A plethora of intercellular signals during Caenorhabditis elegans development

Reproducible cell-cell interactions contribute to the invariance of Caenorhabditis elegans development and allow high resolution study of molecular mechanisms of intercellular signaling. A number of new cell interactions have been discovered in the past year. The power of nematode molecular genetics has been increased through several technical advances and the genome project, and these new approaches are now being successfully applied both to familiar and new signaling mechanisms.     

Bacterial chemoreceptors: high-performance signaling in networked arrays

Chemoreceptors are crucial components in the bacterial sensory systems that mediate chemotaxis. Chemotactic responses exhibit exquisite sensitivity, extensive dynamic range and precise adaptation. The mechanisms that mediate these high-performance functions involve not only actions of individual proteins but also interactions among clusters of components, localized in extensive patches of thousands of molecules. Recently, these patches have been imaged in native cells, important features of chemoreceptor structure and on-off switching have been identified, and new insights have been gained into the structural basis and functional consequences of higher order interactions among sensory components. These new data suggest multiple levels of molecular interactions, each of which contribute specific functional features and together create a sophisticated signaling device.     

Subcellular targeting by membrane lipids

The reversible localization of signaling proteins to both the plasma and the internal membranes of cells is critical for the selective activation of downstream functions and depends on interactions with both proteins and membrane lipids. New structural and biochemical analyses of C1, C2, PH, FYVE, FERM and other domains have led to an unprecedented amount of information on the molecular interactions of these signaling proteins with regulatory lipids. A wave of studies using GFP-tagged membrane binding domains as reporters has led to new quantitative insights into the kinetics of these signaling mechanisms.     

韧皮部取食昆虫诱导的植物防御反应

刺吸式昆虫与寄主植物之间具有特殊的生物互作关系。本文对刺吸式昆虫取食韧皮部诱导的植物防御反应类型、 防御物质变化、 信号途径以及植物反应转录组学研究等方面进行综述。韧皮部取食昆虫取食诱导的植物防御反应机制主要包括： (1)改变自身的营养状况; (2)产生有毒的次生化合物; (3)产生防御蛋白。防御反应与植物水杨酸、 茉莉酸、 乙烯等信号分子密切相关。研究表明, 刺吸式昆虫取食诱导的植物防御反应主要引发以水杨酸为主的信号途径, 但相关分子互作机制还有待明确。日益丰富的基因组资源和不断发展的分子生物学技术为揭示植物防御反应中信号分子的作用机制、 找出植物内生抗性的特异因子以及阐明诱导防御机制奠定了基础。了解刺吸式昆虫取食诱导的植物防御反应, 为深入理解植物-昆虫间协同进化关系提供了依据, 为害虫治理和抗虫植物的培育提供了新的思路。     

Uncovering new aspects of protein interactions through analysis of specificity landscapes in peptide recognition domains

Protein interactions underlie all biological processes. An important class of protein interactions, often observed in signaling pathways, consists of peptide recognition domains binding short protein segments on the surface of their target proteins. Recent developments in experimental techniques have uncovered many such interactions and shed new lights on their specificity. To analyze these data, novel computational methods have been introduced that can accurately describe the specificity landscape of peptide recognition domains and predict new interactions. Combining large-scale analysis of binding specificity data with structure-based modeling can further reveal new biological insights into the molecular recognition events underlying signaling pathways.     

Host innate immune receptors and beyond: making sense of microbial infections

The complexity of the immune system mirrors its manifold mechanisms of host-microbe interactions. A relatively simplified view was posited after the identification of host innate immune receptors that their distinct mechanisms of sensing "microbial signatures" create unique molecular switches to trigger the immune system. Recently, more sophisticated and cooperative strategies for these receptors have been revealed during receptor-ligand interactions, trafficking, and intra- and intercellular signaling, in order to deal with a diverse range of microbes. Continued mapping of the complex networks of host-microbe interactions may improve our understanding of self/non-self discrimination in immunity and its intervention.     

