Matricellular CCN proteins

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Editorial for Issue 1, Jan 2016 title of the editorial 2016 : A year for JCCS Editorial changes and CCN3 KO mice at ICCNS

The year 2016 will see significant improvements for the Journal of Cell Communication and Signaling with the earning of an official Impact Factor and the merger of Springer Science + Business Media and part of Macmillan Sciences and Education. It will also be an important year for the International CCN Society (ICCNS) with the nomination of a new Scientific Board and reinforcement of interactions with other major scientific societies interested in various aspects of Cell Signaling. Starting this year the ICCNS will become an official provider of CCN3 knock out mice to ICCNS members. This first step in opening up access to certified reagents as a service for our CCN scientific community is part of our intention and efforts to attain the highest degree of assistance and enabler of scientific cooperation and communication in Science Communication.     

7th international workshop on the CCN family of genes: Nice to be in nice

In this Editorial, I would like to provide our readers with a brief mid-year update about our activities and efforts to bring together researchers working on intercellular signaling proteins at international meetings. The roots emerged about 20 years ago in the discovery of three genes originally designated cyr61, ctgf, and nov. The proteins encoded by these genes were first proposed to constitute a family of proteins (CCN) which now comprises 6 members (CCN1, CCN2, CCN3, CCN4-6) including the wisp proteins. These proteins were recognized to share a striking structural organization and a high degree of identity although they exhibited quite distinct biological properties. After historical considerations regarding the reasons for using the CCN acronym, and how the ICCNS publishing landscape that drove the ICCNS from Cell Communication and Signaling to the Journal of Cell Communication and Signaling, this short update will focus on the 7th edition of the International Workshop on the CCN family of genes to be held in Nice, Oct 16–19, 2013.     

Impaired gap junction formation and intercellular calcium signaling in urinary bladder cancer cells can be improved by Gö6976

PURPOSE: Calcium wave propagation and connexin 26, 32 and 43 expression were studied in normal and malignant urothelial cells. MATERIALS AND METHODS: Human urothelial cell cultures were established from tissue biopsies obtained from three healthy control persons and compared to human transitional cell carcinoma (TCC) cell line 5637. Fluo-3 was used to study intercellular calcium signaling in urothelial cells. The cells were stimulated mechanically in the presence of inhibitors of gap-junctional or ATP-mediated communication to determine which pathways are operative in intercellular calcium signaling. In addition, G?6976 was used to determine the effects of PKC alpha and betaI inhibition on intercellular calcium signaling. RESULTS: In normal urothelial cells, the primary pathway for intercellular calcium mediated cell signaling was gap junctional intercellular communication (GJIC), but the paracrine ATP-mediated signaling was also operative. In 5637 TCC cells, GJIC and ATP-mediated signaling routes were altered when compared to normal urothelial cells. More specifically, inhibition of GJIC resulted in a complete block of intercellular calcium signaling, while inhibition of ATP-mediated signaling decreased signal transduction in 5637 TCC cells. The results of the present study also demonstrated that connexin 26 was the most abundant gap junction plaque protein in cultured normal human urothelial cells and that it did not form gap junction plaques in 5637 TCC cell culture. Treatment with G?6976 induced gap junction plaque formation by connexin 26 in 5637 TCC cells. In addition, the exposure to G?6976 enhanced intercellular calcium mediated signaling in 5637 TCC cells, but not in normal cells. CONCLUSIONS: The results of the present study suggest that gap junctions play a major role in intercellular calcium signaling in urothelial cells. In addition, intercellular calcium signaling is altered in urinary bladder carcinoma cells, and it can be improved by PKC alpha and betaI inhibition. (Supplementary materials are available for this article. Go to the publisher's online edition of Cell Communication and Adhesion for the following free supplemental resources; Movie files of Fig. 2normal G?6976-, normal G?6976+, TCC G?6976-, TCC G?6976+ and image of Supplementary Figure 1).     

Neuroscience and psychological studies sustain the cognitive benefits of print reading

On behalf of the Journal of Cell Communication and Signaling Editorial board it is my great pleasure to present through this message of peace and love our warmest wishes of health, happiness and professional success. We sincerely hope that 2017 will be a peaceful year worldwide and that solutions will be brought to resolve the great tensions that crystalized last year into terrible acts of violence which reflected the inability of the political powers to bring satisfactory solutions to human dispair and fear. The year 2017 will be the time for celebration of the 10th JCCS anniversary and 9th International Workshop on the CCN family of Genes. Both events should allow us to meet in a productive interactive way. I have had the opportunity to express several times in these columns my deep belief in the power of communication at all levels of human biological and social interactions. Indeed, « Communication is the key » at large.     

