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Most viewed articles in last 30 days from Journal of Molecular Signaling (ISSN 1750-2187) published by
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Molecular mechanisms mediating the G protein-coupled receptor regulation of cell cycle progressionG protein-coupled receptors are key regulators of cellular communication, mediating the efficient coordination of a cell's responses to extracellular stimuli. When stimulated these receptors modulate the activity of a wide range of intracellular signalling pathways that facilitate the ordered development, growth and reproduction of the organism. There is now a growing body of evidence examining the mechanisms by which G protein-coupled receptors are able to regulate the expression, activity, localization and stability of cell cycle regulatory proteins that either promote or inhibit the initiation of DNA synthesis. In this review, we will detail the intracellular pathways that mediate the G protein-coupled receptor regulation of cellular proliferation, specifically the progression from the G1 phase to the S phase of the cell cycle.
http://www.jmolecularsignaling.com/content/2/1/2
David C New and Yung H WongJournal of Molecular Signaling 2007, 2:2Number of accesses: 4622007-02-26doi:10.1186/1750-2187-2-2Journal of Molecular Signaling1750-2187222007-02-26The neurotransmitter dopamine modulates vascular permeability in the endotheliumBackground:
Vascular permeability factor/Vascular endothelial growth factor (VPF/VEGF), a multifunctional cytokine, is a potent inducer of vascular permeability, an important early step in angiogenesis. It is known that the neurotransmitter dopamine can inhibit VPF/VEGF mediated angiogenesis, in particular microvascular permeability, but the effectors of this action remain unclear.
Results:
Here, we define the signaling pathway modulated by dopamine that inhibits VPF/VEGF induced vascular permeability in endothelial cells. Signals from VPF/VEGF lead to changes in the phosphorylation of tight junction protein zonula occludens (ZO-1) and adherens junction proteins like VE-cadherin and associated catenins, thus weakening endothelial cell-cell adhesion and increasing vascular permeability. We found VEGF receptor-2 (VEGFR-2) to be part of a multi-protein complex involving ZO-1, VE-cadherin and β-catenin. VPF/VEGF induced phosphorylations of VE-cadherin, β-catenin and ZO-1 were inhibited by dopamine treatment. Association of occludin with ZO-1 and ZO-1 with VE-cadherin were significantly inhibited by dopamine in VEGF treated cells. Furthermore, we identified Src as an important target for dopamine-mediated inhibition of VPF/VEGF induced permeability.
Conclusion:
Taken together, our results provide molecular insights of dopamine function in the vascular endothelium and suggest a central role of Src in regulating key molecules that control vascular permeability.
http://www.jmolecularsignaling.com/content/3/1/14
Resham Bhattacharya, Sutapa Sinha, Su-Ping Yang, Chittaranjan Patra, Shamit Dutta, Enfeng Wang and Debabrata MukhopadhyayJournal of Molecular Signaling 2008, 3:14Number of accesses: 3622008-07-28doi:10.1186/1750-2187-3-14Journal of Molecular Signaling1750-21873142008-07-28CK2beta gene silencing increases cell susceptibility to influenza A virus infection resulting in accelerated virus entry and higher viral protein contentBackground:
Influenza A virus (IVA) exploits diverse cellular gene products to support its replication in the host. The significance of the regulatory (β) subunit of casein kinase 2 (CK2β) in various cellular mechanisms is well established, but less is known about its potential role in IVA replication. We studied the role of CK2β in IVA-infected A549 human epithelial lung cells.
Results:
Activation of CK2β was observed in A549 cells during virus binding and internalization but appeared to be constrained as replication began. We used small interfering RNAs (siRNAs) targeting CK2β mRNA to silence CK2β protein expression in A549 cells without affecting expression of the CK2α subunit. CK2β gene silencing led to increased virus titers, consistent with the inhibition of CK2β during IVA replication. Notably, virus titers increased significantly when CK2β siRNA-transfected cells were inoculated at a lower multiplicity of infection. Virus titers also increased in cells treated with a specific CK2 inhibitor but decreased in cells treated with a CK2β stimulator. CK2β absence did not impair nuclear export of viral ribonucleoprotein complexes (6 h and 8 h after inoculation) or viral polymerase activity (analyzed in a minigenome system). The enhancement of virus titers by CK2β siRNA reflects increased cell susceptibility to influenza virus infection resulting in accelerated virus entry and higher viral protein content.
