细胞信号网络功能鲁棒的简并性拓扑特征

细胞信号网络对于外界环境的干扰表现出优良的鲁棒性,但是其维持功能鲁棒的内在机制尚未明确,本文研究了细胞信号网络功能鲁棒性的拓扑特征。选择布尔网络模型模拟细胞网络的动态行为,利用网络节点状态的扰动模拟外界环境干扰。基于演化策略探寻不同网络拓扑的功能并分析其在干扰环境下的鲁棒性,采用埃德尔曼提出的基于信息论的计算方法评估网络拓扑的简并度、冗余度和复杂度等拓扑属性,对比分析它们与功能鲁棒度的相关性及作用机理。结果显示,在网络模型的演化过程中,其拓扑简并度与功能鲁棒度显著正相关,相关性水平高于拓扑冗余度与鲁棒度的相关性。并且,随着鲁棒度的提升,网络的节点数和复杂度也随之升高,同样简并度与网络的节点数和复杂度的相关性高于拓扑冗余度与网络的节点数和复杂度的相关性。这说明增加的网络节点以简并的方式同时提高了网络拓扑的鲁棒度和复杂度。因此,细胞网络功能鲁棒性的拓扑特征是简并而不是冗余,简并为解决生物系统的复杂问题提供了有效手段,为人工系统的可靠性设计提供有益的借鉴。     

S-Nitrosylation signaling regulates cellular protein interactions

BACKGROUND: S-Nitrosothiols are made by nitric oxide synthases and other metalloproteins. Unlike nitric oxide, S-nitrosothiols are involved in localized, covalent signaling reactions in specific cellular compartments. These reactions are enzymatically regulated. SCOPE: S-Nitrosylation affects interactions involved in virtually every aspect of normal cell biology. This article is part of a Special Issue entitled Regulation of Cellular Processes by S-nitrosylation. MAJOR CONCLUSIONS AND SIGNIFICANCE: S-Nitrosylation is a regulated signaling reaction.     

Proteomic analysis of cellular signaling

Protein phosphorylation events are key regulators of cellular signaling processes. In the era of functional genomics, rational drug design programs demand large-scale high-throughput analysis of signal transduction cascades. Significant improvements in the area of mass spectrometry-based proteomics have provided exciting opportunities for rapid progress toward global protein phosphorylation analysis. This review summarizes several recent advances made in the field of phosphoproteomics with an emphasis placed on mass spectrometry instrumentation, enrichment methods and quantification strategies. In the near future, these technologies will provide a tool that can be used for quantitative investigation of signal transduction pathways to generate new insights into biologic systems.     

Systems biology of virus-host signaling network interactions

Viruses have evolved to manipulate the host cell machinery for virus propagation, in part by interfering with the host cellular signaling network. Molecular studies of individual pathways have uncovered many viral host-protein targets; however, it is difficult to predict how viral perturbations will affect the signaling network as a whole. Systems biology approaches rely on multivariate, context-dependent measurements and computational analysis to elucidate how viral infection alters host cell signaling at a network level. Here we describe recent advances in systems analyses of signaling networks in both viral and non-viral biological contexts. These approaches have the potential to uncover virus- mediated changes to host signaling networks, suggest new therapeutic strategies, and assess how cell-to-cell variability affects host responses to infection. We argue that systems approaches will both improve understanding of how individual virus-host protein interactions fit into the progression of viral pathogenesis and help to identify novel therapeutic targets.     

Proteomic analysis of cellular signaling

Protein phosphorylation events are key regulators of cellular signaling processes. In the era of functional genomics, rational drug design programs demand large-scale high-throughput analysis of signal transduction cascades. Significant improvements in the area of mass spectrometry-based proteomics have provided exciting opportunities for rapid progress toward global protein phosphorylation analysis. This review summarizes several recent advances made in the field of phosphoproteomics with an emphasis placed on mass spectrometry instrumentation, enrichment methods and quantification strategies. In the near future, these technologies will provide a tool that can be used for quantitative investigation of signal transduction pathways to generate new insights into biologic systems.     

The community structure of human cellular signaling network

Living cell is highly responsive to specific chemicals in its environment, such as hormones and molecules in food or aromas. The reason is ascribed to the existence of widespread and diverse signal transduction pathways, between which crosstalks usually exist, thus constitute a complex signaling network. Evidently, knowledge of topology characteristic of this network could contribute a lot to the understanding of diverse cellular behaviors and life phenomena thus come into being. In this presentation, signal transduction data is extracted from KEGG to construct a cellular signaling network of Homo sapiens, which has 931 nodes and 6798 links in total. Computing the degree distribution, we find it is not a random network, but a scale-free network following a power-law of P(K) approximately K(-gamma), with gamma approximately equal to 2.2. Among three graph partition algorithms, the Guimera's simulated annealing method is chosen to study the details of topology structure and other properties of this cellular signaling network, as it shows the best performance. To reveal the underlying biological implications, further investigation is conducted on ad hoc community and sketch map of individual community is drawn accordingly. The involved experiment data can be found in the supplementary material.     

