A Comprehensive Review of Receptor-Type Tyrosine-Protein Phosphatase Gamma (PTPRG) Role in Health and Non-Neoplastic Disease

Protein tyrosine phosphatase receptor gamma (PTPRG) is known to interact with and regulate several tyrosine kinases, exerting a tumor suppressor role in several type of cancers. Its wide expression in human tissues compared to the other component of group 5 of receptor phosphatases, PTPRZ expressed as a chondroitin sulfate proteoglycan in the central nervous system, has raised interest in its role as a possible regulatory switch of cell signaling processes. Indeed, a carbonic anhydrase-like domain (CAH) and a fibronectin type III domain are present in the N-terminal portion and were found to be associated with its role as [HCO 3 − ] sensor in vascular and renal tissues and a possible interaction domain for cell adhesion, respectively. Studies on PTPRG ligands revealed the contactins family (CNTN) as possible interactors. Furthermore, the correlation of PTPRG phosphatase with inflammatory processes in different normal tissues, including cancer, and the increasing amount of its soluble form (sPTPRG) in plasma, suggest a possible role as inflammatory marker. PTPRG has important roles in human diseases; for example, neuropsychiatric and behavioral disorders and various types of cancer such as colon, ovary, lung, breast, central nervous system, and inflammatory disorders. In this review, we sum up our knowledge regarding the latest discoveries in order to appreciate PTPRG function in the various tissues and diseases, along with an interactome map of its relationship with a group of validated molecular interactors

Analyzing biological network parameters with CentiScaPe

Summary: The increasing availability of large network datasets along with the progresses in experimental high-throughput technologies have prompted the need for tools allowing easy integration of experimental data with data derived form network computational analysis. In order to enrich experimental data with network topological parameters, we have developed the Cytoscape plug-in CentiScaPe. The plug-in computes several network centrality parameters and allows the user to analyze existing relationships between experimental data provided by the users and node centrality values computed by the plug-in. CentiScaPe allows identifying network nodes that are relevant from both experimental and topological viewpoints. CentiScaPe also provides a Boolean logic-based tool that allows easy characterization of nodes whose topological relevance depends on more than one centrality. Finally, different graphic outputs and the included description of biological significance for each computed centrality facilitate the analysis by the end users not expert in graph theory, thus allowing easy node categorization and experimental prioritization

Chemokines and the Signaling Modules Regulating Integrin Affinity

Integrin-mediated adhesion is a general concept referring to a series of adhesive phenomena including tethering–rolling, affinity, valency, and binding stabilization altogether controlling cell avidity (adhesiveness) for the substrate. Arrest chemokines modulate each aspect of integrin activation, although integrin affinity regulation has been recognized as the prominent event in rapid leukocyte arrest induced by chemokines. A variety of inside-out and outside-in signaling mechanisms have been related to the process of integrin-mediated adhesion in different cellular models, but only few of them have been clearly contextualized to rapid integrin affinity modulation by arrest chemokines in primary leukocytes. Complex signaling processes triggered by arrest chemokines and controlling leukocyte integrin activation have been described for ras-related rap and for rho-related small GTPases. We summarize the role of rap and rho small GTPases in the regulation of rapid integrin affinity in primary leukocytes and provide a modular view of these pro-adhesive signaling events. A potential, albeit still speculative, mechanism of rho-mediated regulation of cytoskeletal proteins controlling the last step of integrin activation is also discussed. We also discuss data suggesting a functional integration between the rho- and rap-modules of integrin activation. Finally we examine the universality of signaling mechanisms regulating integrin triggering by arrest chemokines

A deadly migration

CD95 has long been viewed as a death receptor regulating apoptosis. In this issue of Immunity, Letellier et al. (2010) tell us a different story, about the capability of CD95L to regulate leukocyte recruitment to sites of inflammation

A SystemC Platform for Signal Transduction Modelling and Simulation in Systems Biology

Signal transduction is a class of cell\u2019s biological processes,which are commonly represented as highly concurrent reactive systems. In the Systems Biology community, modelling and simulation of signal transduction require overcoming issues like discrete event-based execution of complex systems, description from building blocks through composition and encapsulation, description at different levels of granularity, methods for abstraction and refinement. This paper presents a signal transduction modelling and simulationplatform based on SystemC, and shows how the platform allows handling the system complexity by modelling it at different abstraction levels. The paper reports the results obtained by applying the platform to model the intracellular signalling network controlling integrin activation mediating leukocyte recruitment from the blood into the tissues. The dynamic simulation of the model has been conducted with the aim of exploring oscillating behaviors of such a biochemical circuit and, more in general, to help better understanding properties of the overall dynamics of leukocyte recruitment

RHOA and PRKCZ control different aspects of cell motility in pancreatic cancer metastatic clones

