Transduction of biochemical signals across cell membranes

Biological cells need to be responsive to various stimuli, primarily chemical ligands from their environments. Specific receptor molecules embedded in the plasma membrane detect the different biochemical signals that impact the cell, and these receptors are the conduits for transmission of this information to the cell interior for action. There are several classes of signal transduction receptors and many specific receptors within each of the major classes. This review emphasizes the structural biology of three major classes of transmembrane receptors - tyrosine kinase receptors, histidine kinase sensors, and G-protein coupled receptors. Biophysical principles that govern the processes of signal transduction across cell membranes are also discussed.     

Signal transduction of somatostatin receptors negatively controlling cell proliferation.

Somatostatin acts as an inhibitory peptide of various secretory and proliferative responses. Its effects are mediated by a family of G-protein-coupled receptors (sst1-5) that can couple to diverse signal transduction pathways such as inhibition of adenylate cyclase and guanylate cyclase, modulation of ionic conductance channels, and protein dephosphorylation. The five receptors bind the natural peptide with high affinity but only sst2, sst5 and sst3 bind the short synthetic analogues. Somatostatin negatively regulates the growth of various normal and tumour cells. This effect is mediated indirectly through inhibition of secretion of growth-promoting factors, angiogenesis and modulation of the immune system. Somatostatin can also act directly through sst receptors present on target cells. The five receptors are expressed in various normal and tumour cells, the expression of each receptor being receptor subtype and cell type specific. According to the receptor subtypes, distinct signal transduction pathways are involved in the antiproliferative action of somatostatin. Sst1, 4 and 5 modulate the MAP kinase pathway and induce G1 cell cycle arrest. Sst3 and sst2 promote apoptosis by p53-dependent and -independent mechanisms, respectively.     

Protein Clusters in Phosphotyrosine Signal Transduction

Signal transduction systems based on tyrosine phosphorylation are central to cell–cell communication in multicellular organisms. Typically, in such a system, the signal is initiated by activating tyrosine kinases associated with transmembrane receptors, which induces tyrosine phosphorylation of the receptor and/or associated proteins. The phosphorylated tyrosines then serve as docking sites for the binding of various downstream effector proteins. It has long been observed that the cooperative association of the receptors and effectors produces higher-order protein assemblies (clusters) following signal activation in virtually all phosphotyrosine signal transduction systems. However, mechanistic studies on how such clustering processes affect signal transduction outcomes have only emerged recently. Here we review current progress in decoding the biophysical consequences of clustering on the behavior of the system, and how clustering affects how these receptors process information.     

Alternative dimerization of receptor tyrosine kinases with signal transduction through a cellular membrane

Receptor tyrosine kinases (RTKs) occupy a separate functional niche among membrane receptors, which is determined by the special features of mechanisms of the signal transduction through a cellular membrane. RTKs are involved in the regulation of development and homeostasis of all the tissues of a human organism, playing a central role in cell proliferation, differentiation, and adhesion. A necessary condition of the biochemical signal transduction through a plasmatic membrane is a ligand-dependent or a ligand-independent dimerization (and/or an oligomerization) of RTKs which is accompanied by conformational rearrangements of all the RTK domains, including the α-helical transmembrane segments. In this review, the main aspects of structure-function relationship for RTKs from various receptor subfamilies are briefly discussed. It is shown in the light of the recently obtained biophysical and biochemical data that functioning of RTK receptors is mediated not only by protein–protein interactions, but by the state of the lipid environment as one of the main components of a self-consistent signal transduction system as well. The new principles of intercellular signal transduction through a membrane replenish the molecular mechanisms of the RTK functioning that have been earlier proposed and explain a number of paradoxes which are observed upon activation of wild-type receptors and the receptors with pathogenic transmembrane mutations. Understanding of the complex mechanisms of the signaling processes can facilitate the successful search for new opportunities of influence on the RTK biological functions with potential therapeutic consequences.     

Model for external influences on cellular signal transduction pathways including cytosolic calcium oscillations

Experiments on the effects of extremely-low-frequency (ELF) electric and magnetic fields on cells of the immune system, T-lymphocytes in particular, suggest that the external field interacts with the cell at the level of intracellular signal transduction pathways. These are directly connected with changes in the calcium-signaling processes of the cell. Based on these findings, a theoretical model for receptor-controlled cytosolic calcium oscillations and for external influences on the signal transduction pathway is presented. We discuss the possibility that the external field acts on the kinetics of the signal transduction between the activated receptors at the cell membrane and the G-proteins. It is shown that, depending on the specific combination of cell internal biochemical and external physical parameters, entirely different responses of the cell can occur. We compare the effects of a coherent (periodic) modulation and of incoherent perturbations (noise). The model and the calculations are based on the theory of self-sustained, nonlinear oscillators. It is argued that these systems form an ideal basis for information-encoding processes in biological systems. © 1995 Wiley-Liss, Inc.     

