Phenotypic Heterogeneity Generated by Histidine Kinase-Based Signaling Networks

A complex relationship exists between environmental factors, signaling networks and phenotypic individuality in bacteria. In this review, we will focus on the organization, function and control points of multiple-input histidine kinase-based signaling cascades as a source of phenotypic heterogeneity. In particular, we will examine the quorum sensing cascade in Vibrio harveyi and the pyruvate sensor network in Escherichia coli. We will describe and compare these histidine kinase-based signaling networks in terms of robustness, the molecular mechanisms of signal transduction and the role of RNA switches. Finally, we will discuss the biological significance of phenotypic heterogeneity for the respective bacteria in relation to environmental factors.     

Positional Information and Positional Signalling in Hydra

A model is proposed for regulation and regeneration of the headend of hydra in terms of positional information, which involvestwo gradients. One is a diffusible substance made at the headend, which may be regarded as a positional signal. The otheris a more stable cellular parameter which is the positionalvalue. The rule for head end formation is that the concentrationof the diffusible substance falls a threshold amount below thepositional value. This model, for which some computer simulationis provided, can account for head end formation in a wide varietyof grafts. Evidence for a diffusable signal is provided by experimentsin which the time/distance relationships for head inhibitionby a grafted head are determined. Changes in positional valueduring regulation have been assayed and are much slower awayfrom the boundary. Polarity is interpreted in terms of the interactionbetween the two gradients. The biochemical basis of the gradientsis not known, but an approach to the problem has been made bytreating hydra with a variety of chemical agents.     

Protein Phosphatases and Signaling Cascades in Higher Plants

Protein kinases and phosphatases play a central role in cellular signaling. Although protein kinases have been widely studied in higher plants, protein phosphatases have been largely neglected until recently. The article focuses on the most recent studies that have placed protein phosphatases in the context of several signal cascades in higher plants. These pathways include stomatal regulation and abscisic acid signal transduction, pathogen and stress responses, and developmental control. Studies clearly have demonstrated that protein phosphatases function not only to counterbalance the protein kinases but also take a leading role in many signaling processes.     

Cadherin-mediated Intercellular Adhesion and Signaling Cascades Involving Small GTPases

Epithelia form physical barriers that separate the internal milieu of the body from its external environment. The biogenesis of functional epithelia requires the precise coordination of many cellular processes. One of the key events in epithelial biogenesis is the establishment of cadherin-dependent cell–cell contacts, which initiate morphological changes and the formation of other adhesive structures. Cadherin-mediated adhesions generate intracellular signals that control cytoskeletal reorganization, polarity, and vesicle trafficking. Among such signaling pathways, those involving small GTPases play critical roles in epithelial biogenesis. Assembly of E-cadherin activates several small GTPases and, in turn, the activated small GTPases control the effects of E-cadherin-mediated adhesions on epithelial biogenesis. Here, we focus on small GTPase signaling at E-cadherin-mediated epithelial junctions.Cell–cell adhesions are involved in a diverse range of physiological processes, including morphological changes during tissue development, cell scattering, wound healing, and synaptogenesis (Adams and Nelson 1998; Gumbiner 2000; Halbleib and Nelson 2006; Takeichi 1995; Tepass et al. 2000). In epithelial cells, cell–cell adhesions are classified into three kinds of adhesions: adherens junction, tight junction, and desmosome (for more details, see Meng and Takeichi 2009, Furuse 2009, and Delva et al. 2009, respectively). A key event in epithelial polarization and biogenesis is the establishment of cadherin-dependent cell–cell contacts. Cadherins belong to a large family of adhesion molecules that require Ca²⁺ for their homophilic interactions (Adams and Nelson 1998; Blanpain and Fuchs 2009; Gumbiner 2000; Hartsock and Nelson 2008; Takeichi 1995; Tepass et al. 2000). Cadherins form transinteraction on the surface of neighboring cells (for details, see Shapiro and Weis 2009). For the development of strong and rigid adhesions, cadherins are clustered concomitantly with changes in the organization of the actin cytoskeleton (Tsukita et al. 1992). Classical cadherins are required, but not sufficient, to initiate cell–cell contacts, and other adhesion protein complexes subsequently assemble (for details, see Green et al. 2009). These complexes include the tight junction, which controls paracellular permeability, and desmosomes, which support the structural continuum of epithelial cells. A fundamental problem is to understand how these diverse cellular processes are regulated and coordinated. Intracellular signals, generated when cells attach with one another, mediate these complicated processes.Several signaling pathways upstream or downstream of cadherin-mediated cell–cell adhesions have been identified (Perez-Moreno et al. 2003) (see also McCrea et al. 2009). Among these pathways, small GTPases including the Rho and Ras family GTPases play critical roles in epithelial biogenesis and have been studied extensively. Many key morphological and functional changes are induced when these small GTPases act at epithelial junctions, where they mediate an interplay between cell–cell adhesion molecules and fundamental cellular processes including cytoskeletal activity, polarity, and vesicle trafficking. In addition to these small GTPases, Ca²⁺ signaling and phosphorylation of cadherin complexes also play pivotal roles in the formation and maintenance of cadherin-mediated adhesions. Here, we focus on signaling pathways involving the small GTPases in E-cadherin-mediated cell–cell adhesions. Other signaling pathways are described in recent reviews (Braga 2002; Fukata and Kaibuchi 2001; Goldstein and Macara 2007; McLachlan et al. 2007; Tsukita et al. 2008; Yap and Kovacs 2003; see also McCrea et al. 2009).     