Conclusion:
This study demonstrates the role of cellular CK2β protein in the viral biology. Our results are the first to demonstrate a functional link between siRNA-mediated inhibition of the CK2β protein and regulation of influenza A virus replication in infected cells. Overall, the data suggest that expression and activation of CK2β inhibits influenza virus replication by regulating the virus entry process and viral protein synthesis.
http://www.jmolecularsignaling.com/content/3/1/13
Henju Marjuki, Christoph Scholtissek, Hui-Ling Yen and Robert G WebsterJournal of Molecular Signaling 2008, 3:13Number of accesses: 2442008-07-23doi:10.1186/1750-2187-3-13Journal of Molecular Signaling1750-21873132008-07-23Inhibition of PI3K/AKT and MEK/ERK pathways act synergistically to enhance antiangiogenic effects of EGCG through activation of FOXO transcription factorBackground:
We have recently shown that epigallocatechin-3-gallate (EGCG), a polyphenolic compound from green tea, inhibits angiogenesis. However, the molecular mechanisms by which EGCG inhibits angiogenesis have never been investigated. In this study, we examined the interaction of PI3K/AKT and MEK/ERK pathways on the regulation of FOXO transcription factors, which ultimately control the antiangiogenic effects of EGCG.
Results:
Inhibition of PI3K/AKT and MEK/ERK pathways interact synergistically to inhibit migration and capillary tube formation of HUVEC cells and further enhanced the antiangiogenic effects of EGCG. Inhibition of AKT and MEK kinases synergistically induced FOXO transcriptional activity, which was further enhanced in the presence of EGCG. Phosphorylation deficient mutants of FOXO induced FOXO transcriptional activity, inhibited HUVEC cell migration and capillary tube formation. Inhibition of FOXO phosphorylation also enhanced antiangiogenic effects of EGCG through transcriptional activation of FOXO.
Conclusion:
Inhibition of PI3K/AKT and MEK/ERK pathways act synergistically to regulate antiangiogenic effects of EGCG through activation of FOXO transcription factors. The activation of FOXO transcription factors through inhibition of these two pathways may have physiological significance in management of diabetic retinopathy, rheumatoid arthritis, psoriasis, cardiovascular diseases, and cancer.
http://www.jmolecularsignaling.com/content/3/1/7
Sharmila Shankar, Qinghe Chen and Rakesh K SrivastavaJournal of Molecular Signaling 2008, 3:7Number of accesses: 2152008-03-20doi:10.1186/1750-2187-3-7Journal of Molecular Signaling1750-2187372008-03-20Regulation of thymus-dependent and thymus-independent production of immunoglobulin G subclasses by Galpha12 and Galpha13Background:
A previous study from this laboratory showed that Gα12 members participate in the production of inflammatory cytokines. In spite of the identification of B cell homeostasis responses regulated by Gα13, the functional roles of Gα12 members in the production of immunoglobulin (Ig) isotypes remained unknown. This study investigated whether Gα12 members are involved in the Ig isotype antibody production with the purpose of establishing their functions in thymus-dependent and thymus-independent humoral responses.
Results:
Mice lacking Gα12 and/or Gα13 showed an impaired antigen-specific antibody production promoted by challenge(s) of ovalbumin or trinitrophenyl-lipopolysaccharide (TNP-LPS), used for thymus-dependent and thymus-independent stimuli, respectively. Homozygous knockout (KO) of Gα12 or double heterozygous KO of Gα12/Gα13 significantly reduced the antigen-specific total IgG level after multiple ovalbumin immunizations with decreases in the production of IgG1, IgG2a and IgG2b subclasses, as compared to wild type control. In contrast, IgM production was not decreased. Moreover, mice deficient in Gα12 or partially deficient in Gα13 or Gα12/Gα13 showed significantly low production of IgG2b in response to TNP-LPS. In TNP-LPS-injected mice, IgG1 and IgG2a productions were unaffected by the G protein KOs.
