Leptin-induced signal transduction pathways

Leptin is a multifunctional cytokine and hormone that primarily acts in the hypothalamus and plays a key role in the regulation of food intake and energy expenditure. In addition, it has direct effects on many cell types on the periphery. Leptin acts through its receptor, the product of the db gene, which has six isoforms. Only one of them (OB-Rb) has full signalling capabilities and is able to activate the Jak/STAT pathway, the major pathway used by leptin to exert its effects. However, some signalling events can be initiated by the short isoforms. Besides Jak/STAT, other pathways, such as MAPK and the 5'-AMP-activated protein kinase (AMPK) pathway, are also involved in leptin signalling. Leptin also interacts with insulin signalling. In this paper, we give an overview of the signal transduction mechanisms that are related to the actions of leptin.     

Wnt signal transduction pathways

The Wnt signaling pathway is an ancient and evolutionarily conserved pathway that regulates crucial aspects of cell fate determination, cell migration, cell polarity, neural patterning and organogenesis during embryonic development. The Wnts are secreted glycoproteins and comprise a large family of nineteen proteins in humans hinting to a daunting complexity of signaling regulation, function and biological output. To date major signaling branches downstream of the Fz receptor have been identified including a canonical or Wnt/β-catenin dependent pathway and the non-canonical or β-catenin-independent pathway which can be further divided into the Planar Cell Polarity and the Wnt/Ca²⁺ pathways, and these branches are being actively dissected at the molecular and biochemical levels. In this review, we will summarize the most recent advances in our understanding of these Wnt signaling pathways and the role of these pathways in regulating key events during embryonic patterning and morphogenesis.Key words: Wnt, frizzled, dishevelled, canonical, non-canonical, β-catenin, Planar Cell Polarity     

Wnt signal transduction pathways

The Wnt signaling pathway is an ancient and evolutionarily conserved pathway that regulates crucial aspects of cell fate determination, cell migration, cell polarity, neural patterning and organogenesis during embryonic development. The Wnts are secreted glycoproteins and comprise a large family of nineteen proteins in humans hinting to a daunting complexity of signaling regulation, function and biological output. To date major signaling branches downstream of the Fz receptor have been identified including a canonical or Wnt/β-catenin dependent pathway and the non-canonical or β-catenin-independent pathway which can be further divided into the Planar Cell Polarity and the Wnt/Ca²⁺ pathways, and these branches are being actively dissected at the molecular and biochemical levels. In this review, we will summarize the most recent advances in our understanding of these Wnt signaling pathways and the role of these pathways in regulating key events during embryonic patterning and morphogenesis.     

Mapping signal transduction pathways by phage display

Rapid identification of proteins that interact with a novel gene product is an important element of functional genomics. Here we describe a phage display-based technique for interaction screening of complex cDNA libraries using proteins or synthetic peptides as baits. Starting with the epidermal growth factor receptor (EGFR) cytoplasmic tail, we identified known protein interactions that link EGFR to the Ras/MAP kinase signal transduction cascade and several novel interactions. This approach can be used as a rapid and efficient tool for elucidating protein networks and mapping intracellular signal transduction pathways.     

Targeting signal transduction pathways by chemopreventive agents

Cancer is a dynamic process that involves many complex factors, which may explain why a "magic bullet" cure for cancer has not been found. Death rates are still rising for many types of cancers, which possibly contributes to the increased interest in chemoprevention as an alternative approach to the control of cancer. This strategy for cancer control is based on the presumption that because cancer develops through a multi-step process, each step may be a prospective target for reversing or suppressing the process. Thus, the design and development of chemopreventive agents that act on specific and/or multiple molecular and cellular targets is gaining support as a rational approach to control cancer. Nutritional or dietary factors have attracted a great deal of interest because of their perceived ability to act as highly effective chemopreventive agents. They are professed as being generally safe and may have efficacy as chemopreventive agents by preventing or reversing premalignant lesions and/or reducing second primary tumor incidence. Many of these dietary compounds appear to act on multiple target signaling pathways. Some of the most interesting and well documented are resveratrol and components of tea, including EGCG, theaflavins and caffeine. This review will focus on recent work regarding three well-accepted cellular/molecular mechanisms that may at least partially explain the effectiveness of selected food factors, including those indicated above, as chemopreventive anti-promotion agents. These food compounds may act by: (1) inducing apoptosis in cancer cells; (2) inhibiting neoplastic transformation through the inhibition of AP-1 and/or NF-kappaB activation; and/or (3) suppressing COX-2 overexpression in cancer cells.     

