http://www.biosignaling.com The latest research articles published by Cell Communication and Signaling 2012-01-26T00:00:00Z Background: Tuberculosis (TB), a bacterial infection caused by Mycobacterium tuberculosis (Mtb remains a significant health problem worldwide with a third of the world population infected and nearly nine million new cases claiming 1.1 million deaths every year. The outcome following infection by Mtb is determined by a complex and dynamic host-pathogen interaction in which the phenotype of the pathogen and the immune status of the host play a role. However, the molecular mechanism by which Mtb strains induce different responses during intracellular infection of the host macrophage is not fully understood. To explore the early molecular events triggered upon Mtb infection of macrophages, we studied the transcriptional responses of murine bone marrow-derived macrophages (BMM) to infection with two clinical Mtb strains, CDC1551 and HN878. These strains have previously been shown to differ in their virulence/immunogenicity in the mouse and rabbit models of pulmonary TB. Results: In spite of similar intracellular growth rates, we observed that compared to HN878, infection by CDC1551 of BMM was associated with an increased global transcriptome, up-regulation of a specific early (6 hours) immune response network and significantly elevated nitric oxide production. In contrast, at 24 hours post-infection of BMM by HN878, more host genes involved in lipid metabolism, including cholesterol metabolism and prostaglandin synthesis were up-regulated, compared to infection with CDC1551.In association with the differences in the macrophage responses to infection with the 2 Mtb strains, intracellular CDC1551 expressed higher levels of stress response genes than did HN878. Conclusions: In association with the early and more robust macrophage activation, intracellular CDC1551 cells were exposed to a higher level of stress leading to increased up-regulation of the bacterial stress response genes. In contrast, sub-optimal activation of macrophages and induction of a deregulated host cell lipid metabolism favored a less stressful intracellular environment for HN878. Our findings suggest that the ability of CDC1551 and HN878 to differentially activate macrophages during infection probably determines their ability to either resist host cell immunity and progress to active disease or to succumb to the host protective responses and be driven into a non-replicating latent state in rabbit lungs. http://www.biosignaling.com/content/10/1/2 Mi-Sun Koo Selvakumar Subbian Gilla Kaplan Cell Communication and Signaling 2012, null:2 2012-01-26T00:00:00Z doi:10.1186/1478-811X-10-2 /content/figures/1478-811X-10-2-toc.gif Cell Communication and Signaling 1478-811X ${item.volume} 2 2012-01-26T00:00:00Z PDF In our study we aimed to identify rapidly reacting gravity-responsive mechanisms in mammalian cells in order to understand if and how altered gravity is translated into a cellular response. In a combination of experiments using "functional weightlessness" provided by 2D-clinostats and real microgravity provided by several parabolic flight campaigns and compared to in-flight-1g-controls, we identified rapid gravity-responsive reactions inside the cell cycle regulatory machinery of human T lymphocytes. In response to 2D clinorotation, we detected an enhanced expression of p21 Waf1/Cip1 protein within minutes, less cdc25C protein expression and enhanced Ser147-phosphorylation of cyclinB1 after CD3/CD28 stimulation. Additionally, during 2D clinorotation, Tyr-15-phosphorylation occurred later and was shorter than in the 1 g controls. In CD3/CD28-stimulated primary human T cells, mRNA expression of the cell cycle arrest protein p21 increased 4.1-fold after 20s real microgravity in primary CD4+ T cells and 2.9-fold in Jurkat T cells, compared to 1 g in-flight controls after CD3/CD28 stimulation. The histone acetyltransferase (HAT) inhibitor curcumin was able to abrogate microgravity-induced p21 mRNA expression, whereas expression was enhanced by a histone deacetylase (HDAC) inhibitor. Therefore, we suppose that cell cycle progression in human T lymphocytes requires Earth gravity and that the disturbed expression of cell cycle regulatory proteins could contribute to the breakdown of the human immune system in space. http://www.biosignaling.com/content/10/1/1 Cora Thiel Katrin Paulsen Gesine Bradacs Karoline Lust Svantje Tauber Claudia Dumrese Andre Hilliger Kathrin Schoppmann Josephine Biskup Nadine Golz Chen Sang Urs Ziegler Karl-Heinrich Grote Frauke Zipp Fengyuan Zhuang Frank Engelmann Ruth Hemmersbach Augusto Cogoli