Insulin-like growth factor-induced signals activate mitochondrial respiration

From experiments with lower eukaryotes it is known that the metabolic rate and also the rate of aging are tightly controlled by the insulin-like growth factor (IGF)/insulin signal transduction pathway. The mitochondrial theory of aging implies that an increased metabolic rate leads to increased mitochondrial activity; increased production of reactive oxygen species due to these alterations would speed up the aging process. To address the question if mitochondrial activity is influenced by insulin/IGF signaling, we have established an experimental system to determine the influence of IGF-I-dependent signaling on mitochondrial function. We used DU145 prostate cancer cells, known for the intact IGF signal transduction pathway, to address the influence of IGF receptor activation on mitochondrial function by high-resolution respirometry. These experiments revealed that indeed mitochondrial function is regulated by IGF signaling, and up-regulation of respiration seems to require phosphoinositide 3-kinase/AKT signaling, but is independent of IGF effects on cell cycle progression. Collectively these data establish a regulatory cross-talk between insulin/IGF signal transduction and mitochondrial function, two major pathways implicated in controlling the rate of aging.     

Redox Control of Signal Transduction,Gene Expression and Cellular Senescence

Reactive oxygen species (ROS) act as subcellular messengers in such complex cellular processes as mitogenic signal transduction, gene expression, regulation of cell proliferation, replicative senescence, and apoptosis. They serve to maintain cellular homeostasis and their production is under strict control. However, the mechanisms whereby ROS act are still obscure. Here we review recent advances in our understanding of signaling mechanisms and recent data about the involvement of ROS in: (i) the regulation of the mitogenic transduction elements, particularly protein kinases and phosphatases; (ii) the regulation of gene expression; and (iii) the induction of replicative senescence and the role, if any, in aging and age-related disorders.     

The p53 network: cellular and systemic DNA damage responses in aging and cancer

Genome instability contributes to cancer development and accelerates age-related pathologies as evidenced by a variety of congenital cancer susceptibility and progeroid syndromes that are caused by defects in genome maintenance mechanisms. DNA damage response (DDR) pathways that are mediated through the tumor suppressor p53 play an important role in the cell-intrinsic responses to genome instability, including a transient cell cycle arrest, senescence and apoptosis. Both senescence and apoptosis are powerful tumor-suppressive pathways preventing the uncontrolled proliferation of transformed cells. However, both pathways can potentially deplete stem and progenitor cell pools, thus promoting tissue degeneration and organ failure, which are both hallmarks of aging. p53 signaling is also involved in mediating non-cell-autonomous interactions with the innate immune system and in the systemic adjustments during the aging process. The network of p53 target genes thus functions as an important regulator of cancer prevention and aging.     

Nuclear inositol lipid signaling and its potential involvement in malignant transformation

Growth, differentiation, and apoptosis of eukaryotic cells are mediated by extremely complex signaling pathways and a high degree of coordination is required for regulating cell proliferation.In multicellular organisms homeostasis is achieved through signal transduction events. If these homeostatic mechanisms are interrupted, a disease, such as cancer, may ensue. Lipid second messengers, particularly those derived from polyphosphoinositide cycle, play a pivotal role in several cell signaling networks. Evidence accumulated over the past 15 years has highlighted the presence of an autonomous nuclear inositol lipid metabolism, and suggests that lipid signaling molecules are important components of signaling pathways operating within the nucleus. Recent findings are starting to elucidate how the nuclear phosphoinositide cycle is regulated and what down-stream molecules are targeted through this cycle. In this review, we shall summarize the most updated data about inositol lipid-dependent nuclear signaling pathways that might have a relevance for the development of cancer. In the near future, this knowledge might also prove to have relevance for the diagnosis and treatment of the neoplastic disease.     

Bioinformatics analyses for signal transduction networks

Research in signaling networks contributes to a deeper understanding of organism living activities. With the development of experimental methods in the signal transduction field, more and more mechanisms of signaling pathways have been discovered. This paper introduces such popular bioin-formatics analysis methods for signaling networks as the common mechanism of signaling pathways and database resource on the Internet, summerizes the methods of analyzing the structural properties of networks, including structural Motif finding and automated pathways generation, and discusses the modeling and simulation of signaling networks in detail, as well as the research situation and tendency in this area. Now the investigation of signal transduction is developing from small-scale experiments to large-scale network analysis, and dynamic simulation of networks is closer to the real system. With the investigation going deeper than ever, the bioinformatics analysis of signal transduction would have immense space for development and application.     

SNAVI: Desktop application for analysis and visualization of large-scale signaling networks

Background  

Studies of cellular signaling indicate that signal transduction pathways combine to form large networks of interactions. Viewing protein-protein and ligand-protein interactions as graphs (networks), where biomolecules are represented as nodes and their interactions are represented as links, is a promising approach for integrating experimental results from different sources to achieve a systematic understanding of the molecular mechanisms driving cell phenotype. The emergence of large-scale signaling networks provides an opportunity for topological statistical analysis while visualization of such networks represents a challenge.     

