Entirely Artificial Signal Transduction with Adrenaline

Multifunctional transmembrane-building blocks with recognition sites for adrenaline on one end and the reaction partners for an S_N2 reaction on the opposite end have been embedded in DPPC-liposomes. These doped vesicles can be quantitatively reduced at their disulfide head groups by externally added reducing agents; their composition and chemical processes taking place within can be monitored by NMR spectroscopy and–with limitations—by UV/Vis spectroscopy. Attempted release of thiopyridine as a second messenger into the interior of the liposome on external adrenaline addition could not be proven unambiguously because the detection system does not fulfill the necessary rigorous specificity and sensitivity requirements.     

Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis

The VEGF/VPF (vascular endothelial growth factor/vascular permeability factor) ligands and receptors are crucial regulators of vasculogenesis, angiogenesis, lymphangiogenesis and vascular permeability in vertebrates. VEGF-A, the prototype VEGF ligand, binds and activates two tyrosine kinase receptors: VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk-1). VEGFR1, which occurs in transmembrane and soluble forms, negatively regulates vasculogenesis and angiogenesis during early embryogenesis, but it also acts as a positive regulator of angiogenesis and inflammatory responses, playing a role in several human diseases such as rheumatoid arthritis and cancer. The soluble VEGFR1 is overexpressed in placenta in preeclampsia patients. VEGFR2 has critical functions in physiological and pathological angiogenesis through distinct signal transduction pathways regulating proliferation and migration of endothelial cells. VEGFR3, a receptor for the lymphatic growth factors VEGF-C and VEGF-D, but not for VEGF-A, regulates vascular and lymphatic endothelial cell function during embryogenesis. Loss-of-function variants of VEGFR3 have been identified in lymphedema. Formation of tumor lymphatics may be stimulated by tumor-produced VEGF-C, allowing increased spread of tumor metastases through the lymphatics. Mapping the signaling system of these important receptors may provide the knowledge necessary to suppress specific signaling pathways in major human diseases.     

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.     

蛋白激酶B及其在磷脂酰肌醇3-激酶介导的信号转导中的作用

蛋白激酶Ｂ（ＰＫＢ）是原癌基因ｃ－ａｋｔ的表达产物,它参与由生长因子激活的经磷脂磷肌醇３－激酶（ＰＩ３Ｋ）介导的信号转导过程。与许多蛋白激酶相似,ＰＫＢ分子具有一特殊的ＡＨ／ＰＨ结构域（ＡＨ／ＰＨｄｏｍａｉｎ）,后者能介导信号分子间的相互作用。ＰＫＢ是ＰＩ３Ｋ直接的靶蛋白。ＰＩ３Ｋ产生的脂类第二信使ＰＩ－３,４,Ｐ２和ＰＩ－３,４,５－Ｐ３等均能与ＰＫＢ和磷酸肌醇依赖性蛋白激酶（ＰＤＫ）的ＡＨ／Ｐ     

Platelet-derived growth factors and their receptors: Structural and functional perspectives

The four types of platelet-derived growth factors (PDGFs) and the two types of PDGF receptors (PDGFRs, which belong to class III receptor tyrosine kinases) have important functions in the development of connective tissue cells. Recent structural studies have revealed novel mechanisms of PDGFs in propeptide loading and receptor recognition/activation. The detailed structural understanding of PDGF–PDGFR signaling has provided a template that can aid therapeutic intervention to counteract the aberrant signaling of this normally silent pathway, especially in proliferative diseases such as cancer. This review summarizes the advances in the PDGF system with a focus on relating the structural and functional understandings, and discusses the basic aspects of PDGFs and PDGFRs, the mechanisms of activation, and the insights into the therapeutic antagonism of PDGFRs. This article is part of a Special Issue entitled: Emerging recognition and activation mechanisms of receptor tyrosine kinases.     