蛋白激酶与植物逆境信号传递途径

蛋白质的可逆磷酸化是细胞信号识别与转导的重要环节,蛋白激酶主要催化蛋白质的磷酸化作用,植物中已发现并分离了大量蛋白激酶及其基因,它们介导了植物激素和胞外环境信号等引起的多种生理生化反应。文章着重介绍分裂原激活蛋白激酶（MAPK）、钙依赖而钙调素不依赖的蛋白激酶（CDPK）、受体蛋白激酶（RPK）、核糖体蛋白激酶和转录调控蛋白激酶等多种蛋白激酶在植物逆境信号识别与转导中的作用。     

An Algebraic Approach to Signaling Cascades with n Layers

Posttranslational modification of proteins is key in transmission of signals in cells. Many signaling pathways contain several layers of modification cycles that mediate and change the signal through the pathway. Here, we study a simple signaling cascade consisting of n layers of modification cycles such that the modified protein of one layer acts as modifier in the next layer. Assuming mass-action kinetics and taking the formation of intermediate complexes into account, we show that the steady states are solutions to a polynomial in one variable and in fact that there is exactly one steady state for any given total amounts of substrates and enzymes.     

Signaling from Nucleotide Receptors to Protein Kinase Cascades in Astrocytes

In the CNS, extracellular ATP can function as an excitatory neurotransmitter as well as a trophic factor. These short-term and long-term actions are mediated by nucleotide receptors. Extracellular ATP can also act as a co-mitogen in conjunction with polypeptide growth factors such as basic fibroblast growth factor (FGF2). Cellular proliferation, differentiation and survival are regulated by signaling cascades composed of protein kinases, including extracellular signal regulated protein kinase (ERK) and protein kinase B (also called Akt). Here we summarize recent studies on nucleotide receptor signaling to ERK and Akt in astrocytes and the role of protein kinase cascades in mediating the trophic actions of extracellular ATP, alone or together with FGF2. Because extracellular ATP and FGF2 contribute to the hyperplastic and hypertrophic response of astrocytes to CNS injuries, an understanding of their protein kinase signaling mechanisms may lead to novel therapeutic approaches for neurological conditions that involve gliosis and the generation of reactive astrocytes, such as trauma, stroke, seizure and neurodegenerative and demyelinating disorders.Special issue dedicated to Lawrence F. Eng.     

Signaling Cascades Modulate the Speed of Signal Propagation through Space

Background

Cells are not mixed bags of signaling molecules. As a consequence, signals must travel from their origin to distal locations. Much is understood about the purely diffusive propagation of signals through space. Many signals, however, propagate via signaling cascades. Here, we show that, depending on their kinetics, cascades speed up or slow down the propagation of signals through space, relative to pure diffusion.

Methodology/Principal Findings

We modeled simple cascades operating under different limits of Michaelis-Menten kinetics using deterministic reaction-diffusion equations. Cascades operating far from enzyme saturation speed up signal propagation; the second mobile species moves more quickly than the first through space, on average. The enhanced speed is due to more efficient serial activation of a downstream signaling module (by the signaling molecule immediately upstream in the cascade) at points distal from the signaling origin, compared to locations closer to the source. Conversely, cascades operating under saturated kinetics, which exhibit zero-order ultrasensitivity, can slow down signals, ultimately localizing them to regions around the origin.

Conclusions/Significance

Signal speed modulation may be a fundamental function of cascades, affecting the ability of signals to penetrate within a cell, to cross-react with other signals, and to activate distant targets. In particular, enhanced speeds provide a way to increase signal penetration into a cell without needing to flood the cell with large numbers of active signaling molecules; conversely, diminished speeds in zero-order ultrasensitive cascades facilitate strong, but localized, signaling.     