ROP GTPase-mediated auxin signaling regulates pavement cell interdigitation in Arabidopsis thaliana

In multicellular plant organs, cell shape formation depends on molecular switches to transduce developmental or environmental signals and to coordinate cell‐to‐cell communication. Plants have a specific subfamily of the Rho GT Pase family, usually called Rho of Plants(ROP), which serve as a critical signal transducer involved in many cellular processes. In the last decade, important advances in the ROP‐mediated regulation of plant cell morphogenesis have been made by using Arabidopsis thaliana leaf and cotyledon pavement cells.Especially, the auxin‐ROP signaling networks have been demonstrated to control interdigitated growth of pavement cells to form jigsaw‐puzzle shapes. Here, we review findings related to the discovery of this novel auxin‐signaling mechanism at the cell surface. This signaling pathway is to a large extent independent of the well‐known Transport Inhibitor Response(TIR)–Auxin Signaling F‐Box(AFB) pathway, and instead requires Auxin Binding Protein 1(ABP1) interaction with the plasma membrane‐localized, transmembrane kinase(TMK) receptor‐like kinase to regulate ROP proteins. Once activated, ROP influences cytoskeletal organization and inhibits endocytosis of the auxin transporter PIN1. The present review focuses on ROP signaling and its self‐organizing feature allowing ROP proteins to serve as a bustling signal decoder and integrator for plant cell morphogenesis.     

Hormesis: from mainstream to therapy

This issue of the Journal of Cell Communication and Cell Signaling on hormetic mechanisms represents an important step in the evolution of the hormesis dose response concept. Since its modern resurgence in the late 1970s the widespread occurrence of hormesis has been in search of its underlying mechanisms. The present integrative set of papers builds upon significant recent advances in the elucidation of hormetic mechanisms and provides the reader with a deep and extensive view of the concept of hormesis from a broad range of researcher perspectives and in many biomedical applications.     

Roles of Gap Junctions and Connexins in Non-Neoplastic Pathological Processes in which Cell Proliferation Is Involved

Cell proliferation is an important process for reproduction, growth and renewal of living cells and occurs in several situations during life. Cell proliferation is present in all the steps of carcinogenesis, initiation, promotion and progression. Gap junctions are the only specialization of cell membranes that allows communication between adjacent cells. They are known to contribute to tissue homeostasis and are composed of transmembrane proteins called “connexins.” These junctions are also known to be involved in cell proliferation control. The roles of gap junctions and connexins in cell proliferation are complex and still under investigation. Since pioneer studies by Loewenstein, it is known that neoplastic cells lack communicating junctions. They do not communicate with their neighbors or with non-neoplastic cells from the surrounding area. There are many studies and review articles dedicated to neoplastic tissues. The aim of this review is to present evidence on the roles of gap junctions and connexins in non-neoplastic processes in which cell proliferation is involved.     

The Cell Adhesion Molecules Roughest,Hibris, Kin of Irre and Sticks and Stones Are Required for Long Range Spacing of the Drosophila Wing Disc Sensory Sensilla

Most animal tissues and organ systems are comprised of highly ordered arrays of varying cell types. The development of external sensory organs requires complex cell-cell communication in order to give each cell a specific identity and to ensure a regular distributed pattern of the sensory bristles. This involves both long and short range signaling mediated by either diffusible or cell anchored factors. In a variety of processes the heterophilic Irre Cell Recognition Module, consisting of the Neph-like proteins: Roughest, Kin of irre and of the Nephrin-like proteins: Sticks and Stones, Hibris, plays key roles in the recognition events of different cell types throughout development. In the present study these proteins are apically expressed in the adhesive belt of epithelial cells participating in sense organ development in a partially exclusive and asymmetric manner. Using mutant analysis the GAL4/UAS system, RNAi and gain of function we found an involvement of all four Irre Cell Recognition Module-proteins in the development of a highly structured array of sensory organs in the wing disc. The proteins secure the regular spacing of sensory organs showing partial redundancy and may function in early lateral inhibition events as well as in cell sorting processes. Comparisons with other systems suggest that the Irre Cell Recognition module is a key organizer of highly repetitive structures.     

