MAP Kinase Resource Forum

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PLoS One. 2013;8(2):e51243. doi: 10.1371/journal.pone.0051243. Epub 2013 Feb 6
A critical role for MAPK signalling pathways in the transcriptional regulation of toll like receptors
Peroval MY, Boyd AC, Young JR, Smith AL.

Abstract

Toll-like Receptors (TLR) are phylogenetically conserved transmembrane proteins responsible for detection of pathogens and activation of immune responses in diverse animal species. The stimulation of TLR by pathogen-derived molecules leads to the production of pro-inflammatory mediators including cytokines and nitric oxide. Although TLR-induced events are critical for immune induction, uncontrolled inflammation can be life threatening and regulation is a critical feature of TLR biology. We used an avian macrophage cell line (HD11) to determine the relationship between TLR agonist-induced activation of inflammatory responses and the transcriptional regulation of TLR. Exposure of macrophages to specific TLR agonists induced upregulation of cytokine and nitric oxide pathways that were inhibited by blocking various components of the TLR signalling pathways. TLR activation also led to changes in the levels of mRNA encoding the TLR responsible for recognising the inducing agonist (cognate regulation) and cross-regulation of other TLR (non-cognate regulation). Interestingly, in most cases, regulation of TLR mRNA was independent of NFκB activity but dependent on one or more of the MAPK pathway components. Moreover, the relative importance of ERK, JNK and p38 was dependent upon both the stimulating agonist and the target TLR. These results provide a framework for understanding the complex pathways involved in transcriptional regulation of TLR, immune induction and inflammation. Manipulation of these pathways during vaccination or management of acute inflammatory disease may lead to improved clinical outcome or enhanced vaccine efficacy.

PMID: 23405061 [PubMed - in process]; PMCID: PMC3566169

http://www.ncbi.nlm.nih.gov/pubmed/23405061

Sci Signal. 2013 Feb 12;6(262):ra11. doi: 10.1126/scisignal.2003087.
ERK-Mediated Phosphorylation of Fibroblast Growth Factor Receptor 1 on Ser777 Inhibits Signaling
Zakrzewska M, Haugsten EM, Nadratowska-Wesolowska B, Oppelt A, Hausott B, Jin Y, Otlewski J, Wesche J, Wiedlocha A.

Abstract

Fibroblast growth factor 1 (FGF1) controls cellular activities through the activation of specific cell-surface FGF receptors (FGFRs). Transphosphorylation of tyrosine residues in the kinase domain of FGFRs leads to activation of intracellular signaling cascades, including those mediated by mitogen-activated protein kinases (MAPKs). FGFRs also contain a serine-rich C-terminal tail. We identified a regulatory mechanism of FGFR signaling involving phosphorylation of Ser(777) in the C-terminal region of FGFR1 by the MAPKs extracellular signal-regulated kinase 1 (ERK1) and ERK2. Prevention of the phosphorylation of Ser(777) in FGFR1 or mutation of Ser(777) to alanine enhanced FGF-stimulated receptor tyrosine phosphorylation and increased cell proliferation, cell migration, and axonal growth. A form of FGFR1 with a phosphomimetic mutation at Ser(777) exhibited reduced signaling. Activation of MAPKs by other receptor tyrosine kinases also resulted in phosphorylation of Ser(777) in FGFR1, thereby enabling crosstalk regulation of FGFR activity by other signaling pathways. Our data reveal a negative feedback mechanism that controls FGF signaling and thereby protects the cell from excessive activation of FGFR.

PMID: 23405013 [PubMed - in process]

http://www.ncbi.nlm.nih.gov/pubmed/23405013

Mol Cell. 2013 Jan 24;49(2):249-61. doi: 10.1016/j.molcel.2012.11.002. Epub 2012 Dec 6.
Frequency-Modulated Pulses of ERK Activity Transmit Quantitative Proliferation Signals
Albeck JG, Mills GB, Brugge JS.

Abstract

The EGF-stimulated ERK/MAPK pathway is a key conduit for cellular proliferation signals and a therapeutic target in many cancers. Here, we characterize two central quantitative aspects of this pathway: the mechanism by which signal strength is encoded and the response curve relating signal output to proliferation. Under steady-state conditions, we find that ERK is activated in discrete, asynchronous pulses with frequency and duration determined by extracellular concentrations of EGF spanning the physiological range. In genetically identical sister cells, cell-to-cell variability in pulse dynamics influences the decision to enter S phase. While targeted inhibition of EGFR reduces the frequency of ERK activity pulses, inhibition of MEK reduces their amplitude. Continuous response curves measured in multiple cell lines reveal that proliferation is effectively silenced only when ERK pathway output falls below a threshold of ∼10%, indicating that high-dose targeting of the pathway is necessary to achieve therapeutic efficacy.

PMID: 23219535 [PubMed - in process]

http://www.ncbi.nlm.nih.gov/pubmed/23219535