Hormonal signaling and signal pathway crosstalk in the control of myometrial calcium dynamics

Understanding the basis for the control of myometrial contractant and relaxant signaling pathways is important to understanding how to manage myometrial contractions. Signaling pathways are influenced by the level of expression of the signals and signal pathway components, the location of these components in the appropriate subcellular environment, and covalent modification. Crosstalk between these pathways regulates the effectiveness of signal transduction and represents an important way by which hormones can regulate phenotype. This review deals primarily with signaling pathways that control Ca2+ entry and intracellular release, as well as the interplay between these pathways.     

Signaling complexes: junctions on the intracellular information super highway.

An enigmatic yet fundamental principle of signal transduction is that parallel signaling pathways assembled from a common repertoire of enzymes are able to propagate diverse physiological responses. A key feature of such a mechanism is that separate signaling pathways are organized into localized transduction units, each tailored to respond optimally to a particular signal. Protein-protein interactions maintained by anchoring, adapter and scaffolding proteins provide the molecular glue that holds these signal transduction units together. A major objective of the signaling community is to ascertain how signals flow through compartmentalized transduction units that contain transmembrane receptors, protein kinases, phosphatases and their substrates.     

Using plasma membrane nanoclusters to build better signaling circuits

Cellular signaling pathways do not simply transmit data; they integrate and process signals to operate as switches, oscillators, logic gates, memory modules and many other types of control system. These complex processing capabilities enable cells to respond appropriately to the myriad of external cues that direct growth and development. The idea that crosstalk and feedback loops are used as control systems in biological signaling networks is well established. Signaling networks are also subject to exquisite spatial regulation, yet how spatial control modulates signal outputs is less well understood. Here, we explore the spatial organization of two different signal transduction circuits: receptor tyrosine kinase activation of the mitogen-activated protein kinase module; and glycosylphosphatidylinositol-anchored receptor activation of phospholipase C. With regards to these pathways, recent results have refocused attention on the crucial role of lipid rafts and plasma membrane nanodomains in signal transmission. We identify common design principals that highlight how the spatial organization of signal transduction circuits can be used as a fundamental control mechanism to modulate system outputs in vivo.     

脂多糖信号通路中的蛋白质修饰

革兰氏阴性细菌外膜中的脂多糖,又称内毒素,感染宿主后可导致脓毒症、脓毒性休克和多器官功能障碍综合症. 脂多糖借助信号转导通路诱发宿主的应答,刺激免疫细胞产生大量具有致热效应的炎性细胞因子,引起免疫系统的过度活化. 近年来,研究脂多糖受体TLR4及其信号转导在先天免疫和获得性免疫中的作用,以及脂多糖信号通路的复杂调控机制取得了突破性进展. 其中蛋白质翻译后修饰参与脂多糖信号通路调节的研究成为这一领域的新热点之一. 本文总结了磷酸化修饰、泛素化修饰、ISG15化修饰和SUMO化修饰在调节脂多糖信号通路方面的作用.不仅对被修饰蛋白如何传递和调节脂多糖信号以及翻译后修饰在该过程中的作用进行了阐述,还着眼于不同翻译后修饰形式之间的关联.脂多糖信号通路的深入研究不但有助于阐明内毒素相关疾病的分子机理,还可为临床预防和治疗革兰氏阴性细菌感染所致疾病提供新靶点.     

The membrane and lipids as integral participants in signal transduction: lipid signal transduction for the non-lipid biochemist

Reviews of signal transduction have often focused on the cascades of protein kinases and protein phosphatases and their cytoplasmic substrates that become activated in response to extracellular signals. Lipids, lipid kinases, and lipid phosphatases have not received the same amount of attention as proteins in studies of signal transduction. However, lipids serve a variety of roles in signal transduction. They act as ligands that activate signal transduction pathways as well as mediators of signaling pathways, and lipids are the substrates of lipid kinases and lipid phosphatases. Cell membranes are the source of the lipids involved in signal transduction, but membranes also constitute lipid barriers that must be traversed by signal transduction pathways. The purpose of this review is to explore the magnitude and diversity of the roles of the cell membrane and lipids in signal transduction and to highlight the interrelatedness of families of lipid mediators in signal transduction.     

Sensitivity and specificity amplification in signal transduction

Intracellular signal transduction pathways transmit signals from the cell surface to various intracellular destinations, such as cytoskeleton and nucleus through a cascade of protein-protein interactions and activation events, leading to phenotypic changes such as cell proliferation, differentiation, and death. Over the past two decades, numerous signaling proteins and signal transduction pathways have been discovered and characterized. There are two major classes of signaling proteins: phosphoproteins (e.g., mitogen-activated protein kinases) and guanosine triphosphatases (GTPases; e.g., Ras and G proteins). They both function as molecular switches by addition and removal of one or more high-energy phosphate groups. This review discusses developments that seek to quantify the signal transduction processes with kinetic analysis and mathematical modeling of the signaling phosphoproteins and GTPases. These studies have provided insights into the sensitivity and specificity amplification of biological signals in integrated systems.     

