This is an RSS newsfeed from BioMed Central It is intended to be used with an RSS reader. For more information about RSS newsfeeds from BioMed Central, visit http://www.biomedcentral.com/info/about/rss/ http://www.biosignaling.com The latest articles from Cell Communication and Signaling (ISSN 1478-811X) published by BioMed Central The TNF superfamily member Fas ligand acts as a prototypic death factor. Due to its ability to induce apoptosis in Fas (APO-1, CD95) expressing cells, Fas ligand participates in essential effector functions of the immune system. It is involved in natural killer cell- and T cell-mediated cytotoxicity, the establishment of immune privilege, and in termination of immune responses by induction of activation-induced cell death. In addition, Fas ligand-positive tumours may evade immune surveillance by killing Fas-positive tumour-infiltrating cells. Given these strong cytotoxic capabilities of Fas ligand, it is obvious that its function has to be strictly regulated to avoid uncontrolled damage. In hematopoietic cells, the death factor is stored in secretory lysosomes and is mobilised to the immunological synapse only upon activation. The selective sorting to and the release from this specific lysosomal compartment requires interactions of the Fas ligand cytosolic moiety, which mediates binding to various adapter proteins involved in trafficking and cytoskeletal reorganisation. In addition, Fas ligand surface expression is further regulated by posttranslational ectodomain shedding and subsequent regulated intramembrane proteolysis, releasing a soluble ectodomain cytokine into the extracellular space and an N-terminal fragment with a potential role in intracellular signalling processes. Moreover, other posttranslational modifications of the cytosolic domain, including phosphorylation and ubiquitylation, have been described to affect various aspects of Fas ligand biology. Since FasL is regarded as a potential target for immunotherapy, the further characterisation of its biological regulation and function will be of great importance for the development and evaluation of future therapeutic strategies. http://www.biosignaling.com/content/6/1/11 Matthias Voss, Marcus Lettau, Maren Paulsen and Ottmar Janssen Cell Communication and Signaling 2008, 6:11 2008-12-29 doi:10.1186/1478-811X-6-11 Cell Communication and Signaling 1478-811X 6 11 2008-12-29 The multi-step process of the emigration of cells from the blood stream through the vascular endothelium into the tissue has been termed extravasation. The extravasation of leukocytes is fairly well characterized down to the molecular level, and has been reviewed in several aspects. Comparatively little is known about the extravasation of tumor cells, which is part of the hematogenic metastasis formation. Although the steps of the process are basically the same in leukocytes and tumor cells, i.e. rolling, adhesion, transmigration (diapedesis), the molecules that are involved are different. A further important difference is that leukocyte interaction with the endothelium changes the endothelial integrity only temporarily, whereas tumor cell interaction leads to an irreversible damage of the endothelial architecture. Moreover, tumor cells utilize leukocytes for their extravasation as linkers to the endothelium. Thus, metastasis formation is indirectly susceptible to localization signals that are literally specific for the immune system. We herein compare the extravasation of leukocytes and tumor cells with regard to the involved receptors and the localization signals that direct the cells to certain organs and sites of the body. http://www.biosignaling.com/content/6/1/10 Carina Strell and Frank Entschladen Cell Communication and Signaling 2008, 6:10 2008-12-04 doi:10.1186/1478-811X-6-10 Cell Communication and Signaling 1478-811X 6 10 2008-12-04 Life on Earth developed in the presence and under the constant influence of gravity. Gravity has been present during the entire evolution, from the first organic molecule to mammals and humans. Modern research revealed clearly that gravity is important, probably indispensable for the function of living systems, from unicellular organisms to men. Thus, gravity research is no more or less a fundamental question about the conditions of life on Earth. Since the first space missions and supported thereafter by a multitude of space and ground-based experiments, it is well known that