Reciprocal interactions of Fgf10/Fgfr2b modulate the mouse tongue epithelial differentiation

The molecular mechanisms for epithelial differentiation have been studied by observing skin development in embryogenesis, but the early signaling modulations involved in tongue epithelial differentiation are not completely understood. Based on the gene expression patterns of the Fgf signaling molecules and previous results from Fgf10 and Fgfr2b knockout mice, it was hypothesized that there would be fundamental signaling interactions through the epithelial Fgfr2b and its mesenchymal ligand Fgf10 to regulate tongue epithelium differentiation. To elucidate these reciprocal interactions in tongue epithelial differentiation, this study employed an in vitro tongue organ culture system with antisense-oligodeoxynucleotides (AS-ODNs) and recombinant protein-soaked bead implantation for the loss-of-function and gain-of-function studies. Functional analysis of Fgf signaling revealed precise reciprocal interactions, which showed that mesenchymal Fgf10 rather than Fgf7 modulates tongue epithelial differentiation via Fgfr2b in a temporal- and spatial-specific manner.     

Allosteric control of cyclic di-GMP signaling

Cyclic di-guanosine monophosphate is a bacterial second messenger that has been implicated in biofilm formation, antibiotic resistance, and persistence of pathogenic bacteria in their animal host. Although the enzymes responsible for the regulation of cellular levels of c-di-GMP, diguanylate cyclases (DGC) and phosphodiesterases, have been identified recently, little information is available on the molecular mechanisms involved in controlling the activity of these key enzymes or on the specific interactions of c-di-GMP with effector proteins. By using a combination of genetic, biochemical, and modeling techniques we demonstrate that an allosteric binding site for c-di-GMP (I-site) is responsible for non-competitive product inhibition of DGCs. The I-site was mapped in both multi- and single domain DGC proteins and is fully contained within the GGDEF domain itself. In vivo selection experiments and kinetic analysis of the evolved I-site mutants led to the definition of an RXXD motif as the core c-di-GMP binding site. Based on these results and based on the observation that the I-site is conserved in a majority of known and potential DGC proteins, we propose that product inhibition of DGCs is of fundamental importance for c-di-GMP signaling and cellular homeostasis. The definition of the I-site binding pocket provides an entry point into unraveling the molecular mechanisms of ligand-protein interactions involved in c-di-GMP signaling and makes DGCs a valuable target for drug design to develop new strategies against biofilm-related diseases.     

Protein-protein interactions: principles, techniques, and their potential role in new drug development

A vast network of genes is inter-linked through protein-protein interactions and is critical component of almost every biological process under physiological conditions. Any disruption of the biologically essential network leads to pathological conditions resulting into related diseases. Therefore, proper understanding of biological functions warrants a comprehensive knowledge of protein-protein interactions and the molecular mechanisms that govern such processes. The importance of protein-protein interaction process is highlighted by the fact that a number of powerful techniques/methods have been developed to understand how such interactions take place under various physiological and pathological conditions. Many of the key protein-protein interactions are known to participate in disease-associated signaling pathways, and represent novel targets for therapeutic intervention. Thus, controlling protein-protein interactions offers a rich dividend for the discovery of new drug targets. Availability of various tools to study and the knowledge of human genome have put us in a unique position to understand highly complex biological network, and the mechanisms involved therein. In this review article, we have summarized protein-protein interaction networks, techniques/methods of their binding/kinetic parameters, and the role of these interactions in the development of potential tools for drug designing.     

Target network analysis of adiponectin,a multifaceted adipokine

Application of network analysis to dissect the potential molecular mechanisms of biological processes and complicated diseases has been the new trend in biology and medicine in recent years. Among which, the protein–protein interactions (PPI) networks attract interests of most researchers. Adiponectin, a cytokine secreted from adipose tissue, participates in a number of metabolic processes, including glucose regulation and fatty acid metabolism and involves in a series of complicated diseases from head to toe. Hundreds of proteins including many identified and potential drug targets have been reported to be involved in adiponectin related signaling pathways, which comprised a complicated regulation network. Therapeutic target database (TTD) provides extensive information about the known and explored therapeutic protein targets and the signaling pathway information. In this study, adiponectin associated drug targets based PPI was constructed and its topological properties were analyzed, which might provide some insight into the dissection of adiponectin action mechanisms and promote adiponectin signaling based drug target identification and drug discovery. J. Cell. Biochem. 114: 1145–1152, 2013. © 2012 Wiley Periodicals, Inc.     