Conclusion:
Our results demonstrate that both Gα12 and Gα13 are essentially involved in thymus-dependent and independent production of IgG subclasses, implying that the G-proteins contribute to the process of antigen-specific IgG antibody production.
http://www.jmolecularsignaling.com/content/3/1/12
Song Jin Lee, Woo Hyung Lee, Chang Ho Lee and Sang Geon KimJournal of Molecular Signaling 2008, 3:12Number of accesses: 1492008-07-12doi:10.1186/1750-2187-3-12Journal of Molecular Signaling1750-21873122008-07-12SFRP-4 abrogates Wnt-3a-induced β-catenin and Akt/PKB signalling and reverses a Wnt-3a-imposed inhibition of in vitro mammary differentiationBackground:
Conserved Wnt ligands are critical for signalling during development; however, various factors modulate their activity. Among these factors are the Secreted Frizzled-Related Proteins (SFRP). We previously isolated the SFRP-4 gene from an involuting rat mammary gland and later showed that transgenic mice inappropriately expressing SFRP-4 during lactation exhibited a high level of apoptosis with reduced survival of progeny.
Results:
In order to address the questions related to the mechanism of Wnt signalling and its inhibition by SFRP-4 which we report here, we employed partially-purified Wnt-3a in a co-culture model system. Ectopic expression of SFRP-4 was accomplished by infection with a pBabepuro construct. The co-cultures comprised Line 31E mouse mammary secretory epithelial cells and Line 30F, undifferentiated, fibroblast-like mouse mammary cells. In vitro differentiation of such co-cultures can be demonstrated by induction of the β-casein gene in response to lactogenic hormones.We show here that treatment of cells with partially-purified Wnt-3a initiates Dvl-3, Akt/PKB and GSK-3β hyperphosphorylation and β-catenin activation. Furthermore, while up-regulating the cyclin D1 and connexin-43 genes and elevating transepithelial resistance of Line 31E cell monolayers, Wnt-3a treatment abrogates differentiation of co-cultures in response to the lactogenic hormones prolactin, insulin and glucocorticoid. Cells which express SFRP-4, however, are largely unaffected by Wnt-3a stimulation. Since a physical association between Wnt-3a and SFRP-4 could be demonstrated with immunoprecipitation/Western blotting experiments, this interaction, presumably owing to the Frizzled homology region typical of all SFRPs, explains the refractory response to Wnt-3a which was observed.
Conclusion:
This study demonstrates that Wnt-3a treatment activates the Wnt signalling pathway and interferes with in vitro differentiation of mammary co-cultures to β-casein production in response to lactogenic hormones. Similarly, in another measure of differentiation, following Wnt-3a treatment mammary epithelial cells could be shown to up-regulate the cyclin D1 and connexin-43 genes while phenotypically they show increased transepithelial resistance across the cell monolayer. All these behavioural changes can be blocked in mammary epithelial cells expressing SFRP-4. Thus, our data illustrate in an in vitro model a mechanism by which SFRP-4 can modulate a differentiation response to Wnt-3a.
http://www.jmolecularsignaling.com/content/3/1/10
Thecla Constantinou, Fabrizio Baumann, Markus D Lacher, Susanne Saurer, Robert Friis and Arun DharmarajanJournal of Molecular Signaling 2008, 3:10Number of accesses: 1432008-05-02doi:10.1186/1750-2187-3-10Journal of Molecular Signaling1750-21873102008-05-02Data-driven modeling of cellular stimulation, signaling and output response in RAW 264.7 cellsBackground:
Understanding the relative importance of signaling pathway components which regulate a specific cellular response is a major focus of current efforts in biology. This interest, along with the inherit complexity of these systems, is driving the development of approaches capable of providing both quantitative predictions as well as guiding the design of future experiments. Of particular interest is the establishment of methods for the analysis of cellular-level input-output signaling relationships that have been characterized over time.
Results:
Work by the Alliance for Cellular Signaling (AfCS) has provided an extensive profile of ligand-induced changes in protein phosphorylation state and cytokine output response in macrophage-like RAW 264.7 cells. Using model averaging with partial least squares (PLS) or principal components regression (PCR), we compared multivariate models quantitatively predicting cytokine release and identifying key regulatory components of the underlying signaling pathways. We paid particular attention to the effect of metrics extracted from the experimentally derived signaling time courses so as to determine whether the inclusion of such temporal information improved model predictions. Results indicate that we were able to determine the key biological predictors responsible for generating a specific cytokine response, with model R2 values ranging from 0.48 to 0.93. Furthermore, for this data set, the use of time metrics was found to be of mixed value, with increased and/or more appropriate sampling likely being required to improve predictive performance.