MicroRNA与肿瘤相关的信号转导通路

信号转导通路在细胞代谢、生长、增殖、应激、发育和凋亡等生命活动中具有极为重要的作用。干扰这些通路将可能影响细胞的正常发育, 甚至导致肿瘤。MicroRNA(miRNA)是近年来在真核生物中发现的、在转录后水平负调节基因表达的一类长度约22个核苷酸的非编码小RNA, 其靶基因数目众多, 生物学功能广泛。在多种肿瘤中发现了miRNA的异常表达, 提示后者与肿瘤发生有关, 可能机制为调控癌基因或肿瘤抑制基因的表达。此外亦发现miRNA的靶基因有许多作用于肿瘤相关的信号转导通路。miRNA在肿瘤发生过程中的重要调控功能预示其将成为人类癌症诊断和治疗方面的新星。     

Phytochrome and UV signal transduction pathways

The phytochromes are the best studied plant photoreceptors, controlling a wide variety of responses at both whole plant and single cell levels. Three signal transduction pathways, dependent on cGMP and/or calcium, have been found to be utilized by phytochrome to control the expression of genes required for chloroplast development (e.g., CAB and FNR) and anthocyanin biosynthesis (e.g., CHS). In particular, cGMP is a second messenger positively regulating CHS gene expression whilst calcium and calmodulin act as negative regulators. In addition to phytochrome regulation of CHS we have begun to examine the signal transduction pathways utilized by UV photoreceptors. In contrast to phytochrome-mediated responses, results indicate a role for calcium and calmodulin as positive regulators of CHS gene expression in UV light.     

Integrin-mediated signal transduction pathways.

Integrins serve as adhesion receptors for extracellular matrix proteins and also transduce biochemical signals into the cell. They regulate a variety of cellular functions, including spreading, migration, proliferation and apoptosis. Many signaling pathways downstream of integrins have been identified and characterized and are discussed here. In particular, integrins regulate many protein tyrosine kinases and phosphatases, such as FAK and Src, to coordinate many of the cell processes mentioned above. The regulation of MAP kinases by integrins is important for cell growth or other functions, and the putative roles of Ras and FAK in these pathways are discussed. Phosphatidylinositol lipids and their modifying enzymes, particularly PI 3-kinase, are strongly implicated as mediators of integrin-regulated cytoskeletal changes and cell migration. Similarly, actin cytoskeleton regulation by the Rho family of GTPases is coordinated with integrin signaling to regulate cell spreading and migration, although the exact relationship between these pathways is not clear. Finally, intracellular pH and calcium fluxes by integrins are suggested to affect a variety of cellular proteins and functions.     

Knowledge representation of signal transduction pathways

MOTIVATIONS: Signal transduction is the common term used to define a diverse topic that encompasses a large body of knowledge about the biochemical mechanisms. Since most of the knowledge of signal transduction resides in scientific articles and is represented by texts in natural language or by diagrams, there is the need of a knowledge representation model for signal transduction pathways that can be as readily processed by a computer as it is easily understood by humans. RESULTS: A signal transduction pathway representation model is presented. It is based on a compound graph structure and is designed to handle the diversity and hierarchical structure of pathways. A prototype knowledge base was implemented on a deductive database and a number of biological queries are demonstrated on it.     

