Signal transduction by tumor necrosis factor receptors

Tumor necrosis factor (TNF) is a key mediator in the inflammatory response which is implicated in the onset of a number of diseases. Research on TNF led to the characterization of the largest family of cytokines known until now, the TNF superfamily, which exert their biological effects through the interaction with transmembrane receptors of the TNFR superfamily. TNF itself exerts its biological effects interacting with two different receptors: TNFR1 and TNFR2. TNFR1 presents a death domain on its intracellular region. In contrast to TNFR1, TNFR2 does not have a death domain. Activation of TNFR1 implies the consecutive formation of two different TNF receptor signalling complexes. Complex I controls the expression of antiapoptotic proteins that prevent the triggering of cell death processes, whereas Complex II triggers cell death processes. TNFR2 only signals for antiapoptotic reactions. However, recent evidence indicates that TNFR2 also signals to induce TRAF2 degradation. TRAF2 is a key mediator in signal transduction of both TNFR1 and TNFR2. Thus, this novel signalling pathway has two important implications: on one hand, it represents an auto regulatory loop for TNFR2; on the other hand, when this signal is triggered TNFR1 activity is modified so that antiapoptotic pathways are inhibited and apoptotic reactions are enhanced.     

Signal transduction by vascular endothelial growth factor receptors

VEGFs (vascular endothelial growth factors) control vascular development during embryogenesis and the function of blood vessels and lymphatic vessels in the adult. There are five related mammalian ligands, which act through three receptor tyrosine kinases. Signalling is modulated through neuropilins, which act as VEGF co-receptors. Heparan sulfate and integrins are also important modulators of VEGF signalling. Therapeutic agents that interfere with VEGF signalling have been developed with the aim of decreasing angiogenesis in diseases that involve tissue growth and inflammation, such as cancer. The present review will outline the current understanding and consequent biology of VEGF receptor signalling.     

Signal transduction mediated by antigen receptors on teleost lymphocytes

To generate an adaptive response from the mammalian immune system requires that antigen bind to cognate receptors on T and B cells, a process which activates intracellular signaling pathways. Crosslinking the B cell antigen receptor (BCR) ultimately activates cell proliferation in both higher and lower vertebrates. Recent studies suggest that many functional components of these intracellular pathways were evolutionarily conserved among the vertebrates. Antibody-mediated crosslinking of surface immunoglobulin leads to tyrosine phosphorylation on presumptive accessory molecules of the teleost BCR as well as several intracellular proteins. Crosslinking the teleost BCR also triggers calcium influx and activation of protein kinase C (PKC) which are hallmark components of the phosphatidyl inositol signal transduction pathway in mammalian lymphocytes. The activation of teleost PKC ultimately generates dually-phosphorylated forms of mitogen activated protein kinase. The latter enzyme is viewed as a key cytoplasmic control point for integrating signals arriving from several kinase/phosphatase pathways in mammalian cells. Preliminary evidence suggests that intracellular signaling mediated through antigen receptor complexes may be very sensitive to external factors, including heavy metals such as mercuric chloride which can alter calcium flux and tyrosine phosphorylation patterns in teleost leukocytes. As the process of lymphocyte activation in teleost fish is better understood, it may be possible to provide aquaculturists, environmental regulators and fisheries managers with better information on those natural and man-made conditions which interfere with the development of protective immune responses in natural and captive finfish populations.     

Signal transduction pathways used by NLR-type innate immune receptors

Proteins from the nucleotide-binding domain, LRR containing (NLR) family are involved in sensing bacterial invasion and danger signals in mammalian cells. Activation of these molecules leads to inflammatory responses which help clearance of invading pathogens. Recent data now shed light on the signal transduction pathways used by NLR proteins. This review summarizes advances in our understanding of signalling through NLRs with special emphasis on the Nod1 and Nod2 pathways.     

Signal transduction of bone morphogenetic protein receptors

Bone morphogenetic proteins (BMPs) play a crucial role during all stages of embryonic development. Although only two major signaling pathways have been characterized (the p38 and Smad pathways), the BMP signaling is complex and includes several negative feedback mechanisms. This article reviews the current state of BMP receptor signaling and provides a summary of the crosstalk of the BMP receptor pathway with other major signaling pathways.     

Signal transduction via platelet-derived growth factor receptors

Platelet-derived growth factor (PDGF) exerts its stimulatory effects on cell growth and motility by binding to two related protein tyrosine kinase receptors. Ligand binding induces receptor dimerization and autophosphorylation, allowing binding and activation of cytoplasmic SH2-domain containing signal transduction molecules. Thereby, a number of different signaling pathways are initiated leading to cell growth, actin reorganization migration and differentiation. Recent observations suggest that extensive cross-talk occurs between different signaling pathways, and that stimulatory signals are modulated by inhibitory signals arising in parallel.     

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.     