位置信息与植物发育

位置信息是植物发育的重要机制之一,它在植物体的模式建成、细胞的分化及细胞命运的抉择过程中起重要作用.近些年的研究从细胞壁、激素、可扩散因子和非转录DNA等角度对这一问题进行了大量探索,成为植物发育生物学的一个热点领域.本文试对此作一简要介绍.     

位置信息与植物发育

位置信息是植物发育的重要机制之一, 它在植物体的模式建成、细胞的分化及细胞命运的抉择过程中起重要作用。近些年的研究从细胞壁、激素、可扩散因子和非转录DNA等角度对这一问题进行了大量探索, 成为植物发育生物学的一个热点领域。本文试对此作一简要介绍。     

Intrinsic Feedbacks in MAPK Signaling Cascades Lead to Bistability and Oscillations

Previous studies have demonstrated that double phosphorylation of a protein can lead to bistability if some conditions are fulfilled. It was also shown that the signaling behavior of a covalent modification cycle can be quantitatively and, more importantly, qualitatively modified when this cycle is coupled to a signaling pathway as opposed to being isolated. This property was named retroactivity. These two results are studied together in this paper showing the existence of interesting phenomena—oscillations and bistability—in signaling cascades possessing at least one stage with a double-phosphorylation cycle as in MAPK cascades.     

A Neuron Model with Spatially Distributed Synaptic Input

I have assembled a neuron model simulating contiguous patches of nerve cell membrane. With this model I have examined the functional significance of different spatial and temporal distributions of synaptic inputs. The model consists of two terminal electronic analogue circuits with inputs controlled by a LINC computer. One terminal represents the inside of a membrane patch, the other represents the outside. Two circuit designs are used: one simulates spike-generating regions of the neuron, the other simulates subthreshold activity in inexcitable regions. To simulate a neuron, patches are assembled in various spatial arrangements by suitable connection to the “intracellular” nodes. Thus the relation of neuron geometry to aspects of spatiotemporal summation of synaptic inputs can be investigated readily. Performance of the model is assessed by comparison with results from microelectrode studies in the cochlear nucleus of the cat. In particular, the peristimulus time (PST) histogram and averaged membrane potential are used for quantitative comparison. The model suggests that the geometry of the neuron's receptive surface can account for a wide variety of physiologically observed behavior, particularly in response to dynamic stimuli.     

Spatially Distributed Dendritic Resonance Selectively Filters Synaptic Input

An important task performed by a neuron is the selection of relevant inputs from among thousands of synapses impinging on the dendritic tree. Synaptic plasticity enables this by strenghtening a subset of synapses that are, presumably, functionally relevant to the neuron. A different selection mechanism exploits the resonance of the dendritic membranes to preferentially filter synaptic inputs based on their temporal rates. A widely held view is that a neuron has one resonant frequency and thus can pass through one rate. Here we demonstrate through mathematical analyses and numerical simulations that dendritic resonance is inevitably a spatially distributed property; and therefore the resonance frequency varies along the dendrites, and thus endows neurons with a powerful spatiotemporal selection mechanism that is sensitive both to the dendritic location and the temporal structure of the incoming synaptic inputs.     

Signaling Cascades Governing Cdc42-Mediated Chondrogenic Differentiation and Mensenchymal Condensation

Endochondral ossification consists of successive steps of chondrocyte differentiation, including mesenchymal condensation, differentiation of chondrocytes, and hypertrophy followed by mineralization and ossification. Loss-of-function studies have revealed that abnormal growth plate cartilage of the Cdc42 mutant contributes to the defects in endochondral bone formation. Here, we have investigated the roles of Cdc42 in osteogenesis and signaling cascades governing Cdc42-mediated chondrogenic differentiation. Though deletion of Cdc42 in limb mesenchymal progenitors led to severe defects in endochondral ossification, either ablation of Cdc42 in limb preosteoblasts or knockdown of Cdc42 in vitro had no obvious effects on bone formation and osteoblast differentiation. However, in Cdc42 mutant limb buds, loss of Cdc42 in mesenchymal progenitors led to marked inactivation of p38 and Smad1/5, and in micromass cultures, Cdc42 lay on the upstream of p38 to activate Smad1/5 in bone morphogenetic protein-2-induced mesenchymal condensation. Finally, Cdc42 also lay on the upstream of protein kinase B to transactivate Sox9 and subsequently induced the expression of chondrocyte differential marker in transforming growth factor-β1-induced chondrogenesis. Taken together, by using biochemical and genetic approaches, we have demonstrated that Cdc42 is involved not in osteogenesis but in chondrogenesis in which the BMP2/Cdc42/Pak/p38/Smad signaling module promotes mesenchymal condensation and the TGF-β/Cdc42/Pak/Akt/Sox9 signaling module facilitates chondrogenic differentiation.