Showing papers on "Signal transduction published in 2000"
TL;DR: It is now becoming clear that lipid micro-environments on the cell surface — known as lipid rafts — also take part in this process of signalling transduction, where protein–protein interactions result in the activation of signalling cascades.
Abstract: Signal transduction is initiated by complex protein-protein interactions between ligands, receptors and kinases, to name only a few. It is now becoming clear that lipid micro-environments on the cell surface -- known as lipid rafts -- also take part in this process. Lipid rafts containing a given set of proteins can change their size and composition in response to intra- or extracellular stimuli. This favours specific protein-protein interactions, resulting in the activation of signalling cascades.
6,080 citations
TL;DR: This review will focus on the JNK group of MAP kinases, which are characterized by the sequence TEY and the two stress-activatedMAP kinases: p38 with the sequence TGY, and the c-Jun NH2-terminal kinases (JNK) with the sequences TPY.
4,228 citations
TL;DR: The core protein machinery that is necessary to drive formation and consumption of intermediates in the macroautophagy pathway includes a ubiquitin-like protein conjugation system and a protein complex that directs membrane docking and fusion at the lysosome or vacuole.
Abstract: Macroautophagy is a dynamic process involving the rearrangement of subcellular membranes to sequester cytoplasm and organelles for delivery to the lysosome or vacuole where the sequestered cargo is degraded and recycled. This process takes place in all eukaryotic cells. It is highly regulated through the action of various kinases, phosphatases, and guanosine triphosphatases (GTPases). The core protein machinery that is necessary to drive formation and consumption of intermediates in the macroautophagy pathway includes a ubiquitin-like protein conjugation system and a protein complex that directs membrane docking and fusion at the lysosome or vacuole. Macroautophagy plays an important role in developmental processes, human disease, and cellular response to nutrient deprivation.
3,398 citations
TL;DR: It is shown that caspase-12 is localized to the ER and activated by ER stress, including disruption of ER calcium homeostasis and accumulation of excess proteins in ER, but not by membrane- or mitochondrial-targeted apoptotic signals, which may contribute to amyloid-β neurotoxicity.
Abstract: Apoptosis, or cellular suicide, is important for normal development and tissue homeostasis, but too much or too little apoptosis can also cause disease. The family of cysteine proteases, the so- called caspases, are critical mediators of programmed cell death, and thus far 14 family members have been identified. Some of these, such as caspase-8, mediate signal transduction downstream of death receptors located on the plasma membrane. Others, such as caspase-9, mediate apoptotic signals after mitochondrial damage. Stress in the endoplasmic reticulum (ER) can also result in apoptosis. Here we show that caspase-12 is localized to the ER and activated by ER stress, including disruption of ER calcium homeostasis and accumulation of excess proteins in ER, but not by membrane- or mitochondrial-targeted apoptotic signals. Mice that are deficient in caspase-12 are resistant to ER stress-induced apoptosis, but their cells undergo apoptosis in response to other death stimuli. Furthermore, we show that caspase-12-deficient cortical neurons are defective in apoptosis induced by amyloid-beta protein but not by staurosporine or trophic factor deprivation. Thus, caspase-12 mediates an ER-specific apoptosis pathway and may contribute to amyloid-beta neurotoxicity.
3,290 citations
TL;DR: It is demonstrated that Fc-receptor-dependent mechanisms contribute substantially to the action of cytotoxic antibodies against tumors and indicate that an optimal antibody against tumors would bind preferentially to activation Fc receptors and minimally to the inhibitory partner FcγRIIB.
Abstract: Inhibitory receptors have been proposed to modulate the in vivo cytotoxic response against tumor targets for both spontaneous and antibody-dependent pathways. Using a variety of syngenic and xenograft models, we demonstrate here that the inhibitory FcgammaRIIB molecule is a potent regulator of antibody-dependent cell-mediated cytotoxicity in vivo, modulating the activity of FcgammaRIII on effector cells. Although many mechanisms have been proposed to account for the anti-tumor activities of therapeutic antibodies, including extended half-life, blockade of signaling pathways, activation of apoptosis and effector-cell-mediated cytotoxicity, we show here that engagement of Fcgamma receptors on effector cells is a dominant component of the in vivo activity of antibodies against tumors. Mouse monoclonal antibodies, as well as the humanized, clinically effective therapeutic agents trastuzumab (Herceptin(R)) and rituximab (Rituxan(R)), engaged both activation (FcgammaRIII) and inhibitory (FcgammaRIIB) antibody receptors on myeloid cells, thus modulating their cytotoxic potential. Mice deficient in FcgammaRIIB showed much more antibody-dependent cell-mediated cytotoxicity; in contrast, mice deficient in activating Fc receptors as well as antibodies engineered to disrupt Fc binding to those receptors were unable to arrest tumor growth in vivo. These results demonstrate that Fc-receptor-dependent mechanisms contribute substantially to the action of cytotoxic antibodies against tumors and indicate that an optimal antibody against tumors would bind preferentially to activation Fc receptors and minimally to the inhibitory partner FcgammaRIIB.