Regulation of signal transduction pathways in development by glycosylation

Recent studies from several laboratories have provided evidence that cell surface complex carbohydrates play key roles in the regulation of developmentally relevant signal transduction events. The demonstration that Fringe, a known modifier of Notch function, is a fucose-specific N-acetylglucosaminyltransferase provided strong evidence that the Notch signaling pathway could be regulated by alterations of O-fucose structures. More recently, the demonstration that O-fucose modification of Cripto is essential for Nodal-dependent signaling provides further evidence of a role for glycosylation in signal transduction. These and other examples provide a new paradigm for the regulation of signal transduction events by glycosylation.     

MAPK信号转导通路对炎症反应的调控

丝裂原活化蛋白激酶 (mitogen -activatedproteinkinase ,MAPK)是生物体内重要的信号转导系统之一 ,参与介导生长、发育、分裂、分化、死亡以及细胞间的功能同步等多种细胞过程。在哺乳动物细胞中已发现和克隆了ERKJNK/SAPK、p38/RK、ERK5/BMK1四个MAPK亚族。这些MAPK能被多种炎性刺激所激活 ,并对炎症的发生、发展起重要调控作用。研究感染和炎症反应过程中这些MAPK被激活的机制及其生物学效应 ,探讨MAPK特异性抑制剂的药理学作用及分子基础 ,对于感染的防治及炎症反应的控制有着广泛的应用前景。     

Power-law models of signal transduction pathways

The mathematical modelling of signal transduction pathways has become a valuable aid to understanding the complex interactions involved in intracellular signalling mechanisms. An important aspect of the mathematical modelling process is the selection of the model type and structure. Until recently, the convention has been to use a standard kinetic model, often with the Michaelis-Menten steady state assumption. However this model form, although valuable, is only one of a number of choices, and the aim of this article is to consider the mathematical structure and essential features of an alternative model form--the power-law model. Specifically, we analyse how power-law models can be applied to increase our understanding of signal transduction pathways when there may be limited prior information. We distinguish between two kinds of power law models: a) Detailed power-law models, as a tool for investigating pathways when the structure of protein-protein interactions is completely known, and; b) Simplified power-law models, for the analysis of systems with incomplete structural information or insufficient quantitative data for generating detailed models. If sufficient data of high quality are available, the advantage of detailed power-law models is that they are more realistic representations of non-homogenous or crowded cellular environments. The advantages of the simplified power-law model formulation are illustrated using some case studies in cell signalling. In particular, the investigation on the effects of signal inhibition and feedback loops and the validation of structural hypotheses are discussed.     

MAPK信号转导通路对炎证反应的调控

丝裂原活化蛋白激酶（ｍｉｔｏｈｅｎ－ａｃｔｅｖａｔｃｄ ｐｒｏｔｅｉｎ ｋｉｎａｓａ,ＭＡＰＫ）是生物体内重要的信号转导系统之一,参与介导生长、发育、化裂、分化、死亡以及细胞间的功能同步等多种细胞过程,在哺乳动物细胞中已发现和克隆了ＥＲＫ、ＪＮＫ／ＳＡＰＫ、ｐ３８／ＲＫ、ＥＲＫ５／ＢＭＫ１四个ＭＡＰＫ亚族。这些ＭＡＰＫ能被多种炎性刺激所激活,并对炎症的发生、发展起生重要调控作用。研究感染和炎症反应     

Mitogenic signal transduction by integrin- and growth factor receptor-mediated pathways