Signal transduction by epidermal growth factor occurs through the subclass of high affinity receptors

Many cell types display two classes of epidermal growth factor receptor (EGFR) as judged from EGF binding studies; i.e., a major class of low affinity EGFR and a minor class of high affinity EGFR. We have studied their respective contribution to the cascade of events elicited by EGF in human A431 carcinoma cells, using anti-EGFR mAb 2E9. This antibody specifically blocks EGF binding to low affinity EGFR, without activating receptors in intact cells, and thus enables us to study the effects of exclusive EGF binding to high affinity EGFR. We show that blocking of low affinity EGFR by mAb 2E9 has almost no effect on the activation of the receptor protein-tyrosine kinase by EGF, suggesting that EGFR kinase activation occurs exclusively through the subclass of high affinity EGFR (5-10%). In addition, we provide evidence that high affinity EGFR exists both in monomeric and dimeric forms, and that cross-phosphorylation of low affinity EGFR by high affinity EGFR may take place in dimers of both receptor types. We demonstrate that the following early cellular response to EGF are also unimpaired in the presence of mAb 2E9: (a) inositol phosphate production, (b) release of Ca2+ from intracellular stores, (c) rise in intracellular pH, (d) phosphorylation of EGF on threonine residue 654, (e) induction of c-fos gene expression, and (f) alteration in cell morphology. As possible nonspecific side effects, we observed that the EGF induced Ca2+ influx and fluid-phase pinocytosis were inhibited in A431 cells in the presence of mAb 2E9. We conclude, therefore, that the activation of the EGFR signal transduction cascade can occur completely through exclusive binding of EGF to the subclass of high affinity EGFR.     

Signal transduction of V1-vascular vasopressin receptors.

This review covers the recent developments gained in the exploration of V1-vascular vasopressin (AVP) receptors. We examine the different radioligands available for the pharmacological characterization of these receptors. The immediate transmembrane signaling of V1-vascular AVP receptors involves ligand-receptor complex formation, receptor lateral mobility and internalization, coupling to a Gq protein, activation of phospholipases A2, C and D, translocation and activation of protein kinase C, production of inositol 1,4,5-triphosphate and 1,2-diacylglycerol, mobilization of intracellular calcium, alteration of intracellular pH with activation of the Na+/H+ exchanger, calmodulin activation and myosin light chain phosphorylation. The secondary nuclear signal mechanisms triggered by activation of V1-vascular AVP receptors includes tyrosine phosphorylation, induction of gene expression and protein synthesis.     

基因转录爆发的信号转导机制

随着单分子检测技术水平的提高,学术界发现了与传统认知大相径庭的转录现象——转录爆发。基因转录不是连续平稳且波动较小的过程,而是表现出发生时间极不规律、信使RNA产量波动极大的特征。转录爆发本质上是编码和传递调控信号的方式。本文综述了转录爆发现象、转录爆发的两态模型、转录爆发信号转导机制以及其重要的生物学意义。最后,指出了该领域亟待解决的问题。     

Signal transduction by mitochondrial oxidants

The production of mitochondrial reactive oxygen species occurs as a consequence of aerobic metabolism. Mitochondrial oxidants are increasingly viewed less as byproducts of metabolism and more as important signaling molecules. Here, I review several notable examples, including the cellular response to hypoxia, aspects of innate immunity, the regulation of autophagy, and stem cell self-renewal capacity, where evidence suggests an important regulatory role for mitochondrial oxidants.     

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.     

Signal transduction by reactive oxygen species

Although historically viewed as purely harmful, recent evidence suggests that reactive oxygen species (ROS) function as important physiological regulators of intracellular signaling pathways. The specific effects of ROS are modulated in large part through the covalent modification of specific cysteine residues found within redox-sensitive target proteins. Oxidation of these specific and reactive cysteine residues in turn can lead to the reversible modification of enzymatic activity. Emerging evidence suggests that ROS regulate diverse physiological parameters ranging from the response to growth factor stimulation to the generation of the inflammatory response, and that dysregulated ROS signaling may contribute to a host of human diseases.     

Signal transduction by a protease cascade

The dorsoventral axis of the Drosophila embryo is determined by a spatial cue generated by ovarian somatic cells. This cue is communicated to the embryo through an extracellular serine protease cascade active only on the ventral side of the embryo. Studies of the proteases and somatically expressed proteins involved in this signalling process suggest a working model for how the protease cascade is locally activated hours after the ovarian somatic cells have degenerated.     

Signal transduction by type I interferons

The two classes of interferons, type I (IFNalpha, IFNbeta, IFNomega, and IFNtau) and type II (IFNgamma) are pleiotropic cytokines that exhibit antiviral, antiproliferative, and immunomodulatory effects on their target cells. This article summarizes the advances made in elucidating the molecular events that mediate the biological responses to type I interferons.     

Signal transduction by xenobiotics in fish

Signal transduction by xenobiotics in fish has recently gained much attention. The better known transduction mechanisms are those elicited by organochlorines, organophosphates, carbamates and heavy metals. Organochlorines specifically bind to the membrane bound ouabain sensitive Na+-K+-ATPase affecting neural transmission while the organophosphates and carbamates bind specifically to the membrane bound enzyme acetylcholinesterase again affecting neural transmission. Since the nervous system is one of the important integrative and interactive physiological systems in animals, hypofunction of the nervous system leads to secondary effects in the endocrine system including thyroidal, gonadal, interrenal, pituitary and hypothalamic functions. Even low levels of xenobiotics are efficient enough to bring about remarkable changes in the functional physiology of the non target animals. Heavy metals such as cadmium or mercury belonging to the same group II B in the periodic table probably have a similar mechanism of action. Avidity of these metals to SH-radicals allow them to bind indiscriminately to SH groups in proteins. One pathway of interaction by inorganic mercury with the membrane bound ouabain sensitive Na+-K+-ATPase has been clearly established in fish liver and ovary. Binding of inorganic mercury to the membrane bound enzyme is through sulfhydryl group which inactivates the sodium pump leading to accumulation of the cation in the cytosol. The inorganic mercury is next conjugated by the cytosolar nucleophile, glutathione, and is transported to the nucleus where dissociation occurs and the free metal binds to the metal regulatory element to initiate gene expression. The inducible proteins are 3beta-hydroxysteroid dehydrogenase in the oocyte and metallothionein and C-reactive protein in the liver. The present review deals with the role of xenobiotic as a stress factor.