2,831 citations
TL;DR: Malfolded proteins in the endoplasmic reticulum induce cellular stress and activate c-Jun amino-terminal kinases (JNKs or SAPKs), and Mammalian homologs of yeast IRE1, which activate chaperone genes in response to ER stress, also activated JNK, and I RE1alpha-/- fibroblasts were impaired in JNK activation by ER stress.
Abstract: Malfolded proteins in the endoplasmic reticulum (ER) induce cellular stress and activate c-Jun amino-terminal kinases (JNKs or SAPKs). Mammalian homologs of yeast IRE1, which activate chaperone genes in response to ER stress, also activated JNK, and IRE1alpha-/- fibroblasts were impaired in JNK activation by ER stress. The cytoplasmic part of IRE1 bound TRAF2, an adaptor protein that couples plasma membrane receptors to JNK activation. Dominant-negative TRAF2 inhibited activation of JNK by IRE1. Activation of JNK by endogenous signals initiated in the ER proceeds by a pathway similar to that initiated by cell surface receptors in response to extracellular signals.
2,774 citations
TL;DR: The evidence for ligand-induced generation of ROS, its cellular sources, and the signaling pathways that are activated is examined.
Abstract: Reactive oxygen species (ROS) are generated as by-products of cellular metabolism, primarily in the mitochondria. When cellular production of ROS overwhelms its antioxidant capacity, damage to cellular macromolecules such as lipids, protein, and DNA may ensue. Such a state of “oxidative stress” is thought to contribute to the pathogenesis of a number of human diseases including those of the lung. Recent studies have also implicated ROS that are generated by specialized plasma membrane oxidases in normal physiological signaling by growth factors and cytokines. In this review, we examine the evidence for ligand-induced generation of ROS, its cellular sources, and the signaling pathways that are activated. Emerging concepts on the mechanisms of signal transduction by ROS that involve alterations in cellular redox state and oxidative modifications of proteins are also discussed.
2,757 citations
TL;DR: The results show that MMP-9 is a component of theAngiogenic switch, and MMP inhibitors reduce angiogenic switching, and tumour number and growth, as does genetic ablation of M MP-9.
Abstract: During carcinogenesis of pancreatic islets in transgenic mice, an angiogenic switch activates the quiescent vasculature Paradoxically, vascular endothelial growth factor (VEGF) and its receptors are expressed constitutively Nevertheless, a synthetic inhibitor (SU5416) of VEGF signalling impairs angiogenic switching and tumour growth Two metalloproteinases, MMP-2/gelatinase-A and MMP-9/gelatinase-B, are upregulated in angiogenic lesions MMP-9 can render normal islets angiogenic, releasing VEGF MMP inhibitors reduce angiogenic switching, and tumour number and growth, as does genetic ablation of MMP-9 Absence of MMP-2 does not impair induction of angiogenesis, but retards tumour growth, whereas lack of urokinase has no effect Our results show that MMP-9 is a component of the angiogenic switch
2,657 citations
TL;DR: The role of ErbB receptors as normal signal transducers and their contribution to the process of malignant transformation during tumor development are concentrated on.
Abstract: Cells are continuously exposed to diverse stimuli ranging from soluble endocrine and paracrine factors, to signaling molecules on neighboring cells. It is of great importance that these extracellular signals are correctly interpreted by the cell, in order to achieve an appropriate developmental or proliferative response. Receptors of the tyrosine kinase family play pivotal roles in this process. By binding to specific peptide ligands they are able to integrate these external stimuli with internal signal transduction pathways, contributing in this fashion to the ability of the cell to respond correctly to its environment. In this review, we will concentrate on the role of ErbB receptors as normal signal transducers and their contribution to the process of malignant transformation during tumor development.