Detecting functional interactions in a gene and signaling network by time-resolved somatic complementation analysis

Somatic complementation by fusion of two mutant cells and mixing of their cytoplasms occurs when the genetic defect of one fusion partner is cured by the functional gene product provided by the other. We have found that complementation of mutational defects in the network mediating stimulus-induced commitment and sporulation of Physarum polycephalum may reflect time-dependent changes in the signaling state of its molecular building blocks. Network perturbation by fusion of mutant plasmodial cells in different states of activation, and the time-resolved analysis of somatic complementation effects can be used to systematically probe network structure and dynamics. Time-resolved somatic complementation quantitatively detects regulatory interactions between the functional modules of a network, independent of their biochemical composition or subcellular localization, and without being limited to direct physical interactions.     

Integrated cellular network of transcription regulations and protein-protein interactions

Background  

With the accumulation of increasing omics data, a key goal of systems biology is to construct networks at different cellular levels to investigate cellular machinery of the cell. However, there is currently no satisfactory method to construct an integrated cellular network that combines the gene regulatory network and the signaling regulatory pathway.     

A global analysis of cross-talk in a mammalian cellular signalling network

Cellular information processing requires the coordinated activity of a large network of intracellular signalling pathways. Cross-talk between pathways provides for complex non-linear responses to combinations of stimuli, but little is known about the density of these interactions in any specific cell. Here, we have analysed a large-scale survey of pathway interactions carried out by the Alliance for Cellular Signalling (AfCS) in RAW 264.7 macrophages. Twenty-two receptor-specific ligands were studied, both alone and in all pairwise combinations, for Ca2+ mobilization, cAMP synthesis, phosphorylation of many signalling proteins and for cytokine production. A large number of non-additive interactions are evident that are consistent with known mechanisms of cross-talk between pathways, but many novel interactions are also revealed. A global analysis of cross-talk suggests that many external stimuli converge on a relatively small number of interaction mechanisms to provide for context-dependent signalling.     

Osteoarthritis: cellular and molecular changes in degenerating cartilage

Osteoarthritis (OA) is a disease of high ethical and economical importance. In advanced stages, the patients suffer from severe pain and restriction of mobility. The consequence in many cases is an inability to work and often the substitution of the diseased joint with an artificial implant becomes inevitable. As cartilage tissue itself has only very limited capacities of self-renewing, the development of this disorder is chronic and progressive. Generally, OA is diagnosed in more advanced stages, when clinical and radiographic signs become evident. At this time point the options for therapeutic intervention without surgery are limited. It is, therefore, crucial to know about the basic incidents in the course of OA and especially in early stages to develop new diagnostic and therapeutic strategies. Numerous studies on human osteoarthritic tissue and in animal models have addressed various aspects of OA progression to get a better understanding of the pathophysiology of this disease. This review presents an overview on different aspects of OA research and the cellular and molecular alterations in degenerating cartilage.     

Sequence and structural analysis of cellular retinoic acid-binding proteins reveals a network of conserved hydrophobic interactions

Proteins in the intracellular lipid-binding protein (iLBP) family show remarkably high structural conservation despite their low-sequence identity. A multiple-sequence alignment using 52 sequences of iLBP family members revealed 15 fully conserved positions, with a disproportionately high number of these (n=7) located in the relatively small helical region. The conserved positions displayed high structural conservation based on comparisons of known iLBP crystal structures. It is striking that the beta-sheet domain had few conserved positions, despite its high structural conservation. This observation prompted us to analyze pair-wise interactions within the beta-sheet region to ask whether structural information was encoded in interacting amino acid pairs. We conducted this analysis on the iLBP family member, cellular retinoic acid-binding protein I (CRABP I), whose folding mechanism is under study in our laboratory. Indeed, an analysis based on a simple classification of hydrophobic and polar amino acids revealed a network of conserved interactions in CRABP I that cluster spatially, suggesting a possible nucleation site for folding. Significantly, a small number of residues participated in multiple conserved interactions, suggesting a key role for these sites in the structure and folding of CRABP I. The results presented here correlate well with available experimental evidence on folding of CRABPs and their family members and suggest future experiments. The analysis also shows the usefulness of considering pair-wise conservation based on a simple classification of amino acids, in analyzing sequences and structures to find common core regions among homologues.     

Peptide microarrays for the detection of molecular interactions in cellular signal transduction

The formation of protein complexes is a hallmark of cellular signal transduction. Here, we show that peptide microarrays provide a robust and quantitative means to detect signalling-dependent changes of molecular interactions. Recruitment of a protein into a complex upon stimulation of a cell leads to the masking of an otherwise exposed binding site. In cell lysates this masking can be detected by reduced binding to a microarray carrying a peptide that corresponds to the binding motif of the respective interaction domain. The method is exemplified for the lymphocyte-specific tyrosine kinase 70 kDa zeta-associated protein binding to a bis-phosphotyrosine-motif of the activated T-cell receptor via its tandem SH2 domain. Compared to established techniques, the method provides a significant shortcut to the detection of molecular interactions.     