Cellular mechanisms of signal transduction for neurotrophins

The molecular cloning of new neuroactive growth factors and their receptors has greatly enhanced our understanding of important interactions among receptors and singnaling molecules. These studies have begun to illuminate some of the mechanisms that allow for specificity in neuronal signaling. Model cell systems, such as the PC-12 pheochromocytoma cell line, express receptors for these different neurotirophic factors, leading to comparisons of signaling pathways for these factors. Upon binding their ligands, these receptors undergo phosphorylation on tyrosine residues, which directs their interaction with signaling proteins containing src homology (SH2) domains, sequences that mediate associations with tyrosine-phosphorylated proteins. These SH2 proteins translate the tyrosine kinase activity of receptors into downstream events that result in the specific cellular response. Investigations such as these have revealed that molecular specificity in signaling pathways may arise from combinatorial diversity in interactions between receptors and key regulatory proteins.     

Protein-Protein Interactions: Principles,Techniques, and their Potential Role in New Drug Development

Abstract

A vast network of genes is inter-linked through protein-protein interactions and is critical component of almost every biological process under physiological conditions. Any disruption of the biologically essential network leads to pathological conditions resulting into related diseases. Therefore, proper understanding of biological functions warrants a comprehensive knowledge of protein-protein interactions and the molecular mechanisms that govern such processes. The importance of protein-protein interaction process is highlighted by the fact that a number of powerful techniques/methods have been developed to understand how such interactions take place under various physiological and pathological conditions. Many of the key protein-protein interactions are known to participate in disease-associated signaling pathways, and represent novel targets for therapeutic intervention. Thus, controlling protein-protein interactions offers a rich dividend for the discovery of new drug targets. Availability of various tools to study and the knowledge of human genome have put us in a unique position to understand highly complex biological network, and the mechanisms involved therein. In this review article, we have summarized protein-protein interaction networks, techniques/methods of their binding/kinetic parameters, and the role of these interactions in the development of potential tools for drug designing.     

TGFβ superfamily signaling and uterine decidualization

Decidualization is an intricate biological process where extensive morphological, functional, and genetic changes take place in endometrial stromal cells to support the development of an implanting blastocyst. Deficiencies in decidualization are associated with pregnancy complications and reproductive diseases. Decidualization is coordinately regulated by steroid hormones, growth factors, and molecular and epigenetic mechanisms. Transforming growth factor β (TGFβ) superfamily signaling regulates multifaceted reproductive processes. However, the role of TGFβ signaling in uterine decidualization is poorly understood. Recent studies using the Cre-LoxP strategy have shed new light on the critical role of TGFβ signaling machinery in uterine decidualization. Herein, we focus on reviewing exciting findings from studies using both mouse genetics and in vitro cultured human endometrial stromal cells. We also delve into emerging mechanisms that underlie decidualization, such as non-coding RNAs and epigenetic modifications. We envision that future studies aimed at defining the interrelationship among TGFβ signaling circuitries and their potential interactions with epigenetic modifications/non-coding RNAs during uterine decidualization will open new avenues to treat pregnancy complications associated with decidualization deficiencies.     

Soft tissue mechanotransduction in wound healing and fibrosis

Recent evidence suggests that mechanical forces can significantly impact the biologic response to injury. Integrated mechanical and chemical signaling networks have been discovered that enable physical cues to regulate disease processes such as pathologic scar formation. Distinct molecular mechanisms control how tensional forces influence wound healing and fibrosis. Conceptual frameworks to understand cutaneous repair have expanded beyond traditional cell-cytokine models to include dynamic interactions driven by mechanical force and the extracellular matrix. Strategies to manipulate these biomechanical signaling networks have tremendous therapeutic potential to reduce scar formation and promote skin regeneration.     