LET-23-mediated signal transduction during Caenorhabditis elegans development

We are using Caenorhabditis elegans vulval induction to study intercellular signaling and its regulation. Genes required for vulval induction include the LIN-3 transforming α-like growth factor, the LET-23 epidermal growth factor (EGF)-receptor-like transmembrane tyrosine kinase, the SEM-5 adaptor protein, LET-60 Ras, and the LIN-45 Raf serine/threonine kinase. Inactivation of this pathway results in a failure of vulval differentiation, the “vulvaless” phenotype. Activation of this pathway either by overexpression of LIN-3, a point mutation in the LET-23 extracellular domain, or hyperactivity of LET-60 Ras results in excessive vulval differentiation, the “multivulva” phenotype. In addition to searching for new genes that act positively in this signaling pathway, we have also characterized genes that negatively regulate this inductive signaling pathway. We find that such negative regulators are functionally redundant: mutation of only one of these negative regulators has no effect on vulval differentiation; however, if particular combinations of these genes are inactivated, excessive vulval differentiation occurs. The LIN-15 locus encodes two functionally redundant products, LIN-15A and LIN-15B, that formally act upstream of the LET-23 receptor to prevent its activity in the absence of inductive signal. The LIN-15A and B proteins are novel and unrelated to each other. The unc-101, sli-1, and rok-1 genes encode a distinct set of negative regulators of vulval differentiation. The unc-101 gene encodes an adaptin, proposed to be involved in intracellular protein trafficking. The sli-1 gene encodes a protein with similarity to c-cbl, a mammalian proto-oncogene not previously linked with a tyrosine kinase-Ras-mediated signaling pathway. LIN-3 and LET-23 are required for several aspects of C. elegans development—larval viability, P12 neuroectoblast specification, hermaphrodite vulval induction and fertility, and three inductions during male copulatory spicule development. Fertility and vulval differentiation appear to be mediated by distinct parts of the cytoplasmic tail of LET-23, and by distinct signal transduction pathways. © 1995 wiley-Liss, Inc.     

In silico tools for signal transduction research

Signal transduction is a fundamental process that takes place in all living organisms and understanding how this event occurs at the cellular level is of vital importance to virtually all fields of biomedicine. There are several major steps involved in deciphering the signalling pathways: (a) Which molecules are involved in signalling? (b) Who talks to whom?, ie making sense of the molecular interactions in a context-dependent way. (c) Where are the signalling events taking place?, eg when a resting cell becomes activated. The challenge lies in reconstructing signalling modules and networks evoked in a particular response to a single input as well as correlating the signalling response to different cellular inputs. There is also the need for interpretation of cross-talk between signalling modules in response to single and multiple inputs. To follow up these questions there are many good databases that provide an information system on regulatory networks. This review aims to find some of the bioinformatics tools and websites available to conduct signal transduction research and to discuss the representation of databases available for the processes of signalling. The databases considered here can provide a well-structured overview on the subject and a basis for advanced bioinformatics analysis to interpret the function of genomic sequences or to analyse signalling networks within a cell. However, the knowledge of most signalling pathways is incomplete and for this reason the existing databases will provide insight, but very rarely a more complete picture.     

上皮细胞转分化的信号转导研究进展及其在肾小管的研究现状

上皮细胞在特定生理和病理情况下向间充质细胞转分化的现象是肿瘤及慢性炎症性疾病中的重要细胞生物学现象。近年来研究发现 ,细胞内信号转导途径中的MAPK通路、Rho家族激酶、Src激酶、PI3激酶和Smad通路参与调控上皮细胞转分化过程。肾小管上皮细胞在病理条件下可转分化为肌成纤维细胞 ,其细胞内信号转导机制虽已有初步研究 ,但尚所知甚少。本文将就有关的研究进展及现状进行综述     

Signal transduction by members of the transforming growth factor-β superfamily

Transforming growth factor-β (TGFβ) superfamily members exert their diverse biological effects through their interaction with heteromeric receptor complexes of transmembrane serine/threonine kinases. Both components of the receptor complex, known as receptor I and receptor II are essential for signal transduction. The composition of these complexes can vary significantly due to the promiscuous nature of the ligands and the receptors, and this diversity of interactions can yield a variety of biological responses. Several receptor interacting proteins and potential mediators of signal transduction have now been identified. Recent advances, particularly in our understanding of the function of Mothers against dpp-related (MADR) proteins, are providing new insights into how the TGFβ superfamily signals its diverse biological activities.     