Oliver Ullrich Cell Communication and Signaling 2012, null:1 2012-01-24T00:00:00Z doi:10.1186/1478-811X-10-1 /content/figures/1478-811X-10-1-toc.gif Cell Communication and Signaling 1478-811X ${item.volume} 1 2012-01-24T00:00:00Z XML In this study we investigated if and how cannabinoid receptor stimulation regulates macrophageal differentiation, which is one of the key steps in the immune effector reaction. For that reason, we used a well established differentiation model system of human U937 myelocytic leukemia cells that differentiate along the monocyte/macrophage lineage upon stimulation with the phorbol ester PMA. Constant cannabinoid receptor (CB) stimulation was performed using WIN55212-2, a potent synthetic CB agonist. We found that WIN55212-2 inhibited CB1/2-receptor-dependent PMA-induced differentiation of human myelocytic U937 cells into the macrophageal phenotype, which was associated with impaired vimentin, ICAM-1 and CD11b expression. In the presence of WIN55212-2, cdc2 protein and mRNA expression was progressively enhanced and Tyr-15-phosporylation of cdc2 was reduced in differentiating U937 cells. Additionally, p21Waf1/Cip1 expression was up-regulated. PMA-induced apoptosis was not enhanced by WIN55212-2 and differentiation-associated c-jun expression was not altered. In conclusion, we suppose that WIN55212-2-induced signals interferes with cell-cycle-arrest-signaling in differentiating myelocytic cells and thus inhibits macrophageal differentiation. Thus, it is possible that the cannabinoid system is able to influence one of the key steps in the immune effector function, the monocytic-macrophageal differentiation by alteration of cell cycle control proteins cdc2 and p21, and is therefore representing a promising option for therapeutic intervention in exacerbated immune reactions. http://www.biosignaling.com/content/9/1/33 Katrin Paulsen Svantje Tauber Johanna Timm Nadine Goelz Claudia Dumrese Alexandra Stolzing Ralf Hass Oliver Ullrich Cell Communication and Signaling 2011, null:33 2011-12-28T00:00:00Z doi:10.1186/1478-811X-9-33 /content/figures/1478-811X-9-33-toc.gif Cell Communication and Signaling 1478-811X ${item.volume} 33 2011-12-28T00:00:00Z XML Background: Host cell invasion by the foodborne pathogen Campylobacter jejuni is considered as one of the primary reasons of gut tissue damage, however, mechanisms and key factors involved in this process are widely unclear. It was reported that small Rho GTPases, including Cdc42, are activated and play a role during invasion, but the involved signaling cascades remained unknown. Here we utilised knockout cell lines derived from fibronectin-/-, integrin-beta1-/-, focal adhesion kinase (FAK)-/- and Src/Yes/Fyn-/- deficient mice, and wild-type control cells, to investigate C. jejuni-induced mechanisms leading to Cdc42 activation and bacterial uptake. Results: Using high-resolution scanning electron microscopy, GTPase pull-downs, G-Lisa and gentamicin protection assays we found that each studied host factor is necessary for induction of Cdc42-GTP and efficient invasion. Interestingly, filopodia formation and associated membrane dynamics linked to invasion were only seen during infection of wild-type but not in knockout cells. Infection of cells stably expressing integrin-beta1 variants with well-known defects in fibronectin fibril formation or FAK signaling also exhibited severe deficiencies in Cdc42 activation and bacterial invasion. We further demonstrated that infection of wild-type cells induces increasing amounts of phosphorylated FAK and growth factor receptors (EGFR and PDGFR) during the course of infection, correlating with accumulating Cdc42-GTP levels and C. jejuni invasion over time. In studies using pharmacological inhibitors, silencing RNA (siRNA) and dominant-negative expression constructs, EGFR, PDGFR and PI3-kinase appeared to represent other crucial components upstream of Cdc42 and invasion. siRNA and the use of Vav-1/2-/- knockout cells further showed that the guanine exchange factor Vav2 is required for Cdc42 activation and maximal bacterial invasion. Overexpression of certain mutant constructs indicated that Vav2 is a linker molecule between Cdc42 and activated EGFR/PDGFR/PI3-kinase. Using C. jejuni mutant strains we further demonstrated that the fibronectin-binding protein CadF and intact flagella are involved in Cdc42-GTP induction, indicating that the bacteria may directly target the fibronectin/integrin complex for inducing signaling leading to its host cell entry. Conclusion: Collectively, our findings led us propose that C. jejuni infection triggers a novel fibronectin>integrin-beta1>FAK/Src>EGFR/PDGFR>PI3-kinase>Vav2 