Innate recognition of microbial-derived signals in immunity and inflammation

Microbes generate a vast array of different types of conserved structural components called pathogen-associated molecular patterns(PAMPs),which canbe recognized by cells of the innate immune system.This recognition of "nonself" signatures occurs through host pattern recognition receptors(PRRs),suggesting that microbial-derived signals are good targets for innate immunity to discriminate between self- and nonself.Such PAMP-PRR interactions trigger multiple but distinct downstream signaling cascades,subsequently leading to production of proinflammatory cytokines and interferons that tailor immune responses to particular microbes.Aberrant PRR signals have been associated with various inflammatory diseases and fine regulation of PRR signaling is essential for avoiding excessive inflammatory immune responses and maintaining immune homeostasis.In this review we summarize the ligands and signal transduction pathways of PRRs and highlight recent progress of the mechanisms involved in microbe-specific innate immune recognition during immune responses and inflammation,which may provide new targets for therapeutic intervention to the inflammatory disorders.     

Radiofrequency and microwave interactions between biomolecular systems

The knowledge of mechanisms underlying interactions between biological systems, be they biomacromolecules or living cells, is crucial for understanding physiology, as well as for possible prevention, diagnostics and therapy of pathological states. Apart from known chemical and direct contact electrical signaling pathways, electromagnetic phenomena were proposed by some authors to mediate non-chemical interactions on both intracellular and intercellular levels. Here, we discuss perspectives in the research of nanoscale electromagnetic interactions between biosystems on radiofrequency and microwave wavelengths. Based on our analysis, the main perspectives are in (i) the micro and nanoscale characterization of both passive and active radiofrequency properties of biomacromolecules and cells, (ii) experimental determination of viscous damping of biomacromolecule structural vibrations and (iii) detailed analysis of energetic circumstances of electromagnetic interactions between oscillating polar biomacromolecules. Current cutting-edge nanotechnology and computational techniques start to enable such studies so we can expect new interesting insights into electromagnetic aspects of molecular biophysics of cell signaling.     

Elements of the olfactory signaling pathways in insect antennae

Owing to their enormous ability to recognize airborne molecules, insects have long been used as model systems for studying various aspects of olfaction. Modern biological techniques have opened new avenues for exploring the molecular mechanisms underlying the complex signaling processes in chemosensory neurons. Biochemical and molecular analyses have allowed the identification of molecular elements of the olfactory reaction pathways and have shed light on mechanisms that account for the sensitivity and specificity of the chemosensory system.     

Structural modeling and analysis of signaling pathways based on Petri nets

The purpose of this paper is to discuss how to model and analyze signaling pathways by using Petri net. Firstly, we propose a modeling method based on Petri net by paying attention to the molecular interactions and mechanisms. Then, we introduce a new notion "activation transduction component" in order to describe an enzymic activation process of reactions in signaling pathways and shows its correspondence to a so-called elementary T-invariant in the Petri net models. Further, we design an algorithm to effectively find basic enzymic activation processes by obtaining a series of elementary T-invariants in the Petri net models. Finally, we demonstrate how our method is practically used in modeling and analyzing signaling pathway mediated by thrombopoietin as an example.     

Signaling by estrogens

By regulating activities and expression levels of key signaling molecules, estrogens control mechanisms that are responsible for crucial cellular functions. Ligand binding to estrogen receptor (ER) leads to conformational changes that regulate the receptor activity, its interaction with other proteins and DNA. In the cytoplasm, receptor interactions with kinases and scaffolding molecules regulate cell signaling cascades (extranuclear/nongenomic action). In the nucleus, estrogens control a repertoire of coregulators and other auxiliary proteins that are associated with ER, which in turn determines the nature of regulated genes and level of their expression (genomic action). The combination of genomic and nongenomic actions of estrogens ultimately confers the cell-type and tissue-type selectivity. Recent studies have revealed some important new insights into the molecular mechanisms underlying ER action, which may help to explain the functional basis of existing selective ER modulators (SERMs) and provide evidence into how ER might be selectively targeted to achieve specific therapeutic goals. In this review, we will summarize some new molecular details that relate to estrogen signaling. We will also discuss some new strategies that may potentially lead to the development of functionally selective ER modulators that can separate between the beneficial, prodifferentiative effects in bone, the cardiovascular system and the CNS as well as the "detrimental," proliferative effects in reproductive tissues and organs.