ErbB proteins belong to subclass I of the superfamily of receptor tyrosine kinases (RTKs). There are four members of the ErbB family: epidermal growth factor (EGF) receptor (also termed ErbB1/HER1), ErbB2/Neu/HER2, ErbB3/HER3 and ErbB4/HER4. We will refer to them, henceforth, as the ErbB receptors. All family members have in common an extracellular ligand‐binding domain, a single membrane‐spanning region and a cytoplasmic protein tyrosine kinase domain. A family of ligands, the EGF‐related peptide growth factors, bind the extracellular domain of ErbB receptors leading to the formation of both homo‐ and heterodimers. Dimerization consequently stimulates the intrinsic tyrosine kinase activity of the receptors and triggers autophosphorylation of specific tyrosine residues within the cytoplasmic domain. These phosphorylated residues serve as docking sites for signaling molecules involved in the regulation of intracellular signaling cascades. Ultimately, downstream effects on gene expression determine the biological response to receptor activation.
ErbB receptors are expressed in a variety of tissues of epithelial, mesenchymal and neuronal origin, where they play fundamental roles in development, proliferation and differentiation. Moreover, deregulated expression of ErbB receptors, in particular ErbB1 and ErbB2, has …
2,497 citations
TL;DR: In human tissues, normal homeostasis requires intricately balanced interactions between cells and the network of secreted proteins known as the extracellular matrix, which is clearly evident in the interactions mediated by the cytokine transforming growth factor β (TGF-β).
Abstract: In human tissues, normal homeostasis requires intricately balanced interactions between cells and the network of secreted proteins known as the extracellular matrix. These cooperative interactions involve numerous cytokines acting through specific cell-surface receptors. When the balance between the cells and the extracellular matrix is perturbed, disease can result. This is clearly evident in the interactions mediated by the cytokine transforming growth factor β (TGF-β). TGF-β is a member of a family of dimeric polypeptide growth factors that includes bone morphogenic proteins and activins. All of these growth factors share a cluster of conserved cysteine residues that form a common cysteine . . .
2,432 citations
TL;DR: In this article, the lumenal domains of transmembrane protein kinases (PERK and IRE1) were found to be functionally interchangeable in mediating an ER stress response and that in unstressed cells, both L1 and L2 domains formed a stable complex with the ER chaperone BiP.
Abstract: PERK and IRE1 are type-I transmembrane protein kinases that reside in the endoplasmic reticulum (ER) and transmit stress signals in response to perturbation of protein folding. Here we show that the lumenal domains of these two proteins are functionally interchangeable in mediating an ER stress response and that, in unstressed cells, both lumenal domains form a stable complex with the ER chaperone BiP. Perturbation of protein folding promotes reversible dissociation of BiP from the lumenal domains of PERK and IRE1. Loss of BiP correlates with the formation of high-molecular-mass complexes of activated PERK or IRE1, and overexpression of BiP attenuates their activation. These findings are consistent with a model in which BiP represses signalling through PERK and IRE1 and protein misfolding relieves this repression by effecting the release of BiP from the PERK and IRE1 lumenal domains.
TL;DR: Roles for PARs are beginning to emerge in haemostasis and thrombosis, inflammation, and perhaps even blood vessel development.
Abstract: How does the coagulation protease thrombin regulate cellular behaviour? The protease-activated receptors (PARs) provide one answer. In concert with the coagulation cascade, these receptors provide an elegant mechanism linking mechanical information in the form of tissue injury or vascular leakage to cellular responses. Roles for PARs are beginning to emerge in haemostasis and thrombosis, inflammation, and perhaps even blood vessel development.
TL;DR: The author would like to thank S. H. Roan for all her help and members of the Massague laboratory for insightful discussions.
Journal Article•
TL;DR: Although AT(1) receptors mediate most of the known actions of Ang II, the AT(2) receptor contributes to the regulation of blood pressure and renal function and the development of specific nonpeptide receptor antagonists has led to major advances in the physiology, pharmacology, and therapy of the renin-angiotensin system.
