scholarly journals Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase Signaling Initiates a Dynamic Interplay between Sumoylation and Ubiquitination To Regulate the Activity of the Transcriptional Activator PEA3

2008 ◽  
Vol 29 (11) ◽  
pp. 3204-3218 ◽  
Author(s):  
Baoqiang Guo ◽  
Andrew D. Sharrocks
Keyword(s):  
Transcription Factors ◽  
Map Kinase ◽  
Target Gene ◽  
Kinase Signaling ◽  
Extracellular Signal Regulated Kinase ◽  
Sumo Modification ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Map Kinase Pathway ◽  
Kinase Pathway

ABSTRACT Many transcription factors are controlled through SUMO modification, and in the majority of cases this modification results in enhancements in their repressive properties. In some instances, SUMO modification and its associated repressive activities can be reversed by the action of intracellular signaling pathways, leading to enhanced transcriptional capacities of transcription factors. Here we have investigated sumoylation of the ETS domain transcription factor PEA3 and its interplay with the extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase signaling pathway. PEA3 is modified by SUMO in vitro and in vivo on multiple sites in its N-terminal region. Activation of the ERK MAP kinase pathway promotes sumoylation of PEA3. Importantly, sumoylation of PEA3 is required for maximal activation of target gene promoters, including MMP-1 and COX-2. Molecularly, sumoylation is selectively required for synergistic activation of target gene expression with the coactivator CBP. Moreover, sumoylation of PEA3 is required for ubiquitination of PEA3 and promotes its degradation, suggesting that SUMO-mediated recycling of PEA3 plays a role in PEA3-mediated promoter activation. Thus, in contrast to the majority of other transcription factors studied, sumoylation of PEA3 plays a positive role in PEA3-mediated transcriptional activation and the ERK MAP kinase pathway cooperates with rather than antagonizes this process.

scholarly journals Drosophila PDZ-GEF, a Guanine Nucleotide Exchange Factor for Rap1 GTPase, Reveals a Novel Upstream Regulatory Mechanism in the Mitogen-Activated Protein Kinase Signaling Pathway

2002 ◽  
Vol 22 (21) ◽  
pp. 7658-7666 ◽  
Author(s):  
Jun Hee Lee ◽  
Kyoung Sang Cho ◽  
Jihyun Lee ◽  
Dohoon Kim ◽  
Sung-Bae Lee ◽  
...  
Keyword(s):  
Map Kinase ◽  
Signaling Pathway ◽  
Kinase Signaling ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Mitogen Activated Protein ◽  
Map Kinase Pathway ◽  
Kinase Signaling Pathway ◽  
Kinase Pathway

ABSTRACT PDZ-GEF is a novel guanine nucleotide exchange factor for Rap1 GTPase. Here we isolated Drosophila melanogaster PDZ-GEF (dPDZ-GEF), which contains the all-conserved domains of mammalian and nematode PDZ-GEF including cyclic nucleotide monophosphate-binding, Ras exchange motif, PDZ, RA, and GEF domains. dPDZ-GEF loss-of-function mutants were defective in the development of various organs including eye, wing, and ovary. Many of these phenotypes are strikingly similar to the phenotype of the rolled mutant, implying that dPDZ-GEF functions upstream of the mitogen-activated protein (MAP) kinase pathway. Indeed, we found that dPDZ-GEF is specifically involved in photoreceptor cell differentiation, facilitating its neuronal fate via activation of the MAP kinase pathway. Rap1 was found to link dPDZ-GEF to the MAP kinase pathway; however, Ras was not involved in the regulation of the MAP kinase pathway by dPDZ-GEF and actually had an inhibitory function. The analyses of ovary development in dPDZ-GEF-deficient mutants also demonstrated another role of dPDZ-GEF independent of the MAP kinase signaling pathway. Collectively, our findings identify dPDZ-GEF as a novel upstream regulator of various morphogenetic pathways and demonstrate the presence of a novel, Ras-independent mechanism for activating the MAP kinase signaling pathway.

scholarly journals Mitogen-activated protein kinase activation is insufficient for growth factor receptor-mediated PC12 cell differentiation.

1995 ◽  
Vol 15 (7) ◽  
pp. 3644-3653 ◽  
Author(s):  
R R Vaillancourt ◽  
L E Heasley ◽  
J Zamarripa ◽  
B Storey ◽  
M Valius ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Growth Factor ◽  
Map Kinase ◽  
Pc12 Cells ◽  
Pc12 Cell ◽  
Growth Factor Receptor ◽  
Receptor Activation ◽  
Mitogen Activated Protein ◽  
Map Kinase Pathway ◽  
Kinase Pathway

When expressed in PC12 cells, the platelet-derived growth factor beta receptor (beta PDGF-R) mediates cell differentiation. Mutational analysis of the beta PDGF-R indicated that persistent receptor stimulation of the Ras/Raf/mitogen-activated protein (MAP) kinase pathway alone was insufficient to sustain PC12 cell differentiation. PDGF receptor activation of signal pathways involving p60c-src or the persistent regulation of phospholipase C gamma was required for PC12 cell differentiation. beta PDGF-R regulation of phosphatidylinositol 3-kinase, the GTPase-activating protein of Ras, and the tyrosine phosphatase, Syp, was not required for PC12 cell differentiation. In contrast to overexpression of oncoproteins involved in regulating the MAP kinase pathway, growth factor receptor-mediated differentiation of PC12 cells requires the integration of other signals with the Ras/Raf/MAP kinase pathway.