Engagement of cells with the extracellular matrix (ECM) proteins is crucial for various biological processes, including cell adhesion, spreading, proliferation, differentiation, migration, apoptosis, and gene induction, contributing to maintenance of tissue integrity, embryogenesis, wound healing, and the metastasis of tumor cells (Hynes, 2002b; Juliano, 2002). The engagement involves cell adhesion mediated by integrins, a large family of cell adhesion receptors that are transmembrane glycoproteins which bind to ECM or to counter-receptors on neighbor cells. In this review, the molecular basis of signaling mediated by integrins and their collaboration with growth factor receptors will be discussed, based on recent observations. Although other cell adhesion receptors including cadherins, selectins, syndecans, and the immunoglobulin superfamily of cell adhesion molecules (IgCAMs) can play important roles or be involved in these processes, we suggest readers refer to recent outstanding reviews on them (Barclay, 2003; Brummendorf and Lemmon 2001; Panicker et al. 2003).     

GPCR和CaCC信号传导中的钙信号网络

G蛋白偶联受体(G protein-coupled receptor,GPCR)作为最大的一类人膜蛋白受体家族和最重要的药物靶标而倍受关注,其中钙离子在细胞内信号传导级联放大中起了关键的作用。阐述了GPCR和钙激活的氯离子通道蛋白(calcium-activated chloride channel,CaCC)中的钙信号网络与生理功能以及如何干扰阻断该网络,为药物设计和很多疾病的治疗提供了依据。     

细胞骨架与胰岛素相关信号转导通路

细胞骨架是蛋白质纤维交织形成的立体网架体系,它是一个动态结构,可随着生理条件的改变不断进行组装和去组装,并受到细胞内外因素的调节.胰岛素是参与机体内诸多生理过程如葡萄糖转运、基因表达和DNA合成等的重要激素, 而胰岛素的正常分泌是其功能发挥的重要前提.越来越多的研究表明,细胞骨架在胰岛素行使功能和胰岛素的分泌过程中起重要作用,其具体机制与胰岛素相关的信号转导通路密切相关.当细胞骨架成分发生改变,继而影响到胰岛素相关的信号转导过程时,就会影响胰岛素的分泌,同时会导致胰岛素抵抗的发生.     

Exploitation of host signaling pathways by microbial quorum sensing signals

Environmental and commensal microbes that live within, on and around us have an enormous impact on human health. Recent progress in studies of prokaryotic interplay as well as host-bacteria interactions suggests that secreted microbial products, including quorum sensing signals (QSS), are important mediators of these intrakingdom and interkingdom relations. Reports have assigned QSS diverse and sometimes seemingly contradictory effects on mammalian cell physiology ranging from either blunting of the immune response or exerting pro-inflammatory activities to inducing cellular stress pathways and ultimately apoptosis. Thus, it is still unclear whether microbes utilize QSS to establish and maintain infections via modulation of host signaling pathways or if the eukaryotic host uses the conserved microbial QSS structures as molecular danger beacons to detect and fight infections. Along the same lines exactly how and under what circumstances QSS are detected by host cells remains a mystery, especially considering the distinct chemical properties of the QSS classes with some being small enough to passively diffuse across membranes while others most likely require extracellular recognition mechanisms.     

Wound signal transduction pathways in plants

A significant advancement in our knowledge and understanding of wound-signaling pathways in plants has been made recently. Essential role in the explanation of these processes came from the genetic screens and analysis of mutants which are defective in either jasmonic acid (JA) biosynthesis, JA perception or systemin function. Plants equally react to wound in the tissues directly damaged (local response) as well as in the non-wounded areas (systemic response). Jasmonides and in particular the most studied JA, produced by the octadecanoid pathway, are responsible for the systemic response. Jasmonides functioning as long-distance signal particles transmit the information about wound to distant, non-wounded tissues where defense response is invoked. Peptyd - systemin, identified in some Solanaceous species, acts locally to the wounded area to elicit the production of JA. Jasmonic acid-dependent and -independent wound signal transduction pathways have been identified and partially characterized. JA-dependent wound signaling pathways are responsible for the activation of systemic responses, whereas JA-independent wound signaling pathways, activated close to wound side, have a role in reparation of damaged tissue and in defense against pathogens.