Large‐scale proteomic analysis of tyrosine‐phosphorylation induced by T‐cell receptor or B‐cell receptor activation reveals new signaling pathways

Activation of the T‐cell receptor (TCR) and that of the B‐cell receptor (BCR) elicits tyrosine‐phosphorylation of proteins that belongs to similar functional categories, but result in distinct cellular responses. Large‐scale analyses providing an overview of the signaling pathways downstream of TCR or BCR have not been described, so it has been unclear what components of these pathways are shared and which are specific. We have now performed a systematic analysis and provide a comprehensive list of tyrosine‐phosphorylated proteins (PY proteome) with quantitative data on their abundance in T cell, B cell, and nonlymphoid cell lines. Our results led to the identification of novel tyrosine‐phosphorylated proteins and signaling pathways not previously implicated in immunoreceptor signal transduction, such as clathrin, zonula occludens 2, eukaryotic translation initiation factor 3, and RhoH, suggesting that TCR or BCR signaling may be linked to downstream processes such as endocytosis, cell adhesion, and translation. Thus comparative and quantitative studies of tyrosine‐phosphorylation have the potential to expand knowledge of signaling networks and to promote understanding of signal transduction at the system level.     

Signal transduction during cold, salt, and drought stresses in plants

Abiotic stresses, especially cold, salinity and drought, are the primary causes of crop loss worldwide. Plant adaptation to environmental stresses is dependent upon the activation of cascades of molecular networks involved in stress perception, signal transduction, and the expression of specific stress-related genes and metabolites. Plants have stress-specific adaptive responses as well as responses which protect the plants from more than one environmental stress. There are multiple stress perception and signaling pathways, some of which are specific, but others may cross-talk at various steps. In this review article, we first expound the general stress signal transduction pathways, and then highlight various aspects of biotic stresses signal transduction networks. On the genetic analysis, many cold induced pathways are activated to protect plants from deleterious effects of cold stress, but till date, most studied pathway is ICE-CBF-COR signaling pathway. The Salt-Overly-Sensitive (SOS) pathway, identified through isolation and study of the sos1, sos2, and sos3 mutants, is essential for maintaining favorable ion ratios in the cytoplasm and for tolerance of salt stress. Both ABA-dependent and -independent signaling pathways appear to be involved in osmotic stress tolerance. ROS play a dual role in the response of plants to abiotic stresses functioning as toxic by-products of stress metabolism, as well as important signal transduction molecules and the ROS signaling networks can control growth, development, and stress response. Finally, we talk about the common regulatory system and cross-talk among biotic stresses, with particular emphasis on the MAPK cascades and the cross-talk between ABA signaling and biotic signaling.     

A network-based approach on elucidating the multi-faceted nature of chronological aging in S. cerevisiae

Background

Cellular mechanisms leading to aging and therefore increasing susceptibility to age-related diseases are a central topic of research since aging is the ultimate, yet not understood mechanism of the fate of a cell. Studies with model organisms have been conducted to ellucidate these mechanisms, and chronological aging of yeast has been extensively used as a model for oxidative stress and aging of postmitotic tissues in higher eukaryotes.

Methodology/Principal Findings

The chronological aging network of yeast was reconstructed by integrating protein-protein interaction data with gene ontology terms. The reconstructed network was then statistically “tuned” based on the betweenness centrality values of the nodes to compensate for the computer automated method. Both the originally reconstructed and tuned networks were subjected to topological and modular analyses. Finally, an ultimate “heart” network was obtained via pooling the step specific key proteins, which resulted from the decomposition of the linear paths depicting several signaling routes in the tuned network.

Conclusions/Significance

The reconstructed networks are of scale-free and hierarchical nature, following a power law model with γ  =  1.49. The results of modular and topological analyses verified that the tuning method was successful. The significantly enriched gene ontology terms of the modular analysis confirmed also that the multifactorial nature of chronological aging was captured by the tuned network. The interplay between various signaling pathways such as TOR, Akt/PKB and cAMP/Protein kinase A was summarized in the “heart” network originated from linear path analysis. The deletion of four genes, TCB3, SNA3, PST2 and YGR130C, was found to increase the chronological life span of yeast. The reconstructed networks can also give insight about the effect of other cellular machineries on chronological aging by targeting different signaling pathways in the linear path analysis, along with unraveling of novel proteins playing part in these pathways.     