Localization of receptor-mediated signal transduction pathways: the inside story

Receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR) elicit proliferation, migration, and differentiation in a wide spectrum of cell types through various signal transduction pathways. These activities are attenuated by receptor internalization, intracellular trafficking through endosomes, and degradation in lysosomes, resulting in decreased receptor expression. However, there is now considerable evidence that EGFRs continue to signal in endosomes, forcing us to reevaluate the outcomes of receptor trafficking. An exciting revelation is that internalized receptors extend some signaling activities but not others, suggesting that certain responses, such as cell motility, must be mediated at the cell surface. Still, only when the effects of decreased receptor populations and signaling compartmentalization are integrated can we hope to understand and manipulate receptor function at the molecular level.     

Multiple mechanisms of serotonergic signal transduction

In this article we review serotonergic signal transduction mechanisms in the central and peripheral nervous systems and in a variety of target organs. The various classes of pharmacologically defined serotonergic receptors are coupled to three major effector systems: (1) adenylate cyclase; (2) phospholipase C mediated phosphoinositide (PI) hydrolysis and (3) ion channels (K+ and Ca++). Long term occupancy of serotonergic receptors also appears to induce alterations in mRNA and protein synthesis. For all three types of signal transduction there is evidence accumulating which suggests the involvement of guanine nucleotide regulatory proteins. Recent findings suggest that the distinct types of pharmacologically defined serotonergic receptors (5HT1A, 5HT1B, 5HT1c, 5HT2) may be coupled to one or more signal transduction systems. Thus, 5HT1 receptors may both activate and inhibit adenylate cyclase and increase K+-ion conductance in the hippocampus. 5HT2 receptors which activate PI hydrolysis in the brain, both open voltage-gated calcium channels and activate PI metabolism in certain smooth muscle preparations. Thus, each class of serotonergic receptor may be linked to one or more distinct biochemical transduction mechanisms. The possibility is raised that selective agonists and antagonists might be developed which have specific effects on a particular receptor-linked effector system.     

17-Beta-estradiol-mediated activation of extracellular-signal regulated kinase, phosphatidylinositol 3-kinase/protein kinase B-Akt and N-methyl-D-aspartate receptor phosphorylation in cortical synaptoneurosomes

In addition to its well-known activational mechanism, the steroid hormone 17-beta-estradiol (E2) has been shown to rapidly activate various signal transduction pathways that could participate in estrogen-mediated regulation of synaptic plasticity. Although the mechanisms underlying these effects are not clearly understood, it has been repeatedly suggested that they involve a plasma membrane receptor which has direct links to several intracellular signaling cascades. To further address the question of whether E2 acts directly at the synapse and through membrane-bound receptors, we studied the effects of E2 and of ligands of estrogen receptors on various signaling pathways in cortical synaptoneurosomes. Our results demonstrate that E2 elicits N-methyl-D-aspartate receptor phosphorylation and activates the extracellular signal-regulated kinase and the phosphatidylinositol 3-kinase/Akt signal transduction pathways in this cortical membrane preparation. Furthermore, we provide evidence for the presence of a membrane-bound estrogen receptor responsible for these effects in cortical synaptoneurosomes. Our study demonstrates that E2 directly acts at cortical synapses, and that synaptoneurosomes provide a useful system to investigate the mechanisms by which E2 regulates synaptic transmission and plasticity.     

Kinases and G proteins join the Wnt receptor complex

Wnt proteins form a family of secreted signaling proteins that play a key role in various developmental events such as cell differentiation, cell migration, cell polarity and cell proliferation. It is currently thought that Wnt proteins activate at least three different signaling pathways by binding to seven transmembrane receptors of the Frizzled family and the co-receptor LRP6. Despite our growing knowledge of intracellular components that mediate a Wnt signal, the molecular events at the membrane have remained rather unclear. Now several publications(1-4) indicate that Frizzled receptors are G-protein coupled and kinases were identified that phosphorylate the co-receptor LRP6. These data deepen our understanding of Wnt-mediated signal transduction and provide more insight into how specificity may be achieved.     

Tom1L1在细胞信号转导及受体内吞中的研究进展

Tom1L1（Tom1 like 1）参与并调节细胞信号转导及受体运输通路。在不同细胞中Tom1L1对信号转导具有不同的调节作用。Tom1L1-CHC（clathrinheavychain）复合物减少Src蛋白在小窝（caveolae）处富集,从而阻碍Src蛋白与血小板衍生因子（platelet derived growth factor,PDGF）受体的结合。抑制PDGF受体介导的有丝分裂和转化信号传导。活化的表皮生长因子受体（epidermal growth factor receptor,EGFR）通过Src家族蛋白激酶（src family kinase,SFK）磷酸化T0m1L1,磷酸化的Tom1L1通过Grb2和Shc的桥梁作用与EGFR结合,介导EGFR的内吞进程。Tom1L1和Hrs（hepatocyte growth factor regulated tyrosine kinase substrate）、TSG101（tumor susceptibility gene 101）的相互作用表明,它也可能参与了泛素化蛋白分选入多泡体的过程。该文就其在细胞信号转导通路及受体内吞／分选过程的作用作一综述。     

Receptors for oreksins: structure, localisation and activation mechanisms

The review concerns morpho-functional characteristics of orexin receptors. The data on their structure, signal transduction pathways, biological effects of orexin receptors 1 or 2 depending on association with different G-proteins are presented. Localisation of orexin receptors in various CNS structures as well as in peripheral organs mediates regulation of different physiological functions by orexins. Low concentration of orexins in peripheral blood and orexin-containing cells in ganglions and internal organs suggests a possibility to activate orexin-sensitive cells distantly, paracrinely or autocrinely. The data on effects of selective or non-selective orexin receptor antagonists is analysed.     