Signaling Pathways that Regulate Cell Division

Cell division requires careful orchestration of three major events: entry into mitosis, chromosomal segregation, and cytokinesis. Signaling within and between the molecules that control these events allows for their coordination via checkpoints, a specific class of signaling pathways that ensure the dependency of cell-cycle events on the successful completion of preceding events. Multiple positive- and negative-feedback loops ensure that a cell is fully committed to division and that the events occur in the proper order. Unlike other signaling pathways, which integrate external inputs to decide whether to execute a given process, signaling at cell division is largely dedicated to completing a decision made in G1 phase—to initiate and complete a round of mitotic cell division. Instead of deciding if the events of cell division will take place, these signaling pathways entrain these events to the activation of the cell-cycle kinase cyclin-dependent kinase 1 (CDK1) and provide the opportunity for checkpoint proteins to arrest cell division if things go wrong.     

Cell swelling-induced peptide hormone secretion

Cell swelling induces peptide exocytosis using unique signaling pathway. Hyposmotic-induced secretion in normal cells is not mediated by specific receptors, is independent from extra and intracellular Ca(2+), sodium and potassium channels activity, prostaglandins, leukotriens, does not involve cytoskeleton, cAMP generation, phospholipase A(2), G proteins, protein kinase C. It is promoted by swelling of the secretory vesicles. Resistance to endogenous inhibitors is frequent attribute of this type of secretion. Swelling-induced secretion involves also secretory vesicles not involved in conventional stimulation. Hyposmosis-induced insulin secretion is more sensitive to high cellular cholesterol than conventional one suggesting substantial difference between mechanisms. Participation of sequential exocytosis as dominating mechanism in swelling-induced exocytosis is hypothesized. Signaling and response in tumor cells often differs from native cells and varies markedly between cell lines. Pathogenetic implications: cell swelling could be involved in alcohol induced hypoglycemia in diabetic patients and release of peptides from pituitary and neurons. Swelling-induced products could be mediators of ischemic preconditioning involved also in protection of diabetic heart. Swelling-induced exocytosis is an ancient mechanism generally present in cells; in cells engaged in water and salt regulation is covered by specific response mediated by specific signaling. Disturbance of specific response leads to swelling-induced - inappropriate secretion of antidiuretic hormone - SIADH.     

The systems biology of signaling pathways

Signaling networks play the central role in the regulation of processes in a single cell and in the entire body. A recent breakthrough in technologies for systems biology, which combine experimental and mathematical methods, permits scientists to model signaling pathways in an individual cell and in cell populations. This approach provides new information on mechanisms that regulate a variety of biological processes. Here we discuss the mathematical formalisms that are applied to signaling pathway modeling and relevant experimental methods.     

Erratum to: Pick of the Year 2014

In June 2015, Thomson Reuters informed our publisher Springer that the Journal of Cell Communication and Signaling, the official journal of the International CCN Society, « had been selected for coverage in Thomson Reuter’s products and services. Beginning with V. 1 (1) 2007, this publication would be indexed and abstracted in Science Citation Index Expanded (also known as SciSearch), Journal Citation Reports/Science Edition, Biological Abstracts and BIOSIS Previews ». In this fall editorial I briefly revisit a few milestones of the JCCS life since it was first created in 1988, with the deep and genuine willingness to help in the dissemination, in the highly competitive world of publishing, of the best quality science regarding the roles of CCN proteins in signaling.     

The Effect of Quercetin Nanosuspension on Prostate Cancer Cell Line LNCaP via Hedgehog Signaling Pathway

Background:Prostate cancer (PCa) is the second leading cause of cancer death in American population. In this manner, novel therapeutic approaches for identification of therapeutic targets for PCa has significant clinical implications. Quercetin is a potent cancer therapeutic agent and dietary antioxidant present in fruit and vegetables.Methods:To investigate the underlying mechanism by which the PCa was regulated, nanoparticles of quercetin were administrated to cells. For in vitro experiments, human PCa cell line LNCaP were involved. Cell viability assay and quantitative RT-PCR (qRT-PCR) for hedgehog signaling pathway genes were used to determine the key signaling pathway regulated for PCa progression.Results:The cell viability gradually decreased with increased concentration of quercetin nanoparticles. At 48 h, 40 mM concentration of quercetin treatment showed near 50% of viable cells. Quercetin nanoparticles upregulates Su(Fu) mRNA expressions and downregulates gli mRNA expressions in the LNCaP cells.Conclusion:The results showed that the hedgehog signaling targeted inhibition may have important implications of PCa therapeutics. Additionally, the outcomes provided new mechanistic basis for further examination of quercetin nanoparticles to discover potential treatment strategies and new targets for PCa inhibition.Key Words: Hedgehog, Prostate cancer, Proliferation, Quercetin nanoparticles, Signaling pathway     

Down-regulation of Delta by proteolytic processing

Notch signaling regulates cell fate decisions during development through local cell interactions. Signaling is triggered by the interaction of the Notch receptor with its transmembrane ligands expressed on adjacent cells. Recent studies suggest that Delta is cleaved to release an extracellular fragment, DlEC, by a mechanism that involves the activity of the metalloprotease Kuzbanian; however, the functional significance of that cleavage remains controversial. Using independent functional assays in vitro and in vivo, we examined the biological activity of purified soluble Delta forms and conclude that Delta cleavage is an important down-regulating event in Notch signaling. The data support a model whereby Delta inactivation is essential for providing the critical ligand/receptor expression differential between neighboring cells in order to distinguish the signaling versus the receiving partner.     

