Hormonal signal system of the lower eukaryotes

The literary and the authors' own data on the structural and functional organization of hormonal signaling systems in the lower eukaryotes (yeasts, trypanosomes, ciliates, slide mold Dictyostelium discoideum) have been summarized and analysed. On the basis of a comparative analysis of the primary structures of signal proteins in the lower and higher eukaryotes (G-protein alpha-subunits, enzymes-cyclases-adenylyl and guanylyl cyclases) some possible pathways of the evolution of proteins are suggested. At the level of unicellular organisms, the main blocks of hormone-sensitive signaling systems of the higher eukaryotes were created. Moreover, signaling systems of the lower eukaryotes ar more invariant than these of the higher eukaryotes. It may be associated with the fact that of functional blocks, typical for signaling systems of multicellular animals, fungi and plants, were selected from the numerous variants of signaling system blocks of unicellular organisms.     

Notch signaling: simplicity in design, versatility in function

Notch signaling is evolutionarily conserved and operates in many cell types and at various stages during development. Notch signaling must therefore be able to generate appropriate signaling outputs in a variety of cellular contexts. This need for versatility in Notch signaling is in apparent contrast to the simple molecular design of the core pathway. Here, we review recent studies in nematodes, Drosophila and vertebrate systems that begin to shed light on how versatility in Notch signaling output is generated, how signal strength is modulated, and how cross-talk between the Notch pathway and other intracellular signaling systems, such as the Wnt, hypoxia and BMP pathways, contributes to signaling diversity.     

Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability

Cell signaling systems that contain positive-feedback loops or double-negative feedback loops can, in principle, convert graded inputs into switch-like, irreversible responses. Systems of this sort are termed "bistable". Recently, several groups have engineered artificial bistable systems into Escherichia coli and Saccharomyces cerevisiae, and have shown that the systems exhibit interesting and potentially useful properties. In addition, two naturally occurring signaling systems, the p42 mitogen-activated protein kinase and c-Jun amino-terminal kinase pathways in Xenopus oocytes, have been shown to exhibit bistable responses. Here we review the basic properties of bistable circuits, the requirements for construction of a satisfactory bistable switch, and the recent progress towards constructing and analysing bistable signaling systems.     

Juxtacrine Signaling Is Inherently Noisy

Juxtacrine signaling is an important class of signaling systems that plays a crucial role in various developmental processes ranging from coordination of differentiation between neighboring cells to guiding axon growth during neurogenesis. Such signaling systems rely on the interaction between receptors on one cell and trans-membrane ligands on the membrane of a neighboring cell. Like other signaling systems, the ability of signal-receiving cells to accurately determine the concentration of ligands, is affected by stochastic diffusion processes. However, it is not clear how restriction of ligand movement to the two-dimensional (2D) cell membrane in juxtacrine signaling affects the accuracy of ligand sensing. In this study, we use a statistical mechanics approach, to show that long integration times, from around one second to several hours, are required to reach high-sensing accuracy (better than 10%). Surprisingly, the accuracy of sensing cannot be significantly improved, neither by increasing the number of receptors above three to five receptors per contact area, nor by increasing the contact area between cells. We show that these results impose stringent constraints on the dynamics of processes relying on juxtacrine signaling systems, such as axon guidance mediated by Ephrins and developmental patterns mediated by the Notch pathway.     

The role of motor proteins in signal propagation

The signaling and transport systems of eucaryotic cells are tightly interconnected: intracellular transport along microtubules and microfilaments is required to position signaling-pathway components, while signaling molecules control activity of motor proteins and their interaction with tracks and cargoes. Recent data, however, give evidence that active transport is engaged in signaling as a means of signal transduction. This review focuses on this specific aspect of the interaction of two systems.     

New conceptual approach for search for molecular causes of diabetus mellitus, based on study of functioning of hormonal signaling systems

The review deals with analysis and generalization of our obtained data about the disturbances appearing in hormonal signaling systems under conditions of diabetes mellitus (DM)—in rats with experimental models of types 1 and 2 DM, in patients with DM, and in invertebrate animals (molluscs) with experimental diabetes-like states. There are discussed changes in functional state of the hormonal signaling systems regulated by different hormones, including biogenic amines and peptides of insulin group, in the wide spectrum of tissues. The conclusion has been made that the disturbances in hormonal signaling systems are the key molecular causes of physiological and metabolic disturbances appearing in types 1 and 2 DM. The concept is formulated of the polyhormonal genesis of DM and systemic character of disturbances by hormones of signaling cascades under conditions of DM.     