Reps2: a cellular signaling and molecular trafficking nexus

Since its discovery in the late 1990s as a signaling molecule in the Ras/Ral pathway, Reps2 has emerged as an important player in receptor-mediated endocytosis. Reps2 contains Eps15 homology (EH) domains, proline-rich regions, and a coiled-coil domain that engage in several protein-protein interactions to coordinate the internalization of various receptors with molecular signaling. Reps2 has clinical importance as it suppresses the ability of its binding partner RalBP1 to transport chemotherapeutic drugs, such as doxorubicin, out of a cell. Reps2 is also dysregulated during the progression of prostate cancer and is a potential biomarker for breast and prostate cancer.     

A cellular atlas of calcineurin signaling

Intracellular Ca²⁺ signals are temporally controlled and spatially restricted. Signaling occurs adjacent to sites of Ca²⁺ entry and/or release, where Ca²⁺-dependent effectors and their substrates co-localize to form signaling microdomains. Here we review signaling by calcineurin, the Ca²⁺/calmodulin regulated protein phosphatase and target of immunosuppressant drugs, Cyclosporin A and FK506. Although well known for its activation of the adaptive immune response via NFAT dephosphorylation, systematic mapping of human calcineurin substrates and regulators reveals unexpected roles for this versatile phosphatase throughout the cell. We discuss calcineurin function, with an emphasis on where signaling occurs and mechanisms that target calcineurin and its substrates to signaling microdomains, especially binding of cognate short linear peptide motifs (SLiMs). Calcineurin is ubiquitously expressed and regulates events at the plasma membrane, other intracellular membranes, mitochondria, the nuclear pore complex and centrosomes/cilia. Based on our expanding knowledge of localized CN actions, we describe a cellular atlas of Ca²⁺/calcineurin signaling.     

Quantitative phosphoproteomic analysis of signaling network dynamics

Protein phosphorylation mediated cellular signaling is a highly regulated, dynamic process that controls many aspects of cellular biology. Over the past few years many methods have been developed to quantify temporal dynamics of protein phosphorylation, including mass spectrometry, which can be applied in both an unbiased, discovery mode and in a targeted mode to monitor specific phosphorylation sites. Other methods, such as kinase activity assays and antibody microarrays, have been applied to quantify central nodes in the signaling network, yielding intriguing biological insights. This review provides a concise overview of the latest advances in the quantitative analysis of signaling dynamics including a brief commentary on the future of the field.     

Genetic and molecular analysis of nematode-microbe interactions

Symbiosis, the living together of unlike organisms, such as between microbes and their multicellular eukaryotic hosts, can be categorized as parasitic, commensal or mutualistic. The establishment of symbiosis and the outcome of microbe-host interactions are dictated largely by both microbe- and host-derived factors. Over the last decade, the nematode Caenorhabditis elegans has provided a facile experimental system to study such interactions, with parasitic interactions being the primary focus. The myriad of genetic and molecular tools available has made C. elegans a powerful model system to interrogate the interactions between a host and its pathogens, and has provided a greater understanding of the molecular underpinnings of these interactions, many of which were found to be conserved across other taxa. Commensal and mutualistic interactions between worms and their microbes, although less studied, have the potential to enhance our understanding of genetic and molecular features underlying host-microbe interactions. Here, we highlight new insights obtained in delineating the signalling pathways that function within and between host cells in combating assaults from extracellular and intracellular pathogens. We also discuss potential new insights that could be gained from further studies into commensal and mutualistic relationships between nematodes and microbes.     

Expanding the cellular molecular chaperone network through the ubiquitous cochaperones

Cellular environments are highly complex and contain a copious variety of proteins that must operate in unison to achieve homeostasis. To guide and preserve order, multifaceted molecular chaperone networks are present within each cell type. To handle the vast client diversity and regulatory demands, a wide assortment of chaperones are needed. In addition to the classic heat shock proteins, cochaperones with inherent chaperoning abilities (e.g., p23, Hsp40, Cdc37, etc.) are likely used to complete a system. In this review, we focus on the HSP90-associated cochaperones and provide evidence supporting a model in which select cochaperones are used to differentially modulate target proteins, contribute to combinatorial client regulation, and increase the overall reach of a cellular molecular chaperone network. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90).     

A network of protein-protein interactions in yeast

A global analysis of 2,709 published interactions between proteins of the yeast Saccharomyces cerevisiae has been performed, enabling the establishment of a single large network of 2,358 interactions among 1,548 proteins. Proteins of known function and cellular location tend to cluster together, with 63% of the interactions occurring between proteins with a common functional assignment and 76% occurring between proteins found in the same subcellular compartment. Possible functions can be assigned to a protein based on the known functions of its interacting partners. This approach correctly predicts a functional category for 72% of the 1,393 characterized proteins with at least one partner of known function, and has been applied to predict functions for 364 previously uncharacterized proteins.