G Protein regulation of MAPK networks

Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Oncogene (Impact Factor: 8.56). 06/2007; 26(22):3122-42. DOI: 10.1038/sj.onc.1210407
Source: PubMed

ABSTRACT G proteins provide signal-coupling mechanisms to heptahelical cell surface receptors and are critically involved in the regulation of different mitogen-activated protein kinase (MAPK) networks. The four classes of G proteins, defined by the G(s), G(i), G(q) and G(12) families, regulate ERK1/2, JNK, p38MAPK, ERK5 and ERK6 modules by different mechanisms. The alpha- as well as betagamma-subunits are involved in the regulation of these MAPK modules in a context-specific manner. While the alpha- and betagamma-subunits primarily regulate the MAPK pathways via their respective effector-mediated signaling pathways, recent studies have unraveled several novel signaling intermediates including receptor tyrosine kinases and small GTPases through which these G-protein subunits positively as well as negatively regulate specific MAPK modules. Multiple mechanisms together with specific scaffold proteins that can link G-protein-coupled receptors or G proteins to distinct MAPK modules contribute to the context-specific and spatio-temporal regulation of mitogen-activated protein signaling networks by G proteins.

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    • "T, Supporting information). These genes are involved in signalling cascades initiating cell proliferation and differentiation (Ip & Davis 1998; Goldsmith & Dhanasekaran 2007 "
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    ABSTRACT: Research on the thermal biology of Antarctic marine organisms has increased awareness of their vulnerability to climate change, as a flipside of their adaptation to life in the permanent cold and their limited capacity to acclimate to variable temperatures. Here, we employed a species–specific microarray of the Antarctic eelpout, Pachycara brachycephalum to identify long-term shifts in gene expression after 2 months of acclimation to six temperatures between -1°C and 9°C.Changes in cellular processes comprised signalling, post-translational modification, cytoskeleton remodelling, metabolic shifts and alterations in the transcription as well as translation machinery. The magnitude of transcriptomic responses paralleled the change in whole animal performance. Optimal growth at 3°C occurred at a minimum in gene expression changes indicative of a balanced steady state. The up–regulation of ribosomal transcripts at 5°C and above was accompanied by the transcriptomic activation of differential protein degradation pathways, from proteasome-based degradation in the cold towards lysosomal protein degradation in the warmth. From 7°C upwards increasing transcript levels representing heat shock proteins and an acute inflammatory response indicate cellular stress. Such patterns may contribute to a warm-induced energy deficit and a strong weight loss at temperatures above 6°C.Together, cold or warm acclimation led to specific cellular rearrangements and the progressive development of functional imbalances beyond the optimum temperature. The observed temperature–specific expression profiles reveal the molecular basis of thermal plasticity and refine present understanding of the shape and positioning of the thermal performance curve of ectotherms on the temperature scale.This article is protected by copyright. All rights reserved.
    Molecular Ecology 06/2014; 23(14). DOI:10.1111/mec.12822 · 6.49 Impact Factor
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    • "activation of G-protein by hormones and neurotransmitters, the increased concentration of intracellular calcium, the combination of receptor tyrosine kinase (RTK) with growth factors and cytokines, and stimulation of extracellular matrix to integrin. It was reported that G-protein regulated MAPK by Ras-dependent and Rap1-dependent pathway (paths 1, 7–9 and 11) (Goldsmith and Dhanasekaran 2007; May and Hill 2008). Characteristic intracellular Ca 2+ oscillations also activated MAPK cascade in hepatocyte proliferation after rat 2/3 hepatectomy (path 2) (Kitamura et al. 1995). "