The rice MAPKK–MAPK interactome: the biological significance of MAPK components in hormone signal transduction

Mitogen-activated protein kinase (MAPK) signaling cascades are evolutionarily conserved fundamental signal transduction pathways. A MAPK cascade consists of many distinct MAPKKK–MAPKK–MAPK modules linked to various upstream receptors and downstream targets through sequential phosphorylation and activation of the cascade components. These cascades collaborate in transmitting a variety of extracellular signals and in controlling cellular responses and processes such as growth, differentiation, cell death, hormonal signaling, and stress responses. Although MAPK proteins play central roles in signal transduction pathways, our knowledge of MAPK signaling in hormonal responses in rice has been limited to a small subset of specific upstream and downstream interacting targets. However, recent studies revealing direct MAPK and MAPKK interactions have provided the basis for elucidating interaction specificities, functional divergence, and functional modulation during hormonal responses. In this review, we highlight current insights into MAPKK–MAPK interaction patterns in rice, with emphasis on the biological significance of these interacting pairs in SA (salicylic acid), JA (jasmonic acid), ET (ethylene), and ABA (abscisic acid) responses, and discuss the challenges in understanding functional signal transduction networks mediated by these hormones.     

Physical modulation of intracellular signaling processes by locational regulation.

Recent observations in the field of signal transduction suggest that where a protein is located within a cell can be as important as its activity measured in solution for activation of its downstream pathway. The physical organization of the cell can provide an additional layer of control upon the chemical reaction networks that govern ultimately perceived signals. Using the cytosol and plasma membrane as relevant compartmental distinctions, we analyze the effect of relocation on the rate of association with a membrane-associated target. We quantify this effect as an enhancement factor E in terms of measurable parameters such as the number of available targets, molecular diffusivities, and intrinsic reaction rate constants. We then employ two simple yet relevant example models to illustrate how relocation can affect the dynamics of signal transduction pathways. The temporal profiles and phase behavior of these models are investigated. We also relate experimentally observable aspects of signal transduction such as peak activation and the relative time scales of stimulus and response to quantitative aspects of the relocation mechanisms in our models. In our example schemes, nearly complete relocation of the cytosolic species in the signaling pair is required to generate meaningful activation of the model pathways when the association rate enhancement factor E is as low as 10; when E is 100 or greater, only a small fraction of the protein must be relocated.     

Phosphoproteomics perspective on plant signal transduction and tyrosine phosphorylation

Plants and animal cells use intricate signaling pathways to respond to a diverse array of stimuli. These stimuli include signals from environment, such as biotic and abiotic stress signals, as well as cell-to-cell signaling required for pattern formation during development. The transduction of the signal often relies on the post-translational modification (PTM) of proteins. Protein phosphorylation in eukaryotic cells is considered to be a central mechanism for regulation and cellular signaling. The classic view is that phosphorylation of serine (Ser) and threonine (Thr) residues is more abundant, whereas tyrosine (Tyr) phosphorylation is less frequent. This review provides an overview of the progress in the plant phosphoproteomics field and how this progress has lead to a re-evaluation of the relative contribution of tyrosine phosphorylation to the plant phosphoproteome. In relation to this appreciated contribution of tyrosine phosphorylation we also discuss some of the recent progress on the role of tyrosine phosphorylation in plant signal transduction.     

Integrin signalling in neutrophils and macrophages.

Integrins have been characterized extensively as adhesion receptors capable of transducing signals inside the cell. In myelomonocytic cells, integrin-mediated adhesive interactions regulate different selective cell responses, such as transmigration into the inflammatory site, cytokine secretion, production or reactive oxygen intermediates, degranulation and phagocytosis. In the last few years, great progress has been made in elucidating mechanisms of signal transduction by integrins in neutrophils and macrophages. This review summarises the current information on the role of integrins in regulating myelomonocytic cell functions and highlights the signalling pathways activated by integrin engagement in these cells. Also, exploiting the current knowledge of mechanisms of integrin signal transduction in other cell types, we propose a model to explain how integrins transduce signals inside neutrophils and macrophages, and how signaling pathways leading to regulation of selective cell functions may be coordinated.     

Interactions and intersections of plant signaling pathways.

Plant signal transduction is a rapidly expanding field of research, and during the last decade a wealth of insight into how plants perceive and transmit signals as part of normal development and in response to environmental cues has been and is continuing to be unraveled. Although ?signaling cascades are often viewed as linear chains of events it is now becoming increasingly apparent, through the use of cell biological, molecular and genetic approaches, that plant signal transduction involves extensive cross-talk between different pathways. The numerous interactions and intersections which take place are potentially important to modulate and balance the various inputs from different signaling cascades so that plants can integrate all this information to execute the proper developmental responses.     

Functional proteomics to identify critical proteins in signal transduction pathways

Reversible protein phosphorylation plays a crucial role in the regulation of signaling pathways that control various biological responses, such as cell growth, differentiation, invasion, metastasis and apoptosis. Proteomics is a powerful research approach for fully monitoring global molecular responses to the activation of signal transduction pathways. Identification of different phosphoproteins and their phosphorylation sites by functional proteomics provides informational insights into signaling pathways triggered by all kinds of factors. This review summarizes how functional proteomics can be used to answer specific questions related to signal transduction systems of interest. By examining our own example on identifying the novel phosphoproteins in signaling pathways activated by EB virus-encoded latent membrane protein 1 (LMP1), we demonstrated a functional proteomic strategy to elucidate the molecular activity of phosphorylated annexin A2 in LMP1 signaling pathway. Functional profiling of signaling pathways is promising for the identification of novel targets for drug discovery and for the understanding of disease pathogenesis.     

Chemosensation: molecular mechanisms in worms and mammals

Communication with the environment and other animals through chemical cues is an essential process for the survival of many multicellular organisms. Specialized signal transduction pathways are employed in chemodetection and the transformation of information into the electrical signals that elicit behaviors. In organisms as diverse as mice and nematodes, similar molecules are involved in the odorant signaling pathways. Studying the mechanisms of signal transduction in these two systems using biochemical, molecular and genetic approaches has elucidated pathways for odor perception and the roles of specific proteins and second messenger molecules in the signaling cascades.