ◽  
Wan-Wan LIN
Keyword(s):  
Gene Expression ◽  
P38 Mapk ◽  
Proteasome Inhibitor ◽  
Mapk Pathway ◽  
Proteasome Inhibitors ◽  
Mitogen Activated Protein Kinase ◽  
Pyrrolidine Dithiocarbamate ◽  
Nuclear Factor ◽  
Mitogen Activated Protein ◽  
Haem Oxygenase

Regulation of intracellular protein stability by the ubiquitin-dependent proteasome system plays a crucial role in cell function. HO-1 (haem oxygenase) is a stress response protein, which confers cytoprotection against oxidative injury and provides a vital function in maintaining tissue homoeostasis. In the present study, we found a novel action of proteasome inhibitors MG132 and MG262 on HO-1 induction, and characterized the underlying mechanisms. MG132 (≥0.1 µM) treatment resulted in a marked time- and concentration-dependent induction of the steady-state level of HO-1 mRNA in RAW264.7 macrophages, followed by a corresponding increase in HO-1 protein. Actinomycin D and cycloheximide inhibited MG132-responsive HO-1 protein expression, indicating a requirement for transcription and de novo protein synthesis. The involvement of signal pathways in MG132-induced HO-1 gene expression was examined using chemical inhibitors. Antioxidant N-acetylcysteine and SB203580, an antioxidant and inhibitor of p38 MAPK (mitogen-activated protein kinase), abolished MG132-inducible HO-1 expression. Furthermore, MG132 activated the p38 MAPK pathway. The half-life of HO-1 protein was prolonged by MG132, indicating that the upregulation of HO-1 by proteasome inhibitor is partially attributable to the inhibition of protein degradation. MG132 can ablate IκBα degradation and NF-κB (nuclear factor κB) activation induced by lipopolysaccharide, similar to the effect of another NF-κB inhibitor pyrrolidine dithiocarbamate. We found HO-1 upregulation by MG132 and pyrrolidine dithiocarbamate is unrelated to their inhibition of NF-κB, since leptomycin B, another NF-κB inhibitor, did not elicit similar induction of HO-1. Taken together, we found a novel effect of proteasome inhibitor on induction of HO-1 expression. This action is ascribed to the activation of the p38 MAPK pathway, but is not dependent on NF-κB inhibition.

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