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    ABSTRACT: Although it is known that hormones, growth factors and integrin promote hepatocyte proliferation in liver regeneration (LR) through ERK1/2 signalling pathway, reports about regulating processes of its intracellular paths in hepatocytes of LR are limited. This study aims at exploring which paths of ERK1/2 signalling pathway participate in the regulation of rat LR, especially in hepatocyte proliferation, and how they do so. In all, 14 paths and 165 genes are known to be involved in ERK1/2 signalling pathway. Of them, 161 genes are included in Rat Genome 230 2.0 Array. This array was used to detect expression changes of genes related to ERK1/2 signalling pathway in isolated hepatocytes of rat LR, showing that 60 genes were related to hepatocytes of LR. In addition, bioinformatics and systems biology methods were used to analyse the roles of 14 above paths in regenerating hepatocytes. We found that three paths, RTK→SHC→GRB2/SOS→RAS→RAF, IntegrinΒ→FAK→RAC→PAK→RAF and GΒγ→PI3KΒγ→RAC→PAK→RAF, promoted the G1 phase progression of hepatocytes by activating ERK1/2. A further four paths, Gq→PLCΒ→PKC→SRC/PYK2→GRB2/SOS→RAS→RAF, RTK→PLCγ→PKC→SRC/PYK2→GRB2/SOS→RAS→RAF, IntegrinΒ→FAK/SRC→GRB2/SOS→RAS→RAF and IntegrinΒ→FAK→RAC→PAK→RAF, advanced the cell progression of S phase and G(2)/M checkpoint by activating ERK1/2, and so did PP1/2→Mek1/2 by decreasing the negative influence on ERK1/2. At the late phase of LR, Gαs→AC→EPAC→Rap1→Raf blocked hepatocyte proliferation by decreasing the activity of ERK1/2 and so did PP1/2→Mek1/2. In summary, 60 genes and 8 paths of ERK1/2 signalling pathway regulated hepatocyte proliferation in rat LR.
    Journal of Genetics 12/2011; 90(3):435-42. DOI:10.1007/s12041-011-0107-5 · 1.01 Impact Factor
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    • "These results indicate that at least two signaling pathways can contribute to bradykinin -induced ERK1/2 phosphorylation in trabecular meshwork cells, and it seems likely that the contribution of a particular pathway will vary with physiological or pharmacological conditions. Regardless of the upstream events, however, a common final step in ERK1/2 activation by a variety of signaling cascades is phosphorylation of ERK1/2 by MAP kinase kinase (MEK) (Goldsmith and Dhanasekaran, 2007). This was also determined to be a key component in the action of bradykinin in trabecular meshwork cells as inhibition of MEK with U0126 completely blocked bradykinin stimulation of ERK1/2 activity. "
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    ABSTRACT: Bradykinin stimulation of B(2) kinin receptors has been shown to promote matrix metallo-proteinase (MMP) secretion from trabecular meshwork cells and to increase conventional outflow facility. Because acute secretion of MMPs can be dependent on the activity of extracellular signal-regulated MAP kinases (ERK1/2), experiments were performed to determine bradykinin effects on ERK1/2 in cultured human trabecular meshwork cells and the relationship of these effects to MMP-9 release. Treatment of cells with bradykinin produced a rapid 4-to 6-fold increase in ERK1/2 phosphorylation. Stimulation of ERK1/2 activity peaked within 2 min and then declined to control levels by 60 min. The response maximum occurred with 100nM bradykinin and the estimated EC₅₀ was 0.7nM. Treatment of cells with the B₂ kinin receptor agonist, Tyr⁸- bradykinin, also stimulated ERK1/2 phosphorylation while the B₁ agonist, Lys- [Des-Arg⁹]- bradykinin had no significant effect. In addition, activation of ERK1/2 by bradykinin or Tyr⁸- bradykinin was blocked by the selective B₂ receptor antagonist, Hoe-140. Inhibition of MAP kinase kinase (MEK) with U0126 also blocked bradykinin-induced ERK1/2 phosphorylation. Suppression of protein kinase C activity with the nonselective inhibitor, GF109203X, or by down-regulation with phorbol ester, diminished, but did not eliminate, bradykinin activation of ERK1/2. A similar decrease of ERK1/2 stimulation was observed when Src kinase was inhibited by 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2). Finally, blockade of bradykinin-induced ERK1/2 activation substantially reduced the peptide's action to stimulate MMP-9 release into the extracellular environment. The data demonstrate that bradykinin promotes ERK1/2 activation in human trabecular meshwork cells. The effect is mediated by B₂ kinin receptors, involves two different signaling pathways, and results in increased secretion of MMP-9.
    Experimental Eye Research 03/2011; 92(6):495-501. DOI:10.1016/j.exer.2011.03.009 · 3.02 Impact Factor
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