Structural fingerprints,interactions, and signaling networks of RAS family proteins beyond RAS isoforms

Among the signaling molecules indirectly linked to many different cell surface receptors, RAS proteins essentially respond to a diverse range of extracellular cues. They control activities of multiple signaling pathways and consequently a wide array of cellular processes, including survival, growth, adhesion, migration, and differentiation. Any dysregulation of these pathway leads, thus, to cancer, developmental disorders, metabolic, and cardiovascular diseases. The biochemistry of RAS family proteins has become multifaceted since the discovery of the first members, more than 40 years ago. Substantial knowledge has been attained about molecular mechanisms underlying post-translational modification, membrane localization, regulation, and signal transduction through diverse effector molecules. However, the increasing complexity of the underlying signaling mechanisms is considerable, in part due to multiple effector pathways, crosstalks between them and eventually feedback mechanisms. Here, we take a broad view of regulatory and signaling networks of all RAS family proteins that extends beyond RAS paralogs. As described in this review, a lot is known but a lot has to be discovered yet.     

Reactive nitrogen species in cellular signaling

The transduction of cellular signals occurs through the modification of target molecules. Most of these modifications are transitory, thus the signal transduction pathways can be tightly regulated. Reactive nitrogen species are a group of compounds with different properties and reactivity. Some reactive nitrogen species are highly reactive and their interaction with macromolecules can lead to permanent modifications, which suggested they were lacking the specificity needed to participate in cell signaling events. However, the perception of reactive nitrogen species as oxidizers of macromolecules leading to general oxidative damage has recently evolved. The concept of redox signaling is now well established for a number of reactive oxygen and nitrogen species. In this context, the post-translational modifications introduced by reactive nitrogen species can be very specific and are active participants in signal transduction pathways. This review addresses the role of these oxidative modifications in the regulation of cell signaling events.     

Scaffold蛋白介导细胞信号转导专一性的定量分析

细胞使用相对有限的蛋白质组分传递大量的信号,因此不同的信号通常由相同的蛋白质组分传递。这些蛋白质组分是如何选择性地参与不同的信号通路,“高保真”地传递不同的刺激,从而产生特定的细胞应答,是目前细胞生物学领域中的研究热点和难点之一。鉴于Scaffold蛋白在确保信号转导专一性和保真性中的关键作用,作者基于酵母S.cerevisiae的生物学实验数据,建立了由Scaffold介导的丝裂原活化蛋白激酶(mitogenactivatedproteinkinase,MAPK)级联信号转导网络的数学模型。并对已报道的工作进行扩展,给出了多条信号级联网络的“专一性(specificity)”和“保真性(fidelity)”的精确数学定义,计算了MAPK信号网络的专一性和保真性的解析解。用这些解定量分析细胞信号转导的专一性和保真性与信号通路各种动力学参数(输入信号的强度和时间、反应率、磷酸化和去磷酸化系数、降解系数等)之间的关系,从理论上阐述Scaffold蛋白通过隔离(sequestration)和选择性激活(selectiveactivation)等机制增强信号转导网络的专一性和保真性。从而有助于加深对细胞信号转导及其调控过程的系统理解,为揭示某些因细胞信号转导异常所致疾病的发生机理,寻找治疗药物提供新的思路。     

High-fat-diet-induced obesity and heart dysfunction are regulated by the TOR pathway in Drosophila

High-fat-diet (HFD)-induced obesity is a major contributor to diabetes and cardiovascular disease, but the underlying genetic mechanisms are poorly understood. Here, we use Drosophila to test the hypothesis that HFD-induced obesity and associated cardiac complications have early evolutionary origins involving nutrient-sensing signal transduction pathways. We find that HFD-fed flies exhibit increased triglyceride (TG) fat and alterations in insulin/glucose homeostasis, similar to mammalian responses. A HFD also causes cardiac lipid accumulation, reduced cardiac contractility, conduction blocks, and severe structural pathologies, reminiscent of diabetic cardiomyopathies. Remarkably, these metabolic and cardiotoxic phenotypes elicited by HFD are blocked by inhibiting insulin-TOR signaling. Moreover, reducing insulin-TOR activity (by expressing TSC1-2, 4EBP or FOXO), or increasing lipase expression-only within the myocardium-suffices to efficiently alleviate cardiac fat accumulation and dysfunction induced by HFD. We conclude that deregulation of insulin-TOR signaling due to a HFD is responsible for mediating the detrimental effects on metabolism and heart function.     

Systematic Prediction of Scaffold Proteins Reveals New Design Principles in Scaffold-Mediated Signal Transduction

Scaffold proteins play a crucial role in facilitating signal transduction in eukaryotes by bringing together multiple signaling components. In this study, we performed a systematic analysis of scaffold proteins in signal transduction by integrating protein-protein interaction and kinase-substrate relationship networks. We predicted 212 scaffold proteins that are involved in 605 distinct signaling pathways. The computational prediction was validated using a protein microarray-based approach. The predicted scaffold proteins showed several interesting characteristics, as we expected from the functionality of scaffold proteins. We found that the scaffold proteins are likely to interact with each other, which is consistent with previous finding that scaffold proteins tend to form homodimers and heterodimers. Interestingly, a single scaffold protein can be involved in multiple signaling pathways by interacting with other scaffold protein partners. Furthermore, we propose two possible regulatory mechanisms by which the activity of scaffold proteins is coordinated with their associated pathways through phosphorylation process.