http://www.biosignaling.com The most accessed research articles published by Cell Communication and Signaling 2012-01-26T00:00:00Z Protein phosphorylation participates in the regulation of all fundamental biological processes, and protein kinases have been intensively studied. However, while the focus was on catalytic activities, accumulating evidence suggests that non-catalytic properties of protein kinases are essential, and in some cases even sufficient for their functions. These non-catalytic functions include the scaffolding of protein complexes, the competition for protein interactions, allosteric effects on other enzymes, subcellular targeting, and DNA binding. This rich repertoire often is used to coordinate phosphorylation events and enhance the specificity of substrate phosphorylation, but also can adopt functions that do not rely on kinase activity. Here, we discuss such kinase independent functions of protein and lipid kinases focussing on kinases that play a role in the regulation of cell proliferation, differentiation, apoptosis, and motility. http://www.biosignaling.com/content/9/1/23 Jens Rauch Natalia Volinsky David Romano Walter Kolch Cell Communication and Signaling 2011, null:23 2011-10-28T00:00:00Z doi:10.1186/1478-811X-9-23 beyond kinase catalysis This is a much needed up-to-date summary of non-catalytic kinase functions which highlights, for example, kinase contributions to cellular signaling network architectures. /content/figures/1478-811X-9-23-toc.gif Cell Communication and Signaling 1478-811X ${item.volume} 23 2011-10-28T00:00:00Z XML The mesenchymal stroma harbors an important population of cells that possess stem cell-like characteristics including self renewal and differentiation capacities and can be derived from a variety of different sources. These multipotent mesenchymal stem cells (MSC) can be found in nearly all tissues and are mostly located in perivascular niches. MSC have migratory abilities and can secrete protective factors and act as a primary matrix for tissue regeneration during inflammation, tissue injuries and certain cancers.These functions underlie the important physiological roles of MSC and underscore a significant potential for the clinical use of distinct populations from the various tissues. MSC derived from different adult (adipose tissue, peripheral blood, bone marrow) and neonatal tissues (particular parts of the placenta and umbilical cord) are therefore compared in this mini-review with respect to their cell biological properties, surface marker expression and proliferative capacities. In addition, several MSC functions including in vitro and in vivo differentiation capacities within a variety of lineages and immune-modulatory properties are highlighted. Differences in the extracellular milieu such as the presence of interacting neighbouring cell populations, exposure to proteases or a hypoxic microenvironment contribute to functional developments within MSC populations originating from different tissues, and intracellular conditions such as the expression levels of certain micro RNAs can additionally balance MSC function and fate. http://www.biosignaling.com/content/9/1/12 Ralf Hass Cornelia Kasper Stefanie Bohm Roland Jacobs Cell Communication and Signaling 2011, null:12 2011-05-14T00:00:00Z doi:10.1186/1478-811X-9-12 /content/figures/1478-811X-9-12-toc.gif Cell Communication and Signaling 1478-811X ${item.volume} 12 2011-05-14T00:00:00Z XML 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 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 The Receptor for Activated C Kinase 1 (RACK1) is a member of the tryptophan-aspartate repeat (WD-repeat) family of proteins and shares significant homology to the β subunit of G-proteins (Gβ). RACK1 adopts a seven-bladed β-propeller structure which facilitates protein binding. RACK1 has a significant role to play in shuttling proteins around the cell, anchoring proteins at particular locations and in stabilising protein activity. It interacts with the ribosomal machinery, with several cell surface receptors and with proteins in the nucleus. As a result, RACK1 is a key mediator of various pathways and contributes to numerous aspects of cellular function. Here, we discuss RACK1 gene and structure and its role in specific signaling pathways, and address how posttranslational modifications facilitate subcellular location and translocation of RACK1. This review condenses several recent studies suggesting a role for RACK1 in physiological processes such as development, cell migration, central nervous system (CN) function and circadian rhythm as well as reviewing the role of RACK1 in disease. http://www.biosignaling.com/content/9/1/22 David Adams Dorit Ron Patrick Kiely Cell Communication and Signaling 2011, null:22 2011-10-06T00:00:00Z doi:10.1186/1478-811X-9-22 /content/figures/1478-811X-9-22-toc.gif Cell Communication and Signaling 1478-811X ${item.volume} 22 2011-10-06T00:00:00Z XML Rho GTPases represent a family of small GTP-binding proteins involved in cell cytoskeleton organization, migration, transcription, and proliferation. A common theme of these processes is a dynamic reorganization of actin cytoskeleton which has now emerged as a major switch control mainly carried out by Rho and Rac GTPase subfamilies, playing an acknowledged role in adaptation of cell motility to the microenvironment. Cells exhibit three distinct modes of migration when invading the 3 D environment. Collective motility leads to movement of cohorts of cells