immune cell function is severely suppressed in microgravity, which renders the cells of the immune system an ideal model organism to investigate the influence of gravity on the cellular and molecular level. Here we review the current knowledge about the question, if and how cellular signal transduction depends on the existence of gravity, with special focus on cells of the immune system. Since immune cell function is fundamental to keep the organism under imnological surveillance during the defence against pathogens, to investigate the effects and possible molecular mechanisms of altered gravity is indispensable for long-term space flights to Earth Moon or Mars. Thus, understanding the impact of gravity on cellular functions on Earth will provide not only important informations about the development of life on Earth, but also for therapeutic and preventive strategies to cope successfully with medical problems during space exploration. http://www.biosignaling.com/content/6/1/9 Oliver Ullrich, Kathrin Huber and Kerstin Lang Cell Communication and Signaling 2008, 6:9 2008-10-28 doi:10.1186/1478-811X-6-9 Cell Communication and Signaling 1478-811X 6 9 2008-10-28 Background: Notch signalling is essential for the development and maintenance of the colonic epithelium. Its inhibition induces a differentiation phenotype in vivo and reduces adenomas in APCmin mice. Whether Notch signals are also required in colorectal cancer (CRC) has remained elusive. Therefore, 64 CRC cell lines were analysed for the occurrence of proteolytically processed, active Notch. Results: 63 CRC lines contained a fragment with approximately the size of the Notch1 intracellular domain (NICD), which is required for signalling. Subsequent analyses with an antibody that specifically recognises the free Val1744 residue generated by γ-secretase-mediated cleavage of Notch1 showed that a subset of CRC cells lacks this specific Val1744-NICD. Surprisingly, inhibition of Val1744-NICD signalling with different γ-secretase inhibitors (GSI) did not lead to substantial effects on CRC cell line growth or survival. However, transient activation of Erk upon GSI treatment was detected. Since cisplatin relies on Erk activation for bioactivity in some cells, platinum compounds were tested together with GSI and enhanced cell killing in a subset of Val1744-NICD-positive CRC cell lines was detected. Erk inhibition ablated this combination effect. Conclusion: We conclude that γ-secretase inhibition results in activation of the MAP kinases Erk1/2 and, when used in conjunction, enhances cell death induced by platinum compounds in a large subset of colorectal cancer cell lines.Furthermore the activation of Erk appears to be of particular importance in mediating the enhanced effect seen, as its inhibition abrogates the observed phenomenon. These findings do not only highlight the importance of signalling pathway crosstalk but they may also suggest a new avenue of combination therapy for some colorectal cancers. http://www.biosignaling.com/content/6/1/8 Tamara Aleksic and Stephan M Feller Cell Communication and Signaling 2008, 6:8 2008-10-24 doi:10.1186/1478-811X-6-8 Cell Communication and Signaling 1478-811X 6 8 2008-10-24 Background: Src family kinases (SFK) are implicated in the development of some colorectal cancers (CRC). One SFK member, Lck, is not detectable in normal colonic epithelium, but becomes aberrantly expressed in a subset of CRCs. Although SFK have been extensively studied in fibroblasts and different types of immune cells, their physical and functional targets in many epithelial cancers remain poorly characterised. Results: 64 CRC cell lines were tested for expression of Lck. SW620 CRC cells, which express high levels of Lck and also contain high basal levels of tyrosine phosphorylated (pY) proteins, were then analysed to identify novel SFK targets. Since SH2 domains of SFK are known to often bind substrates after phosphorylation by the kinase domain, the LckSH2 was compared with 14 other SH2s for suitability as affinity chromatography reagent. Mass spectrometric analyses of LckSH2-purified pY proteins subsequently identified several proteins readily known as SFK kinase substrates, including cortactin, Tom1L1 (SRCASM), GIT1, vimentin and AFAP1L2 (XB130). Additional proteins previously reported as substrates of other tyrosine kinase were also detected, including the EGF and PDGF receptor target Odin. Odin was further