Hypothesis of evolutionary origin of several human and animal diseases

Studies of our Laboratory in the field of molecular and evolutionary endocrinology have allowed us to put forward a hypothesis about evolutionary origin of endocrine and other diseases of human and animals. This hypothesis is considered using a model of hormonal signaling systems. It is based on the concept formulated by the authors about molecular defects in hormonal signaling systems as the key causes of endocrine diseases; on evolutionary conservatism of hormonal signaling systems, which stems logically from the authors’ concept of the prokaryotic genesis and endosymbiotic emergence in the course of evolution of chemosignaling systems in the higher eukaryotes; from the fact that the process of formation of hormonal signaling systems with participation of endosymbiosis including the horizontal transfer of genes is accompanied by transfer not only of normal, but also of the defected genetic material. There are considered examples of the principal possibility of transfer of defected genes between bacteria and eukaryotic organisms. Analysis of the current literature allows suggesting inheritance of pathogenic factors from evolutionary ancestors in the lineage prokaryotes—lower eukaryotes—higher eukaryotes.     

Rewiring the specificity of two-component signal transduction systems

Two-component signal transduction systems are the predominant means by which bacteria sense and respond to environmental stimuli. Bacteria often employ tens or hundreds of these paralogous signaling systems, comprised of histidine kinases (HKs) and their cognate response regulators (RRs). Faithful transmission of information through these signaling pathways and avoidance of detrimental crosstalk demand exquisite specificity of HK-RR interactions. To identify the determinants of two-component signaling specificity, we examined patterns of amino acid coevolution in large, multiple sequence alignments of cognate kinase-regulator pairs. Guided by these results, we demonstrate that a subset of the coevolving residues is sufficient, when mutated, to completely switch the substrate specificity of the kinase EnvZ. Our results shed light on the basis of molecular discrimination in two-component signaling pathways, provide a general approach for the rational rewiring of these pathways, and suggest that analyses of coevolution may facilitate the reprogramming of other signaling systems and protein-protein interactions.     

Novel contact-dependent bone morphogenetic protein (BMP) signaling mediated by heparan sulfate proteoglycans

We previously proposed a model that DALLY, a Drosophila glypican, acts as a trans co-receptor to regulate BMP signaling in the germ line stem cell niche. To investigate the molecular mechanisms of contact-dependent BMP signaling, we developed novel in vitro assay systems to monitor trans signaling using Drosophila S2 cells. Using immunoblot-based as well as single-cell assay systems, we present evidence that Drosophila glypicans indeed enhance BMP signaling in trans in a contact-dependent manner in vitro. Our analysis showed that heparan sulfate modification is required for the trans co-receptor activity of DALLY. Two BMP-like molecules, Decapentaplegic (DPP) and Glass bottom boat, can mediate trans signaling through a heparan sulfate proteoglycan co-receptor in S2 cells. The in vitro systems reflect the molecular characteristics of heparan sulfate proteoglycan functions observed previously in vivo, such as ligand specificity and biphasic activity dependent on the ligand dosage. In addition, experiments using a DALLY-coated surface suggested that DALLY regulates DPP signaling in trans by its effect on the stability of DPP protein on the surface of the contacting cells. Our findings provide the molecular foundation for novel contact-dependent signaling, which defines the physical space of the stem cell niche in vivo.     

Serotonin and the orchestration of energy balance

The phylogenetically ancient signaling molecule serotonin is found in all species that possess nervous systems and orchestrates diverse behavioral and physiological processes in the service of energy balance. In some instances, the manner in which serotonin signaling influences these processes appears comparable among invertebrate and vertebrate species. Within mammalian species, central nervous system serotonergic signaling influences both behavioral and physiological determinants of energy balance. Within the gastrointestinal tract, serotonin mediates diverse sensory, motor, and secretory functions. Further examinations of serotonergic influences on peripheral organ systems are likely to uncover novel functions consistent with an apparently pervasive association between serotonergic signaling and physiological substrates of energy balance.     

活性氧、钙和心力衰竭

活性氧信号和钙信号广泛存在于机体内,两者相互作用,共同参与调节机体多种生理功能及病理过程。本文对这两个信号系统之间的相互作用及相关机制、在心力衰竭过程中的作用及可能的临床应用前景进行了综述。     

Simple Biochemical Pathways far from Steady State Can Provide Switchlike and Integrated Responses

Covalent modification cycles (systems in which the activity of a substrate is regulated by the action of two opposing enzymes) and ligand/receptor interactions are ubiquitous in signaling systems and their steady-state properties are well understood. However, the behavior of such systems far from steady state remains unclear. Here, we analyze the properties of covalent modification cycles and ligand/receptor interactions driven by the accumulation of the activating enzyme and the ligand, respectively. We show that for a large range of parameters both systems produce sharp switchlike response and yet allow for temporal integration of the signal, two desirable signaling properties. Ultrasensitivity is observed also in a region of parameters where the steady-state response is hyperbolic. The temporal integration properties are tunable by regulating the levels of the deactivating enzyme and receptor, as well as by adjusting the rate of accumulation of the activating enzyme and ligand. We propose that this tunability is used to generate precise responses in signaling systems.     