signaling cascade, which plays a crucial role for Cdc42 GTPase activity associated with filopodia formation and enhances bacterial invasion. http://www.biosignaling.com/content/9/1/32 Malgorzata Krause-Gruszczynska Manja Boehm Manfred Rohde Nicole Tegtmeyer Seiichiro Takahashi Laszlo Buday Omar Oyarzabal Steffen Backert Cell Communication and Signaling 2011, null:32 2011-12-28T00:00:00Z doi:10.1186/1478-811X-9-32 /content/figures/1478-811X-9-32-toc.gif Cell Communication and Signaling 1478-811X ${item.volume} 32 2011-12-28T00:00:00Z PDF Background: Lipid rafts present on the plasma membrane play an important role in spatiotemporal regulation of cell signaling. Physical and chemical characterization of lipid raft size and assessment of their composition before, and after cell stimulation will aid in developing a clear understanding of their regulatory role in cell signaling. We have used visual and biochemical methods and approaches for examining individual and lipid raft sub-populations isolated from a mouse CD4+ T cell line in the absence of detergents. Results: Detergent-free rafts were analyzed before and after their interaction with antigen presenting cells. We provide evidence that the average diameter of lipid rafts isolated from un-stimulated T cells, in the absence of detergents, is less than 100 nm. Lipid rafts on CD4+ T cell membranes coalesce to form larger structures, after interacting with antigen presenting cells even in the absence of a foreign antigen. Conclusions: Findings presented here indicate that lipid raft coalescence occurs during cellular interactions prior to sensing a foreign antigen. http://www.biosignaling.com/content/9/1/31 Colleen Kennedy Matthew Nelson Anil Bamezai Cell Communication and Signaling 2011, null:31 2011-12-08T00:00:00Z doi:10.1186/1478-811X-9-31 /content/figures/1478-811X-9-31-toc.gif Cell Communication and Signaling 1478-811X ${item.volume} 31 2011-12-08T00:00:00Z PDF The evolutionary synthesis, the standard 20th century view of how evolutionary change occurs, is based on selection, heritable phenotypic variation and a very simple view of genes. It is therefore unable to incorporate two key aspects of modern molecular knowledge: first is the richness of genomic variation, so much more complicated than simple mutation, and second is the opaque relationship between the genotype and its resulting phenotype. Two new and important books shed some light on how we should view evolutionary change now. Evolution: a view from the 21st century by J.A. Shapiro (2011, FT Press Science, New Jersey, USA. pp. 246.) examines the richness of genomic variation and its implications. Transformations of Lamarckism: from Subtle Fluids to Molecular Biology edited by S.B. Gissis & E. Jablonka (2011, MIT Press, Cambridge, USA. pp. 457) includes some 40 papers that anyone with an interest in the history of evolutionary thought and the relationship between the environment and the genome will want to read. This review discusses both books within the context of contemporary evolutionary thinking and points out that neither really comes to terms with today's key systems-biology question: how does mutation-induced variation in a molecular network generate variation in the resulting phenotype? http://www.biosignaling.com/content/9/1/30 Jonathan Bard Cell Communication and Signaling 2011, null:30 2011-11-03T00:00:00Z doi:10.1186/1478-811X-9-30 /content/figures/1478-811X-9-30-toc.gif Cell Communication and Signaling 1478-811X ${item.volume} 30 2011-11-03T00:00:00Z XML Helicobacter pylori is a highly successful pathogen uniquely adapted to colonize humans. Gastric infections with this bacterium can induce pathology ranging from chronic gastritis and peptic ulcers to gastric cancer. More virulent H. pylori isolates harbour numerous well-known adhesins (BabA/B, SabA, AlpA/B, OipA and HopZ) and the cag (cytotoxin-associated genes) pathogenicity island encoding a type IV secretion system (T4SS). The adhesins establish tight bacterial contact with host target cells and the T4SS represents a needle-like pilus device for the delivery of effector proteins into host target cells such as CagA. BabA and SabA bind to blood group antigen and sialylated proteins respectively, and a series of T4SS components including CagI, CagL, CagY and CagA have been shown to target the integrin β1 receptor followed by injection of CagA across the host cell membrane. The interaction of CagA with membrane-anchored phosphatidylserine may also play a role in the delivery process. While substantial progress has been made in our current understanding of many of the above factors, the host cell receptors for