Cell‐to‐cell and type‐to‐type heterogeneity of signaling networks: insights from the crowd

Recent technological developments allow us to measure the status of dozens of proteins in individual cells. This opens the way to understand the heterogeneity of complex multi‐signaling networks across cells and cell types, with important implications to understand and treat diseases such as cancer. These technologies are, however, limited to proteins for which antibodies are available and are fairly costly, making predictions of new markers and of existing markers under new conditions a valuable alternative. To assess our capacity to make such predictions and boost further methodological development, we organized the Single Cell Signaling in Breast Cancer DREAM challenge. We used a mass cytometry dataset, covering 36 markers in over 4,000 conditions totaling 80 million single cells across 67 breast cancer cell lines. Through four increasingly difficult subchallenges, the participants predicted missing markers, new conditions, and the time‐course response of single cells to stimuli in the presence and absence of kinase inhibitors. The challenge results show that despite the stochastic nature of signal transduction in single cells, the signaling events are tightly controlled and machine learning methods can accurately predict new experimental data.     

NF-kappa B controls cell fate specification, survival, and molecular differentiation of immunoregulatory natural T lymphocytes

Ontogenetic, homeostatic, and functional deficiencies within immunoregulatory natural T (iNKT) lymphocytes underlie various inflammatory immune disorders including autoimmunity. Signaling events that control cell fate specification and molecular differentiation of iNKT cells are only partly understood. Here we demonstrate that these processes within iNKT cells require classical NF-kappaB signaling. Inhibition of NF-kappaB signaling blocks iNKT cell ontogeny at an immature stage and reveals an apparent, novel precursor in which negative selection occurs. Most importantly, this block occurs due to a lack of survival signals, as Bcl-x(L) overexpression rescues iNKT cell ontogeny. Maturation of immature iNKT cell precursors induces Bcl-2 expression, which is defective in the absence of NF-kappaB signaling. Bcl-x(L) overexpression also rescues this maturation-induced Bcl-2 expression. Thus, antiapoptotic signals relayed by NF-kappaB critically control cell fate specification and molecular differentiation of iNKT cells and, hence, reveal a novel role for such signals within the immune system.     

The alliance for cellular signaling plasmid collection: a flexible resource for protein localization studies and signaling pathway analysis

Cellular responses to inputs that vary both temporally and spatially are determined by complex relationships between the components of cell signaling networks. Analysis of these relationships requires access to a wide range of experimental reagents and techniques, including the ability to express the protein components of the model cells in a variety of contexts. As part of the Alliance for Cellular Signaling, we developed a robust method for cloning large numbers of signaling ORFs into Gateway entry vectors, and we created a wide range of compatible expression platforms for proteomics applications. To date, we have generated over 3000 plasmids that are available to the scientific community via the American Type Culture Collection. We have established a website at www.signaling-gateway.org/data/plasmid/ that allows users to browse, search, and blast Alliance for Cellular Signaling plasmids. The collection primarily contains murine signaling ORFs with an emphasis on kinases and G protein signaling genes. Here we describe the cloning, databasing, and application of this proteomics resource for large scale subcellular localization screens in mammalian cell lines.     

Cell signaling networks ontology

Although databases for cell signaling pathways include numbers of reaction data of the pathways, the reaction data cannot be used yet to deduce biological functions from them. For the deduction, we need systematic and consistent interpretation of biological functions of reactions in cell signaling pathways in the context of "information transmission". To address this issue, we have developed a functional ontology for cell signaling pathways, Cell Signaling Network Ontology (CSN-Ontology), which provides framework for the functional interpretation presenting some important concepts as information, selectivity, movability, and signaling rules including passage of time.     

Distinct and Dynamic Requirements for mTOR Signaling in Hematopoiesis and Leukemogenesis

Signaling involving PI3K and AKT regulates cell growth, partly through the mTOR kinase complexes 1 and 2. In this issue of Cell Stem Cell, Kalaitzidis et?al. and Magee et?al. reveal unique requirements for mTORC1 and mTORC2 signaling during blood development and leukemogenesis induced by loss of PTEN.