Background: Our understanding of the mechanism regulating pancreatic cancer metastatic phenotype is limited. We analyzed the role of RHOA and PRKCZ in the motility attitude of two subclones of the pancreatic adenocarcinoma cell line SUIT-2 (S2), with different in vivo metastatic potential in nude mice: S2-m with a low metastatic potential and highly metastatic S2-CP9 using RHOA and PRKCZ cell-permeable inhibitory peptides.Methods: Adhesion assays, cell permeable peptides, RHOA activity assay, western blottingResults: When used in combination cell-permeable inhibitory peptides partially inhibited cell adhesion by about 50% in clone S2-CP9. In clone S2-m, the effect was limited to 15% inhibition. In a wound healing assay, S2-CP9 was sensitive only to treatment with the combination of both RHOA and PRKCZ inhibitory peptides. Conversely, S2-m was unable to migrate toward both ends of the wound in basal conditions. Migration of cells through a membrane with 8 mu m pores was completely abolished in both clones by individual treatment with RHOA and PRKCZ inhibitory peptides.Conclusion: Herein, we demonstrate a critical role for RHOA and PRKCZ in the regulation of different aspects of cell motility of pancreatic adenocarcinoma and demonstrate the need to inhibit both pathways to obtain a functionally relevant effect in most assays. These results indicate that RHOA and PRKCZ, and their downstream effectors, can represent important pharmacological targets that could potentially control the highly metastatic attitude of PDAC

Oxyresveratrol-Loaded PLGA Nanoparticles Inhibit Oxygen Free Radical Production by Human Monocytes: Role in Nanoparticle Biocompatibility

Oxyresveratrol, a polyphenol extracted from the plant Artocarpus lakoocha Roxb, has been reported to be an antioxidant and an oxygen-free radical scavenger. We investigated whether oxyresveratrol affects the generation of superoxide anion (O2 ) by human monocytes, which are powerful reactive oxygen species (ROS) producers. We found that oxyresveratrol inhibited the O2 production induced upon stimulation of monocytes with -glucan, a well known fungal immune cell activator. We then investigated whether the inclusion of oxyresveratrol into nanoparticles could modulate its effects on O2 release. We synthesized poly(lactic-co-glycolic acid) (PLGA) nanoparticles, and we assessed their effects on monocytes. We found that empty PLGA nanoparticles induced O2 production by resting monocytes and enhanced the formation of this radical in -glucan-stimulated monocytes. Interestingly, the insertion of oxyresveratrol into PLGA nanoparticles significantly inhibited the O2 production elicited by unloaded nanoparticles in resting monocytes as well as the synergistic effect of nanoparticles and -glucan. Our results indicate that oxyresveratrol is able to inhibit ROS production by activated monocytes, and its inclusion into PLGA nanoparticles mitigates the oxidative effects due to the interaction between these nanoparticles and resting monocytes. Moreover, oxyresveratrol can contrast the synergistic effects of nanoparticles with fungal agents that could be present in the patient tissues. Therefore, oxyresveratrol is a natural compound able to make PLGA nanoparticles more biocompatible

Evidence of ζ Protein Kinase C Involvement in Polymorphonuclear Neutrophil Integrin-dependent Adhesion and Chemotaxis

Classical chemoattractants and chemokines trigger integrin-dependent adhesion of blood leukocytes to vascular endothelium and also direct subsequent extravasation and migration into tissues. In studies of human polymorphonuclear neutrophil responses to formyl peptides and to interleukin 8, we show evidence of involvement of the atypical zeta protein kinase C in the signaling pathway leading to chemoattractant-triggered actin assembly, integrin-dependent adhesion, and chemotaxis. Selective inhibitors of classical and novel protein kinase C isozymes do not prevent chemoattractant-induced neutrophil adhesion and chemotaxis. In contrast, chelerythrine chloride and synthetic myristoylated peptides with sequences based on the endogenous zeta protein kinase C pseudosubstrate region block agonist-induced adhesion to fibrinogen, chemotaxis and F-actin accumulation. Biochemical analysis shows that chemoattractants trigger rapid translocation of zeta protein kinase C to the plasma membrane accompanied by rapid but transient increase of the kinase activity. Moreover, pretreatment with C3 transferase, a specific inhibitor of Rho small GTPases, blocks zeta but not alpha protein kinase C plasma membrane translocation. Synthetic peptides from zeta protein kinase C also inhibit phorbol ester-induced integrin-dependent adhesion but not NADPH-oxidase activation, and C3 transferase pretreatment blocks phorbol ester-triggered translocation of zeta but not alpha protein kinase C. These data suggest the involvement of zeta protein kinase C in chemoattractant-induced leukocyte integrin-dependent adhesion and chemotaxis. Moreover, they highlight a potential link between atypical protein kinase C isozymes and Rho signaling pathways leading to integrin-activation

Biological network analysis with CentiScaPe: centralities and experimental dataset integration

The growing dimension and complexity of the available experimental data generating biological networks have increased the need for tools that help in categorizing nodes by their topological relevance. Here we present CentiScaPe, a Cytoscape app specifically designed to calculate centrality indexes used for the identification of the most important nodes in a network. CentiScaPe is a comprehensive suite of algorithms dedicated to network nodes centrality analysis, computing several centralities for undirected, directed and weighted networks. The results of the topological analysis can be integrated with data set from lab experiments, like expression or phosphorylation levels for each protein represented in the network. Our app opens new perspectives in the analysis of biological networks, since the integration of topological analysis with lab experimental data enhance the predictive power of the bioinformatics analysis