which maintain the adherens junctions and move by photolytic degradation of matrix barriers. Single cell mesenchymal-type movement is characterized by an elongated cellular shape and again requires extracellular proteolysis and integrin engagement. In addition it depends on Rac1-mediated cell polarization and lamellipodia formation. Conversely, in amoeboid movement cells have a rounded morphology, the movement is independent from proteases but requires high Rho GTPase to drive elevated levels of actomyosin contractility. These two modes of cell movement are interconvertible and several moving cells, including tumor cells, show an high degree of plasticity in motility styles shifting ad hoc between mesenchymal or amoeboid movements. This review will focus on the role of Rac and Rho small GTPases in cell motility and in the complex relationship driving the reciprocal control between Rac and Rho granting for the opportunistic motile behaviour of aggressive cancer cells. In addition we analyse the role of these GTPases in cancer progression and metastatic dissemination. http://www.biosignaling.com/content/8/1/23 Matteo Parri Paola Chiarugi Cell Communication and Signaling 2010, null:23 2010-09-07T00:00:00Z doi:10.1186/1478-811X-8-23 /content/figures/1478-811X-8-23-toc.gif Cell Communication and Signaling 1478-811X ${item.volume} 23 2010-09-07T00:00:00Z XML microRNAs are small, non-coding RNAs that influence diverse biological functions through the repression of target genes during normal development and pathological responses. Widespread use of microRNA arrays to profile microRNA expression has indicated that the levels of many microRNAs are altered during development and disease. These findings have prompted a great deal of investigation into the mechanism and function of microRNA-mediated repression. However, the mechanisms which govern the regulation of microRNA biogenesis and activity are just beginning to be uncovered. Following transcription, mature microRNA are generated through a series of coordinated processing events mediated by large protein complexes. It is increasingly clear that microRNA biogenesis does not proceed in a 'one-size-fits-all' manner. Rather, individual classes of microRNAs are differentially regulated through the association of regulatory factors with the core microRNA biogenesis machinery. Here, we review the regulation of microRNA biogenesis and activity, with particular focus on mechanisms of post-transcriptional control. Further understanding of the regulation of microRNA biogenesis and activity will undoubtedly provide important insights into normal development as well as pathological conditions such as cardiovascular disease and cancer. http://www.biosignaling.com/content/7/1/18 Brandi Davis Akiko Hata Cell Communication and Signaling 2009, null:18 2009-08-10T00:00:00Z doi:10.1186/1478-811X-7-18 /content/figures/1478-811X-7-18-toc.gif Cell Communication and Signaling 1478-811X ${item.volume} 18 2009-08-10T00:00:00Z XML Phosphorylation is the most common and pleiotropic modification in biology, which plays a vital role in regulating and finely tuning a multitude of biological pathways. Transport across the nuclear envelope is also an essential cellular function and is intimately linked to many degeneration processes that lead to disease. It is therefore not surprising that phosphorylation of cargos trafficking between the cytoplasm and nucleus is emerging as an important step to regulate nuclear availability, which directly affects gene expression, cell growth and proliferation. However, the literature on phosphorylation of nucleocytoplasmic trafficking cargos is often confusing. Phosphorylation, and its mirror process dephosphorylation, has been shown to have opposite and often contradictory effects on the ability of cargos to be transported across the nuclear envelope. Without a clear connection between attachment of a phosphate moiety and biological response, it is difficult to fully understand and predict how phosphorylation regulates nucleocytoplasmic trafficking. In this review, we will recapitulate clue findings in the field and provide some general rules on how reversible phosphorylation can affect the nuclear-cytoplasmic localization of substrates. This is only now beginning to emerge as a key regulatory step in biology. http://www.biosignaling.com/content/8/1/32 Jonathan Nardozzi Kaylen Lott Gino Cingolani Cell Communication and Signaling 2010, null:32 2010-12-23T00:00:00Z doi:10.1186/1478-811X-8-32 /content/figures/1478-811X-8-32-toc.gif Cell Communication and Signaling 1478-811X ${item.volume} 32 2010-12-23T00:00:00Z 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 Sirt1 (member of the sirtuin family) is a nicotinamide adenosine dinucleotide (NAD)-dependent deacetylase that removes acetyl groups from various proteins. Sirt1 performs a wide variety of functions in biological systems. The current review focuses on the biological functions of Sirt1 in obesity-associated metabolic diseases, cancer, adipose tissue, aging, cellular senescence, cardiac aging and stress, prion-mediated neurodegeneration, inflammatory signaling in response to environmental stress, development and placental cell survival. http://www.biosignaling.com/content/9/1/11 Shahedur Rahman Rezuanul Islam Cell Communication and Signaling 2011, null:11 2011-05-08T00:00:00Z doi:10.1186/1478-811X-9-11 /content/figures/1478-811X-9-11-toc.gif Cell Communication and Signaling 1478-811X ${item.volume} 11 2011-05-08T00:00:00Z XML