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: 8.46). 06/2007; 26(22):3122-42. DOI: 10.1038/sj.onc.1210407
Source: PubMed


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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Available from: Danny N Dhanasekaran, Oct 07, 2015
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    • "Specifically, it was reported that GPRs were regulated in response to TBI in rat brain [52]. One example of GPR-mediated signal transduction is MAPK pathway [53], which was also enriched by GO term analysis. MAPK signaling cascades consist of three main kinase pathways: extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK, which are sensitive to various environmental change and stress conditions [54]. "
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    ABSTRACT: With wide adoption of explosive-dependent weaponry during military activities, Blast-induced neurotrauma (BINT)-induced traumatic brain injury (TBI) has become a significant medical issue. Therefore, a robust and accessible biomarker system is in demand for effective and efficient TBI diagnosis. Such systems will also be beneficial to studies of TBI pathology. Here we propose the mammalian hair follicles as a potential candidate. An Advanced Blast Simulator (ABS) was developed to generate shock waves simulating traumatic conditions on brains of rat model. Microarray analysis was performed in hair follicles to identify the gene expression profiles that are associated with shock waves. Gene set enrichment analysis (GSEA) and sub-network enrichment analysis (SNEA) were used to identify cell processes and molecular signaling cascades affected by simulated bomb blasts. Enrichment analyses indicated that genes with altered expression levels were involved in central nervous system (CNS)/peripheral nervous system (PNS) responses as well as signal transduction including Ca2+, K+-transportation-dependent signaling, Toll-Like Receptor (TLR) signaling and Mitogen Activated Protein Kinase (MAPK) signaling cascades. Many of the pathways identified as affected by shock waves in the hair follicles have been previously reported to be TBI responsive in other organs such as brain and blood. The results suggest that the hair follicle has some common TBI responsive molecular signatures to other tissues. Moreover, various TBI-associated diseases were identified as preferentially affected using a gene network approach, indicating that the hair follicle may be capable of reflecting comprehensive responses to TBI conditions. Accordingly, the present study demonstrates that the hair follicle is a potentially viable system for rapid and non-invasive TBI diagnosis.
    PLoS ONE 08/2014; 9(8):e104518. DOI:10.1371/journal.pone.0104518 · 3.23 Impact Factor
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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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    • "Both G-protein and β-arrestin mediated signaling pathways can lead to ERK activation [30, 32]. The activation of ERK cascades through G-protein α subunits including Gs, Gi, and Gq and G-protein βγ subunit signaling to Ras has been described [33-39]. "
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    ABSTRACT: It has become clear in recent years that multiple signal transduction pathways are employed upon GPCR activation. One of the major cellular effectors activated by GPCRs is extracellular signal-regulated kinase (ERK). Both G-protein and β-arrestin mediated signaling pathways can lead to ERK activation. However, depending on activation pathway, the subcellular destination of activated ERK1/2 may be different. G-protein -dependent ERK activation results in the translocation of active ERK to the nucleus, whereas ERK activated via an arrestin-dependent mechanism remains largely in the cytoplasm. The subcellular location of activated ERK1/2 determines the downstream signaling cascade. Many substrates of ERK1/2 are found in the nucleus: nuclear transcription factors that participate in gene transcription, cell proliferation and differentiation. ERK1/2 substrates are also found in cytosol and other cellular organelles: they may play roles in translation, mitosis, apoptosis and cross-talk with other signaling pathways. Therefore, determining specific subcellular locations of activated ERK1/2 mediated by GPCR ligands would be important in correlating signaling pathways with cellular physiological functions. While GPCR-stimulated selective ERK pathway activation has been studied in several receptor systems, exploitation of these different signaling cascades for therapeutics has not yet been seriously pursued. Many old drug candidates were identified from screens based on G-protein signaling assays, and their activity on β-arrestin signaling pathways being mostly unknown, especially regarding their subcellular ERK pathways. With today’s knowledge of complicated GPCR signaling pathways, drug discovery can no longer rely on single-pathway approaches. Since ERK activation is an important signaling pathway and associated with many physiological functions, targeting the ERK pathway, especially specific subcellular activation pathways should provide new avenues for GPCR drug discovery.
    07/2013; 7:9-15. DOI:10.2174/2213988501307010009
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