Abstract: The cardiovascular and other actions of angiotensin II (Ang II) are mediated by AT(1) and AT(2) receptors, which are seven transmembrane glycoproteins with 30% sequence similarity. Most species express a single autosomal AT(1) gene, but two related AT(1A) and AT(1B) receptor genes are expressed in rodents. AT(1) receptors are predominantly coupled to G(q/11), and signal through phospholipases A, C, D, inositol phosphates, calcium channels, and a variety of serine/threonine and tyrosine kinases. Many AT(1)-induced growth responses are mediated by transactivation of growth factor receptors. The receptor binding sites for agonist and nonpeptide antagonist ligands have been defined. The latter compounds are as effective as angiotensin converting enzyme inhibitors in cardiovascular diseases but are better tolerated. The AT(2) receptor is expressed at high density during fetal development. It is much less abundant in adult tissues and is up-regulated in pathological conditions. Its signaling pathways include serine and tyrosine phosphatases, phospholipase A(2), nitric oxide, and cyclic guanosine monophosphate. The AT(2) receptor counteracts several of the growth responses initiated by the AT(1) and growth factor receptors. The AT(4) receptor specifically binds Ang IV (Ang 3-8), and is located in brain and kidney. Its signaling mechanisms are unknown, but it influences local blood flow and is associated with cognitive processes and sensory and motor functions. Although AT(1) receptors mediate most of the known actions of Ang II, the AT(2) receptor contributes to the regulation of blood pressure and renal function. The development of specific nonpeptide receptor antagonists has led to major advances in the physiology, pharmacology, and therapy of the renin-angiotensin system.
TL;DR: TGF‐β family members are multifunctional hormones, the nature of their effects depending on what has been called ‘the cellular context’ warrants mention at the outset.
Abstract: The deployment of a cell's genetic program in a multicellular organism must be tightly controlled for the sake of the organism as a whole. Over the past 20 years the transforming growth factor‐β (TGF‐β) family of secretory polypeptides has emerged as a major source of signals exerting this type of control. This family includes various forms of TGF‐β, the bone morphogenetic proteins (BMPs), the Nodals, the Activins, the anti‐Mullerian hormone, and many other structurally related factors in vertebrates, insects and nematodes (Massague, 1998). Produced by diverse cell types, these factors regulate cell migration, adhesion, multiplication, differentiation and death throughout the life span of the organism. Many of these responses result from changes in the expression of key target genes. Hence, transcriptional control by the TGF‐β family has become a subject of intense investigation in recent years. The present knowledge of these mechanisms is reviewed here.
One basic concept concerning the role of the TGF‐β family as hormonally active agents warrants mention at the outset. Unlike classical hormones, whose actions are few and concrete, the members of the TGF‐β family have many different effects depending on the type and state of the cell. For example, in the same healing wound TGF‐β may stimulate or inhibit cell proliferation depending on whether the target is a fibroblast or a keratinocyte (Ashcroft et al ., 1999); in mammary epithelial cells TGF‐β will cause growth arrest or metastatic behavior depending on the level of oncogenic Ras activity present in the cell (Oft et al ., 1996); and human BMP4 and its Drosophila ortholog, DPP, can signal dorsalization in the fly (Padgett et al ., 1993) yet bone formation in a vertebrate (Sampath et al ., 1993). TGF‐β family members are multifunctional hormones, the nature of their effects depending on what has been called ‘the cellular context’.
It was plausible …
TL;DR: Findings reveal that the target of rapamycin TOR controls an unusually abundant and diverse set of readouts all of which are important for cell growth, suggesting that this conserved kinase is such a central regulator.
TL;DR: Mice created with a neuron-specific disruption of the IR gene showed increased food intake, and both male and female mice developed diet-sensitive obesity with increases in body fat and plasma leptin levels, mild insulin resistance, elevated plasma insulin levels, and hypertriglyceridemia.
Abstract: Insulin receptors (IRs) and insulin signaling proteins are widely distributed throughout the central nervous system (CNS). To study the physiological role of insulin signaling in the brain, we created mice with a neuron-specific disruption of the IR gene (NIRKO mice). Inactivation of the IR had no impact on brain development or neuronal survival. However, female NIRKO mice showed increased food intake, and both male and female mice developed diet-sensitive obesity with increases in body fat and plasma leptin levels, mild insulin resistance, elevated plasma insulin levels, and hypertriglyceridemia. NIRKO mice also exhibited impaired spermatogenesis and ovarian follicle maturation because of hypothalamic dysregulation of luteinizing hormone. Thus, IR signaling in the CNS plays an important role in regulation of energy disposal, fuel metabolism, and reproduction.
TL;DR: A number of novel p75NTR-interacting proteins have been identified that transmit growth, survival, and apoptotic signals.
TL;DR: The principal molecular components of the apoptosis programme in neurons include Apaf-1 (apoptotic protease-activating factor 1) and proteins of the Bcl-2 and caspase families, which regulate neuronal apoptosis through the action of critical protein kinase cascades.