Signal transduction through the T cell receptor is dynamically regulated by balancing kinase and phosphatase activities

Within seconds of T cell receptor engagement, a well-characterized series of tyrosine phosphorylation events mediate cellular activation. It is widely accepted that these initial phosphorylations remain stable until protein tyrosine phosphatases return the cell to its basal level. Based on a model of peripheral blood T cell activation, in which the kinetics of phosphorylation can be modulated, we propose an alternate hypothesis that T cell signaling is highly dynamic. Our results demonstrate that tyrosine phosphorylation and dephosphorylation are occurring co-temporally after T cell receptor cross-linking, regulated by a delicate balance of kinases and phosphatases.     

心肌细胞肥大的信号转导通路

心肌肥厚是肥大刺激诱导核内基因异常表达的结果,细胞内信号转导通路是肥大刺激与核内基因转录活化的偶联环节。然而,淡同刺激诱导的心肌肥大可能具有不同的“分子表型”,这主要取决于它们启动的信号转导通路。对心肌肥大信号转导通路的深入认识,不仅胡助于阐明心肌肥厚的细胞分子机制,而且可为药物干预防治心肌肥厚提供新思路。     

抗病毒感染固有免疫应答的信号转导

入侵病毒的探知和适应性免疫应答启动均依靠固有免疫系统。三种模式识别受体(PRRs)在宿主防御系统第一线占据极其重要地位:Toll样受体、维甲酸诱导基因I样受体、核苷酸结合寡聚化结构域样受体。PRRs识别病原相关分子模式(PAMP)或危险信号分子模式(DAMPs)启动和调节固有免疫和适应性免疫应答。每种PRR都有单独的识别配体和细胞定位。激活的PRRs将信号分子传递给其配体分子(MyD88,TRIF,IRAK,IPS-1),配体活化后作为信使激活信号途径下游激酶(IKK复合物,MAPKs,TBK1,RIP-1)和转录因子(NF-κB,AP-1,IRF3),最终产生细胞因子、趋化因子、促炎细胞因子和I型干扰素。本文重点讨论PRRs信号通路及该领域取得的成果,以期为人类健康和免疫疾病防治提供策略。     

Pathogen recognition and signal transduction by the Pto kinase

In tomato, the disease resistance genePto confers resistance to bacterial speck disease by recognizing the expression of a corresponding avirulence gene,avrPto, in the pathogenPseudomonas syringae pv.tomato (Martinet al. 1993). Similar “gene-for-gene” interactions occur in many plant-pathogen associations (Flor 1971). Such recognition events often lead to the activation in the plant of a variety of defense responses including a rapid induction of localized necrosis at the site of infection (the hypersensitive response, HR), increased expression of defense-related genes, production of antimicrobial compounds, lignin formation, and the oxidative burst (Lambet al. 1989, Mehdy 1994). As a result, the pathogen is contained at the infection site and its growth is inhibited.Pto encodes a serine/threonine protein kinase and belongs to a clustered multigene family. Another member of thePto family calledFen confers no known disease resistance, but mediates a hypersensitive-like reaction in the plant to the insecticide fenthion (Martinet al. 1994). We are interested in a number of fundamental questions concerning the Pto signaling pathways. What is the molecular basis of thePto-avrPto gene-for-gene interaction? What are the components involved in thePto-mediated signal transduction chain? How does thePto kinase activate complex defense responses? This paper summarizes our recent progress towards understanding these questions.     