OipA, HopZ and AlpA/B during infection are still unknown. Here we review the recent progress in characterizing the interactions of the various adhesins and structural T4SS proteins with host cell factors. The contribution of these interactions to H. pylori colonization and pathogenesis is discussed. http://www.biosignaling.com/content/9/1/28 Steffen Backert Marguerite Clyne Nicole Tegtmeyer Cell Communication and Signaling 2011, null:28 2011-11-01T00:00:00Z doi:10.1186/1478-811X-9-28 /content/figures/1478-811X-9-28-toc.gif Cell Communication and Signaling 1478-811X ${item.volume} 28 2011-11-01T00:00:00Z XML Dynamic rearrangement of the actin cytoskeleton is a significant hallmark of Helicobacter pylori (H. pylori) infected gastric epithelial cells leading to cell migration and invasive growth. Considering the cellular mechanisms, the type IV secretion system (T4SS) and the effector protein cytotoxin-associated gene A (CagA) of H. pylori are well-studied initiators of distinct signal transduction pathways in host cells targeting kinases, adaptor proteins, GTPases, actin binding and other proteins involved in the regulation of the actin lattice. In this review, we summarize recent findings of how H. pylori functionally interacts with the complex signaling network that controls the actin cytoskeleton of motile and invasive gastric epithelial cells. http://www.biosignaling.com/content/9/1/27 Silja Wessler Mario Gimona Gabriele Rieder Cell Communication and Signaling 2011, null:27 2011-11-01T00:00:00Z doi:10.1186/1478-811X-9-27 /content/figures/1478-811X-9-27-toc.gif Cell Communication and Signaling 1478-811X ${item.volume} 27 2011-11-01T00:00:00Z XML VacA, the vacuolating cytotoxin A of Helicobacter pylori, induces apoptosis in epithelial cells of the gastic mucosa and in leukocytes. VacA is released by the bacteria as a protein of 88 kDa. At the outer surface of host cells, it binds to the sphingomyelin of lipid rafts. At least partially, binding to the cells is facilitated by different receptor proteins. VacA is internalized by a clathrin-independent mechanism and initially accumulates in GPI-anchored proteins-enriched early endosomal compartments. Together with early endosomes, VacA is distributed inside the cells. Most of the VacA is eventually contained in the membranes of vacuoles. VacA assembles in hexameric oligomers forming an anion channel of low conductivity with a preference for chloride ions. In parallel, a significant fraction of VacA can be transferred from endosomes to mitochondria in a process involving direct endosome-mitochondria juxtaposition. Inside the mitochondria, VacA accumulates in the mitochondrial inner membrane, probably forming similar chloride channels as observed in the vacuoles. Import into mitochondria is mediated by the hydrophobic N-terminus of VacA. Apoptosis is triggered by loss of the mitochondrial membrane potential, recruitment of Bax and Bak, and release of cytochrome c. http://www.biosignaling.com/content/9/1/26 Joachim Rassow Cell Communication and Signaling 2011, null:26 2011-11-01T00:00:00Z doi:10.1186/1478-811X-9-26 /content/figures/1478-811X-9-26-toc.gif Cell Communication and Signaling 1478-811X ${item.volume} 26 2011-11-01T00:00:00Z XML Persistent infection with the gastric bacterial pathogen Helicobacter pylori causes gastritis and predisposes carriers to a high gastric cancer risk, but has also been linked to protection from allergic, chronic inflammatory and autoimmune diseases. In the course of tens of thousands of years of co-existence with its human host, H. pylori has evolved elaborate adaptations that allow it to persist in the hostile environment of the stomach in the face of a vigorous innate and adaptive immune response. For this review, we have identified several key immune cell types and signaling pathways that appear to be preferentially targeted by the bacteria to establish and maintain persistent infection. We explore the mechanisms that allow the bacteria to avoid detection by innate immune cells via their pattern recognition receptors, to escape T-cell mediated adaptive immunity, and to reprogram the immune system towards tolerance rather than immunity. The implications of the immunomodulatory properties of the bacteria for the prevention of allergic and auto-immune diseases in chronically infected individuals are also discussed. http://www.biosignaling.com/content/9/1/25 Anne Muller Mathias Oertli Isabelle Arnold Cell Communication and Signaling 2011, null:25 2011-11-01T00:00:00Z doi:10.1186/1478-811X-9-25 /content/figures/1478-811X-9-25-toc.gif Cell Communication and Signaling 1478-811X ${item.volume} 25 2011-11-01T00:00:00Z XML