analysed and found to contain substantially less pY upon inhibition of SFK activity in SW620 cells, indicating that it is a formerly unknown SFK target in CRC cells. Conclusion: Rapid identification of known and novel SFK targets in CRC cells is feasible with SH2 domain affinity chromatography. The elucidation of new SFK targets like Odin in epithelial cancer cells is expected to lead to novel insight into cancer cell signalling mechanisms and may also serve to indicate new biomarkers for monitoring tumor cell responses to drug treatments. http://www.biosignaling.com/content/6/1/7 Muhammad Emaduddin, Mariola J Edelmann, Benedikt M Kessler and Stephan M Feller Cell Communication and Signaling 2008, 6:7 2008-10-09 doi:10.1186/1478-811X-6-7 Cell Communication and Signaling 1478-811X 6 7 2008-10-09 Rho GTPases are a distinct subfamily of the superfamily of Ras GTPases. The best-characterised members are RhoA, Rac and Cdc42 that regulate many diverse actions such as actin cytoskeleton reorganisation, adhesion, motility as well as cell proliferation, differentiation and gene transcription. Among the 20 members of that family, only Rac2 and RhoH show an expression restricted to the haematopoietic lineage.RhoH was first discovered in 1995 as a fusion transcript with the transcriptional repressor LAZ3/BCL6. It was therefore initially named translation three four (TTF) but later on renamed RhoH due to its close relationship to the Ras/Rho family of GTPases. Since then, RhoH has been implicated in human cancer as the gene is subject to somatic hypermutation and by the detection of RHOH as a translocation partner for LAZ3/BCL6 or other genes in human lymphomas. Underexpression of RhoH is found in hairy cell leukaemia and acute myeloid leukaemia.Some of the amino acids that are crucial for GTPase activity are mutated in RhoH so that the protein is a GTPase-deficient, so-called atypical Rho GTPase. Therefore other mechanisms of regulating RhoH activity have been described. These include regulation at the mRNA level and tyrosine phosphorylation of the protein's unique ITAM-like motif. The C-terminal CaaX box of RhoH is mainly a target for farnesyl-transferase but can also be modified by geranylgeranyl-transferase. Isoprenylation of RhoH and changes in subcellular localisation may be an additional factor to fine-tune signalling.Little is currently known about its signalling, regulation or interaction partners. Recent studies have shown that RhoH negatively influences the proliferation and homing of murine haematopoietic progenitor cells, presumably by acting as an antagonist for Rac1. In leukocytes, RhoH is needed to keep the cells in a resting, non-adhesive state, but the exact mechanism has yet to be elucidated. RhoH has also been implicated as a regulatory molecule in the NFκB, PI3 kinase and Map kinase pathways. The recent generation of RhoH knockout mice showed a defect in thymocyte selection and TCR signalling of thymic and peripheral T-cells. However, RhoH-deficient mice did not develop lymphomas or showed obvious defects in haematopoiesis. http://www.biosignaling.com/content/6/1/6 Florian Fueller and Katharina F Kubatzky Cell Communication and Signaling 2008, 6:6 2008-09-29 doi:10.1186/1478-811X-6-6 Cell Communication and Signaling 1478-811X 6 6 2008-09-29 Thymic stromal lymphopoietin (TSLP), a novel interleukin-7-like cytokine, triggers dendritic cell-mediated inflammatory responses ultimately executed by T helper cells of the Th2 subtype. TSLP emerged as a central player in the development of allergic symptoms, especially in the airways, and is a prime regulatory cytokine at the interface of virus- or antigen-exposed epithelial cells and dendritic cells (DCs). DCs activated by epithelium-derived TSLP can promote naïve CD4+ T cells to adopt a Th2 phenotype, which in turn recruite eosinophilic and basophilic granulocytes as well as mast cells into the airway mucosa. These different cells secrete inflammatory cytokines and chemokines operative in inducing an allergic inflammation and atopic asthma. TSLP is, thus, involved in the control of both an innate and an adaptive immune response. Since TSLP links contact of allergen with the airway epithelium to the onset and maintainance of the asthmatic syndrome, defining the signal transduction underlying TSLP expression and function is of profound interest for a better understandimg of the disease and for the development of new