scholarly journals IQGAP1 Is a Scaffold for Mitogen-Activated Protein Kinase Signaling

2005 ◽  
Vol 25 (18) ◽  
pp. 7940-7952 ◽  
Author(s):  
Monideepa Roy ◽  
Zhigang Li ◽  
David B. Sacks
Keyword(s):  
Growth Factor ◽  
Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Signaling ◽  
Cellular Functions ◽  
Molecular Scaffold ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Erk Activity

ABSTRACT IQGAP1 modulates many cellular functions such as cell-cell adhesion, transcription, cytoskeletal architecture, and selected signaling pathways. We previously documented that IQGAP1 binds extracellular signal-regulated kinase (ERK) 2 and regulates growth factor-stimulated ERK activity. Here we show that MEK, the molecule immediately upstream of ERK in the Ras/mitogen-activated protein (MAP) kinase signaling cascade, also interacts directly with IQGAP1. Both MEK1 and MEK2 bound IQGAP1 in vitro and coimmunoprecipitated with IQGAP1. The addition of ERK2 enhanced by fourfold the in vitro interaction of MEK2 with IQGAP1 without altering binding of MEK1. Similarly, ERK1 promoted MEK binding to IQGAP1, but either MEK protein altered the association between IQGAP1 and ERK. Epidermal growth factor (EGF) differentially regulated binding, enhancing MEK1 interaction while reducing MEK2 binding to IQGAP1. In addition, both knockdown and overexpression of IQGAP1 reduced EGF-stimulated activation of MEK and ERK. Analyses with selective IQGAP1 mutant constructs indicated that MEK binding is crucial for IQGAP1 to modulate EGF activation of ERK. Our data strongly suggest that IQGAP1 functions as a molecular scaffold in the Ras/MAP kinase pathway.

Dibucaine and Tetracaine Inhibit the Activation of Mitogen-activated Protein Kinase Mediated by L-type Calcium Channels in PC12 Cells 

1999 ◽  
Vol 91 (6) ◽  
pp. 1798-1798 ◽  
Author(s):  
Masumi Kansha ◽  
Taro Nagata ◽  
Kazuo Irita ◽  
Shosuke Takahashi
Keyword(s):  
Map Kinase ◽  
Pc12 Cells ◽  
Local Anesthetics ◽  
Mitogen Activated Protein ◽  
Ic50 Values ◽  
Map Kinase Pathway ◽  
Kinase Signaling Pathway ◽  
Kinase Pathway ◽  
Map Kinase Signaling Pathway ◽  
Ca2 Channels

Background An elevation of the intracellular calcium level, which is mediated by N-methyl-D-aspartate receptors and L-type Ca2+ channels both, activates the mitogen-activated protein (MAP) kinase signaling pathway involved in synaptic modification. It has recently been suggested that MAP kinase plays a role in coupling the synaptic excitation to gene expression in the nucleus of postsynaptic neurons. Because the effects of local anesthetics on cellular signal transduction in neuronal cells are not well-known, the authors investigated whether they affect the MAP kinase signaling pathway using PC12 cells. Methods The cells were stimulated with either 50 mM KCl or 1 microM ionomycin, and activated MAP kinase was thus immunoprecipitated. The immunocomplexes were then subjected to an Elk1 phosphorylation assay. Both the phosphorylation of MAP kinase and the induction of c-Fos were detected by immunoblotting. Results Pretreatment of the cells with 1 mM (ethylenedioxy)-diethyl-enedinitrilotetraacetic acid or 5 micron nifedipine blocked the MAP kinase activation induced by 50 mM KCl, whereas pretreatment with 2 microM omega-conotoxin GIVA did not. The expression of c-Fos induced by potassium chloride was also suppressed by dibucaine, tetracaine (concentrations that inhibited 50% of the activity of positive control [IC50s] were 16.2+/-0.2 and 73.2+/-0.7 microM, respectively), and PD 98059, a mitogen-activated/extracellular receptor-regulated kinase inhibitor. Higher concentrations of dibucaine and tetracaine were needed to suppress the activation of MAP kinase induced by ionomycin (the IC50 values of dibucaine and tetracaine were 62.5+/-2.2 and 330.5+/-32.8 microM, respectively) compared with potassium chloride (the IC50 values of dibucaine and tetracaine were 17.7+/-1.0 and 70.2+/-1.2 microM, respectively). Although probable targets of these local anesthetics might be L-type Ca2+ channels or components between Ca2+ and Ras in MAP kinase pathway, the possibility that they directly affect MAP kinase still remains. Conclusions Dibucaine and tetracaine at clinical concentrations were found to inhibit the activation of MAP kinase and the expression of c-Fos mediated by L-type Ca2+ channels in PC12 cells. The suppression of MAP kinase pathway may thus be a potential target site for the actions of dibucaine and tetracaine, including the modification of the synaptic functions.

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