Abstract: Neuronal apoptosis sculpts the developing brain and has a potentially important role in neurodegenerative diseases. The principal molecular components of the apoptosis programme in neurons include Apaf-1 (apoptotic protease-activating factor 1) and proteins of the Bcl-2 and caspase families. Neurotrophins regulate neuronal apoptosis through the action of critical protein kinase cascades, such as the phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase pathways. Similar cell-death-signalling pathways might be activated in neurodegenerative diseases by abnormal protein structures, such as amyloid fibrils in Alzheimer's disease. Elucidation of the cell death machinery in neurons promises to provide multiple points of therapeutic intervention in neurodegenerative diseases.
TL;DR: The evidence for critical roles of STATs in oncogenesis is presented and the potential for development of novel cancer therapies based on mechanistic understanding of STAT signaling is discussed.
Abstract: Since their discovery as key mediators of cytokine signaling, considerable progress has been made in defining the structure-function relationships of Signal Transducers and Activators of Transcription (STATs). In addition to their central roles in normal cell signaling, recent studies have demonstrated that diverse oncoproteins can activate specific STATs (particularly Stat3 and Stat5) and that constitutively-activated STAT signaling directly contributes to oncogenesis. Furthermore, extensive surveys of primary tumors and cell lines derived from tumors indicate that inappropriate activation of specific STATs occurs with surprisingly high frequency in a wide variety of human cancers. Together, these findings provide compelling evidence that aberrant STAT activation associated with oncogenesis is not merely adventitious but instead contributes to the process of malignant transformation. These studies are beginning to reveal the molecular mechanisms leading to STAT activation in the context of oncogenesis, and candidate genes regulated by STATs that may contribute to oncogenesis are being identified. Recent studies suggest that activated STAT signaling participates in oncogenesis by stimulating cell proliferation and preventing apoptosis. This review presents the evidence for critical roles of STATs in oncogenesis and discusses the potential for development of novel cancer therapies based on mechanistic understanding of STAT signaling. Oncogene (2000).
TL;DR: It is shown here that JNK is required for UV-induced apoptosis in primary murine embryonic fibroblasts, and data indicate that mitochondria are influenced by proapoptotic signal transduction through the JNK pathway.
Abstract: The c-Jun NH2-terminal kinase (JNK) is activated when cells are exposed to ultraviolet (UV) radiation. However, the functional consequence of JNK activation in UV-irradiated cells has not been established. It is shown here that JNK is required for UV-induced apoptosis in primary murine embryonic fibroblasts. Fibroblasts with simultaneous targeted disruptions of all the functional Jnk genes were protected against UV-stimulated apoptosis. The absence of JNK caused a defect in the mitochondrial death signaling pathway, including the failure to release cytochrome c. These data indicate that mitochondria are influenced by proapoptotic signal transduction through the JNK pathway.
TL;DR: The mechanism by which PKB is activated and the downstream actions of this multifunctional kinase are reviewed, as well as the evidence that PDK1 may be involved in the activation of protein kinases other than PKB, and the possibility that some of the currently postulated PKB substrates targets might in fact be phosphorylated byPDK1-regulated kinasesother than P KB.
Abstract: Phosphoinositide 3-kinases (PI3Ks) generate specific inositol lipids that have been implicated in the regulation of cell growth, proliferation, survival, differentiation and cytoskeletal changes One of the best characterized targets of PI3K lipid products is the protein kinase Akt or protein kinase B (PKB) In quiescent cells, PKB resides in the cytosol in a low-activity conformation Upon cellular stimulation, PKB is activated through recruitment to cellular membranes by PI3K lipid products and phosphorylation by 3'-phosphoinositide-dependent kinase-1 (PDK1) Here we review the mechanism by which PKB is activated and the downstream actions of this multifunctional kinase We also discuss the evidence that PDK1 may be involved in the activation of protein kinases other than PKB, the mechanisms by which this activity of PDK1 could be regulated and the possibility that some of the currently postulated PKB substrates targets might in fact be phosphorylated by PDK1-regulated kinases other than PKB
TL;DR: Findings indicate that CD14 is a co-receptor for HSP70-mediated signaling in human monocytes and are indicative of an previously unrecognized function for H SP70 as an extracellular protein with regulatory effects on human monocyte, having a dual role as chaperone and cytokine.