p38 MAPK信号传导通路

丝裂原活化蛋白激酶（ｍｉｔｏｇｅｎ－ａｃｔｉｖａｔｅｄｐｏｒｏｔｅｉｎｋｉｎａｓｅ,ＭＡＰＫ）介导了生长、发育,分裂,死亡,以及细胞间的功能同步等多种细胞生理功能,在哺乳动物细胞中已发现和克隆了ＥＲＫ、ＪＮＫ／ＳＡＰＫ,ＥＲＫ５／ＢＭＫ１和ｐ３８／ＲＫ四个ＭＡＰＫ亚族,这些新的ＭＡＰＫ介导了物理,化学反激,细菌产物,炎性细胞因子等多种刺激引起的细胞反应,ｐ３８亚族至少包括ｐ３８（α）,ｐ３８β,ｐ     

A screen for upstream components of the yeast protein kinase C signal transduction pathway identifies the product of the SLG1 gene

We employed the constitutive BCK1-20 allele of the gene for the MAP kinase kinase kinase (MAPKKK) in the yeast Pkc signal transduction pathway to develop a genetic screen for mutants in genes encoding upstream components. Transposon mutagenesis yielded a mutant that was completely dependent on the active allele in the absence of osmotic stabilization. The transposon had integrated at the yeast SLG1 (HCS77) locus. This gene encodes a putative membrane protein. Haploid slg1 deletion strains are sensitive to caffeine, as expected for mutants in the Pkc pathway, as well as a variety of other drugs. The response to elevated temperatures and the dependence on osmotic stabilization depends on the genetic background. Thus, in the strain used for mutagenesis, disruption of SLG1 causes the cells to become non-viable in the absence of osmotic stabilization at both 30° C and 37° C. In a different genetic background this phenotype was not observed. Sensitivity of the haploid deletion mutants to caffeine can be partially suppressed by overexpression of genes for other components of the Pkc pathway, such as PKC1, SLT2, ROM2, and STE20. In addition, a SLG1-lacZ reporter construct shows higher expression in the presence of caffeine or magnesium chloride in a wild-type diploid background. Received: 2 December 1997 / Accepted: 15 December 1997     

Signal transduction and motility ofDictyostelium

This review is concerned with the roles of cyclic GMP and Ca²⁺ ions in signal transduction for chemotaxis ofDictyostelium. These molecules are involved in signalling between the cell surface cyclic AMP receptors and cytoskeletal myosin II involved in chemotactic cell movement. Evidence is presented for uptake and/or eflux of Ca²⁺ being regulated by cyclic GMP. The link between Ca²⁺, cyclic GMP and chemotactic cell movement has been explored using streamer F mutants whose primary defect is in the structural gene for the cyclic GMP-specific phosphodiesterase. This mutation causes the mutants to produce an abnormally prolonged peak of cyclic GMP accumulation in response to stimulation with the chemoattractant cyclic AMP. The production and relay of cyclic AMP signals is normal in these mutants, but certain events associated with movement are (like the cyclic GMP response) abnormally prolonged in the mutants. These events include Ca²⁺ uptake, myosin II association with the cytoskeleton and regulation of both myosin heavy and light chain phosphorylation. These changes can be correlated with changes in the shape of the amoebae after chemotactic stimulation. Other mutants in which the accumulation of cyclic GMP in response to cyclic AMP stimulation was absent produced no myosin II responses.A model is described in which cyclic GMP (directly or indirectly via Ca²⁺) regulates accumulation of myosin II on the cytoskeleton by regulating phosphorylation of the myosin heavy and light chain kinases.     

胰岛素信号转导障碍与胰岛素抵抗的形成

胰岛素生理作用的发挥,起始于胰岛素与其受体的结合,并由此引起细胞内一系列信号转导,最终到达各效应器产生各种生理效应。胰岛素信号转导在胰岛素生理作用的发挥中起着至关重要的作用。胰岛素信号转导减弱或受阻,使得胰岛素生理作用减弱,导致胰岛素抵抗形成。本文综述了胰岛素信号转导失调在胰岛素抵抗形成中的作用。