Histidine kinases and response regulator proteins in two-component signaling systems.

Phosphotransfer-mediated signaling pathways allow cells to sense and respond to environmental stimuli. Autophosphorylating histidine protein kinases provide phosphoryl groups for response regulator proteins which, in turn, function as molecular switches that control diverse effector activities. Structural studies of proteins involved in two-component signaling systems have revealed a modular architecture with versatile conserved domains that are readily adapted to the specific needs of individual systems.     

Exponential Signaling Gain at the Receptor Level Enhances Signal-to-Noise Ratio in Bacterial Chemotaxis

Cellular signaling systems show astonishing precision in their response to external stimuli despite strong fluctuations in the molecular components that determine pathway activity. To control the effects of noise on signaling most efficiently, living cells employ compensatory mechanisms that reach from simple negative feedback loops to robustly designed signaling architectures. Here, we report on a novel control mechanism that allows living cells to keep precision in their signaling characteristics – stationary pathway output, response amplitude, and relaxation time – in the presence of strong intracellular perturbations. The concept relies on the surprising fact that for systems showing perfect adaptation an exponential signal amplification at the receptor level suffices to eliminate slowly varying multiplicative noise. To show this mechanism at work in living systems, we quantified the response dynamics of the E. coli chemotaxis network after genetically perturbing the information flux between upstream and downstream signaling components. We give strong evidence that this signaling system results in dynamic invariance of the activated response regulator against multiplicative intracellular noise. We further demonstrate that for environmental conditions, for which precision in chemosensing is crucial, the invariant response behavior results in highest chemotactic efficiency. Our results resolve several puzzling features of the chemotaxis pathway that are widely conserved across prokaryotes but so far could not be attributed any functional role.     

TGFβ Activated Kinase-1: New Insights into the Diverse Roles of TAK1 in Development and Immunity

A number of recent publications have examined the role of TAK1 in model systems ranging from fly to mouse. Rather than fit into a clearly defined linear molecular pathway, TAK1 seems to act in a signaling nexus that responds to a variety of upstream signals, including inflammatory molecules and developmental cues. TAK1 then influences a number of downstream processes ranging from innate immune responses to patterning and differentiation via JNK, NFκB, and TCFβ-catenin signaling. These differences in function are not simply a matter of cell type. For example, NFκB signaling in a particular cell may or may not require TAK1 depending on the nature of the activating signal. Interestingly, the multi-task functionality of TAK1 is conserved between vertebrate and invertebrate species. Studies of TAK1 in multiple experimental systems is likely to reveal more roles for this kinase and also elucidate mechanisms by which other signaling molecules fulfill diverse signaling roles. Here we provide an overview of the data concerning TAK1 from its discovery to more recent findings and provide a synthesis of the conclusions that have arisen from the multiple model systems and experimental approaches.     

Simple Biochemical Pathways far from Steady State Can Provide Switchlike and Integrated Responses

Covalent modification cycles (systems in which the activity of a substrate is regulated by the action of two opposing enzymes) and ligand/receptor interactions are ubiquitous in signaling systems and their steady-state properties are well understood. However, the behavior of such systems far from steady state remains unclear. Here, we analyze the properties of covalent modification cycles and ligand/receptor interactions driven by the accumulation of the activating enzyme and the ligand, respectively. We show that for a large range of parameters both systems produce sharp switchlike response and yet allow for temporal integration of the signal, two desirable signaling properties. Ultrasensitivity is observed also in a region of parameters where the steady-state response is hyperbolic. The temporal integration properties are tunable by regulating the levels of the deactivating enzyme and receptor, as well as by adjusting the rate of accumulation of the activating enzyme and ligand. We propose that this tunability is used to generate precise responses in signaling systems.     

Noise generation, amplification and propagation in chemotactic signaling systems of living cells

Theoretical considerations of stochastic signal transduction in living cells have revealed the gain-fluctuation relation, which provides a theoretical framework to describe quantitatively how noise is generated, amplified and propagated along a signaling cascade in living cells. We chose the chemotactic signaling of bacteria and eukaryotic cells as a typical example of noisy signal transduction and applied the gain-fluctuation relation to these signaling systems in order to analyze the effects of noise on signal transduction. Comparing our theoretical analysis with the experimental results of chemotaxis in bacteria Escherichia coli and eukaryote Dictyostelium discoideum revealed that noise in signal transduction systems limits the cells' chemotactic ability and contributes to their behavioral variability. Based on the kinetic properties of signaling molecules in living cells, the gain-fluctuation relation can quantitatively explain stochastic cellular behaviors.