therapeutics. http://www.biosignaling.com/content/6/1/5 Katrin Sebastian, Andreas Borowski, Michael Kuepper and Karlheinz Friedrich Cell Communication and Signaling 2008, 6:5 2008-08-25 doi:10.1186/1478-811X-6-5 Cell Communication and Signaling 1478-811X 6 5 2008-08-25 The concept of a pre-emptive strike as a good means to prevent greater harm may be frequently over-stressed in daily life. However, biological systems in a homeostatic balance are prepared to withstand a certain degree of hostile fire by rather passive means. This also applies to the maintenance of cell survival, where a plethora of protective proteins provide safeguard against erroneous activation of death pathways. Apart from these mechanisms active processes are also essential for the maintenance of cellular homeostasis, commonly referred to as survival signaling. Frequently their targets may be mitochondrial, assuring organelle integrity, which is essential for continued energy production and survival. Transient or permanent failures in these cellular defense strategies result in pathophysiological conditions, which manifest themselves e.g. as cancer or ischemia/reperfusion-associated organ damage. http://www.biosignaling.com/content/6/1/4 Martin Hermann, Andrey Kuznetsov, Manuel Maglione, Julija Smigelskaite, Raimund Margreiter and Jakob Troppmair Cell Communication and Signaling 2008, 6:4 2008-08-19 doi:10.1186/1478-811X-6-4 Cell Communication and Signaling 1478-811X 6 4 2008-08-19 T cells play a central role in many inflammatory diseases, hence the identification and validation of T cell-specific target genes will increase the understanding of T cell function in pathologic inflammatory situations. RNA interference (RNAi), with its ability to induce specific gene silencing in mammalian cells, represents a powerful technology to investigate and validate the function of pharmaceutical target genes in vitro and in vivo. The aim of the present study was to systematically explore RNAi-mediated gene-silencing of known T cell-specific model signaling molecules in primary murine T cells in vitro and in vivo. We demonstrate that siRNA delivery and subsequent silencing of T cell specific genes is substantially increased, if murine T cells were activated prior siRNA transfection. Silencing of ZAP70, p56Lck as well as PLC-γ1 protein expression resulted in impaired function of T cells in vitro. Furthermore, delayed type hypersensitivity (DTH) was ameliorated in vivo after adoptive transfer of ZAP70-silenced T cells. The combination of RNAi-mediated gene silencing and adoptive transfer of gene-silenced T cells, thus, may allow the identification and analysis of T cell-specific targets for therapeutic intervention. Additionally, this model system may represent an alternative to conventional time consuming and cost intensive gene targeting approaches. http://www.biosignaling.com/content/6/1/3 Tatjana C Gust, Luisa Neubrandt, Claudia Merz, Khusru Asadullah, Ulrich Zügel and Arne von Bonin Cell Communication and Signaling 2008, 6:3 2008-08-06 doi:10.1186/1478-811X-6-3 Cell Communication and Signaling 1478-811X 6 3 2008-08-06 Highly dynamic integrin-based focal adhesions provide an important structural basis for anchoring the cellular actin cytoskeleton to the surrounding extracellular matrix. The human pathogen Helicobacter pylori (H. pylori) directly targets integrins with drastic consequences on the epithelial cell morphology and migration, which might contribute to the disruption of the gastric epithelium in vivo. In this review, we summarize the recent findings concerning the complex mechanism through which H. pylori interferes with host integrin signaling thereby deregulating focal adhesions and the actin cytoskeleton of motile epithelial cells. http://www.biosignaling.com/content/6/1/2 Sabine Schneider, Christiane Weydig and Silja Wessler Cell Communication and Signaling 2008, 6:2 2008-08-06 doi:10.1186/1478-811X-6-2 Cell Communication and Signaling 1478-811X 6 2 2008-08-06 None http://www.biosignaling.com/content/6/1/1 Stephan M Feller, Ralf Hass, Ottmar Janssen and Karlheinz Friedrich Cell Communication and Signaling 2008, 6:1 2008-08-06 doi:10.1186/1478-811X-6-1 Cell Communication and Signaling 1478-811X 6 1 2008-08-06 editorial http://www.biosignaling.com/content/5/1/1 Bernard Perbal Cell Communication and Signaling 2007, 5:1 2007-06-05 doi:10.1186/1478-811X-5-1 Cell Communication and Signaling 1478-811X 5 1 2007-06-05