Structure and mechanism of immunoreceptors: New horizons in T cell and B cell receptor biology and beyond

Immunoreceptors, also named non-catalytic tyrosine-phosphorylated receptors, are a large class of leukocyte cell-surface proteins critically involved in innate and adaptive immune responses. Their most characteristic defining feature is a shared signal transduction machinery where binding events of cell surface-anchored ligands to the small extracellular receptor domains are translated into phosphorylation of conserved tyrosine-containing cytosolic sequence motifs initiating downstream signal transduction cascades. Despite their central importance to immunology, the molecular mechanism of how ligand binding activates the receptors and results in robust intracellular signaling has remained enigmatic. Recent breakthroughs in our understanding of the architecture and triggering mechanism of immunoreceptors come from cryogenic electron microscopy studies of the B cell and T cell antigen receptors.     

Detection of altered retinoic acid receptor expression in tissue sections using in situ hybridization

Nuclear retinoid receptors mediate retinoid effects in controlling cell growth, differentiation, apoptosis, and carcinogenesis. Altered expression or activity of these receptors could abolish the retinoid signal transduction pathway and be associated with human carcinogenesis. In situ hybridization is a powerful tool for analyzing gene expression in formalin-fixed, paraffin-embedded tissue sections, especially for newly cloned genes or when no antibodies are available. Detection of altered retinoid receptor expression using in situ hybridization in premalignant and malignant tissues has provided important information about the roles of these receptors in cancer development and the response of these tissues to retinoid treatment. Among these receptors, altered expression of retinoic acid receptor-beta (RAR-beta) has been mostly detected in human cancers, including those of the head and neck, lung, esophagus, mammary gland, pancreas, and cervix. RAR-beta is thus currently used as a surrogate endpoint biomarker in different clinical prevention trials of various cancers.     

The Nck SH2/SH3 adaptor protein: a regulator of multiple intracellular signal transduction events

The process generally termed signal transduction involves the coordinated relay of information from extracellular cues to intracellular effectors, subsequently leading to a specified cellular response. The formation of multimeric protein complexes is a critical step in the activation of most intracellular signal transduction cascades. In many cases, these processes are initiated by a family of molecules consisting of protein association motifs known as src homology 2 and 3 (SH2 and SH3) domains. This review focuses on a group of proteins within this family that lack intrinsic enzymatic functions and consist almost entirely of SH2 and SH3 domains. Termed “adaptors,” these proteins serve to physically bridge activated cell surface receptors to various intracellular signal transduction pathways. Here, I briefly summarize current knowledge concerning the various adaptor proteins and place a particular emphasis on Nck. Various data are discussed which collectively support a role for Nck in the regulation of multiple intracellular signaling events. BioEssays 20:913–921, 1998. © 1998 John Wiley & Sons, Inc.     

An algebra of dimerization and its implications for G-protein coupled receptor signaling

Many species of receptors form dimers, but how can we use this information to make predictions about signal transduction? This problem is particularly difficult when receptors dimerize with many different species, leading to a combinatoric increase in the possible number of dimer pairs. As an example system, we focus on receptors in the G-protein coupled receptor (GPCR) family. GPCRs have been shown to reversibly form dimers, but this dimerization does not directly affect signal transduction. Here we present a new theoretical framework called a dimerization algebra. This algebra provides a systematic and rational way to represent, manipulate, and in some cases simplify large and often complicated networks of dimerization interactions. To compliment this algebra, Monte Carlo simulations are used to predict dimerization's effect on receptor organization on the membrane, signal transduction, and internalization. These simulation results are directly comparable to various experimental measures such as fluorescence resonance energy transfer (FRET), and as such provide a link between the dimerization algebra and experimental data. As an example, we show how the algebra and computational results can be used to predict the effects of dimerization on the dopamine D2 and somatastatin SSTR1 receptors. When these predictions were compared to experimental findings from the literature, good agreement was found, demonstrating the utility of our approach. Applications of this work to the development of a novel class of dimerization-modulating drugs are also discussed.     

Collagen-platelet interaction: platelet non-integrin receptors

Platelet-collagen interaction is a complex event that involves ligand-receptor interaction. There are many adhesive non-integrin receptors for platelets to interact with various types of collagens. These non-integrin receptors also serve as signal transducers both from the outside of platelets to the inside and possibly vice versa. The present review covers basic aspects of non-integrin receptor function and various signal transduction pathways.