Conclusion:
The use of multivariate approaches and model averaging provides a valuable predictive framework for quantitative studies of these complex biological processes. Results of this work also point to several issues for consideration in the design of similar large-scale interrogations.
http://www.jmolecularsignaling.com/content/3/1/11
Yang Wu, Gary L Johnson and Shawn M GomezJournal of Molecular Signaling 2008, 3:11Number of accesses: 1282008-05-22doi:10.1186/1750-2187-3-11Journal of Molecular Signaling1750-21873112008-05-22Enhanced catharanthine and vindoline production in suspension cultures of Catharanthus roseus by ultraviolet-B lightSuspension cultures of Catharanthus roseus were used to evaluate ultraviolet-B (UV-B) treatment as an abiotic elicitor of secondary metabolites. A dispersed cell suspension culture from C. roseus leaves in late exponential phase and stationary phase were irradiated with UV-B for 5 min. The stationary phase cultures were more responsive to UV-B irradiation than late exponential phase cultures. Catharanthine and vindoline increased 3-fold and 12-fold, respectively, on treatment with a 5-min UV-B irradiation.
http://www.jmolecularsignaling.com/content/3/1/9
Shilpa Ramani and Chelliah JayabaskaranJournal of Molecular Signaling 2008, 3:9Number of accesses: 1182008-04-25doi:10.1186/1750-2187-3-9Journal of Molecular Signaling1750-2187392008-04-25Scaffolding proteins in G-protein signalingHeterotrimeric G proteins are ubiquitous signaling partners of seven transmembrane-domain G-protein-coupled receptors (GPCRs), the largest (and most important pharmacologically) receptor family in mammals. A number of scaffolding proteins have been identified that regulate various facets of GPCR signaling. In this review, we summarize current knowledge concerning those scaffolding proteins that are known to directly bind heterotrimeric G proteins, and discuss the composition of the protein complexes they assemble and their effects on signal transduction. Emerging evidence about possible ways of regulation of activity of these scaffolding proteins is also discussed.
http://www.jmolecularsignaling.com/content/2/1/13
Alexandra V Andreeva, Mikhail A Kutuzov and Tatyana A Voyno-YasenetskayaJournal of Molecular Signaling 2007, 2:13Number of accesses: 1092007-10-30doi:10.1186/1750-2187-2-13Journal of Molecular Signaling1750-21872132007-10-30Multiple paxillin binding sites regulate FAK functionBackground:
FAK localization to focal adhesions is essential for its activation and function. Localization of FAK is mediated through the C-terminal focal adhesion targeting (FAT) domain. Recent structural analyses have revealed two paxillin-binding sites in the FAT domain of FAK. To define the role of paxillin binding to each site on FAK, point mutations have been engineered to specifically disrupt paxillin binding to each docking site on the FAT domain of FAK individually or in combination.
Results:
These mutants have been characterized and reveal an important role for paxillin binding in FAK subcellular localization and signaling. One paxillin-binding site (comprised of α-helices 1 and 4 of the FAT domain) plays a more prominent role in localization than the other. Mutation of either paxillin-binding site has similar effects on FAK activation and downstream signaling. However, the sites aren't strictly redundant as each mutant exhibits phosphorylation/signaling defects distinct from wild type FAK and a mutant completely defective for paxillin binding.
Conclusion:
The studies demonstrate that the two paxillin-binding sites of FAK are not redundant and that both sites are required for FAK function.
http://www.jmolecularsignaling.com/content/3/1/1
Danielle M Scheswohl, Jessica R Harrell, Zenon Rajfur, Guanghua Gao, Sharon L Campbell and Michael D SchallerJournal of Molecular Signaling 2008, 3:1Number of accesses: 1052008-01-02doi:10.1186/1750-2187-3-1Journal of Molecular Signaling1750-2187312008-01-02