Abstract: Here, we demonstrate a previously unknown function for the 70-kDa heat-shock protein (HSP70) as a cytokine. HSP70 bound with high affinity to the plasma membrane, elicited a rapid intracellular calcium flux, activated nuclear factor (NF)-kappaB and upregulated the expression of pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 in human monocytes. Furthermore, two different signal transduction pathways were activated by exogenous HSP70: one dependent on CD14 and intracellular calcium, which resulted in increased IL-1beta, IL-6 and TNF-alpha; and the other independent of CD14 but dependent on intracellular calcium, which resulted in an increase in TNF-alpha but not IL-1beta or IL-6. These findings indicate that CD14 is a co-receptor for HSP70-mediated signaling in human monocytes and are indicative of an previously unrecognized function for HSP70 as an extracellular protein with regulatory effects on human monocytes, having a dual role as chaperone and cytokine.
TL;DR: The characteristics of the major components of the p38 signalling transduction pathway are summarized and the targets of this pathway are highlighted and the physiological function ofThe p38 activation is highlighted.
TL;DR: This review examines the structural basis for 14-3- 3-ligand interactions, proposed functions of 14-1-3 in various signaling pathways, and emerging views of mechanisms that regulate 14-2-3 actions.
Abstract: The 14-3-3 proteins are a family of conserved regulatory molecules expressed in all eukaryotic cells. A striking feature of the 14-3-3 proteins is their ability to bind a multitude of functionally diverse signaling proteins, including kinases, phosphatases, and transmembrane receptors. This plethora of interacting proteins allows 14-3-3 to play important roles in a wide range of vital regulatory processes, such as mitogenic signal transduction, apoptotic cell death, and cell cycle control. In this review, we examine the structural basis for 14-3-3-ligand interactions, proposed functions of 14-3-3 in various signaling pathways, and emerging views of mechanisms that regulate 14-3-3 actions.
TL;DR: Aβ immunization reduces both deposition of cerebral fibrillar Aβ and cognitive dysfunction in the TgCRND8 murine model of Alzheimer's disease without, however, altering total levels of Aβ in the brain, which implies that either a ∼50% reduction in dense-cored Aβ plaques is sufficient to affect cognition, or that vaccination may modulate the activity/abundance of a small subpopulation of especially toxic Aβ species.
Abstract: Much evidence indicates that abnormal processing and extracellular deposition of amyloid-β peptide (Aβ), a proteolytic derivative of the β-amyloid precursor protein (βAPP), is central to the pathogenesis of Alzheimer's disease (reviewed in ref. 1). In the PDAPP transgenic mouse model of Alzheimer's disease, immunization with Aβ causes a marked reduction in burden of the brain amyloid2,3. Evidence that Aβ immunization also reduces cognitive dysfunction in murine models of Alzheimer's disease would support the hypothesis that abnormal Aβ processing is essential to the pathogenesis of Alzheimer's disease, and would encourage the development of other strategies directed at the ‘amyloid cascade’. Here we show that Aβ immunization reduces both deposition of cerebral fibrillar Aβ and cognitive dysfunction in the TgCRND8 murine model of Alzheimer's disease without, however, altering total levels of Aβ in the brain. This implies that either a ∼50% reduction in dense-cored Aβ plaques is sufficient to affect cognition, or that vaccination may modulate the activity/abundance of a small subpopulation of especially toxic Aβ species.
TL;DR: The authors showed that H2O2 is a potent activator of mitogen-activated protein kinases (MAPKs) in Arabidopsis leaf cells using epitope tagging and a protoplast transient expression assay.
Abstract: Despite the recognition of H2O2 as a central signaling molecule in stress and wounding responses, pathogen defense, and regulation of cell cycle and cell death, little is known about how the H2O2 signal is perceived and transduced in plant cells We report here that H2O2 is a potent activator of mitogen-activated protein kinases (MAPKs) in Arabidopsis leaf cells Using epitope tagging and a protoplast transient expression assay, we show that H2O2 can activate a specific Arabidopsis mitogen-activated protein kinase kinase kinase, ANP1, which initiates a phosphorylation cascade involving two stress MAPKs, AtMPK3 and AtMPK6 Constitutively active ANP1 mimics the H2O2 effect and initiates the MAPK cascade that induces specific stress-responsive genes, but it blocks the action of auxin, a plant mitogen and growth hormone The latter observation provides a molecular link between oxidative stress and auxin signal transduction Finally, we show that transgenic tobacco plants that express a constitutively active tobacco ANP1 orthologue, NPK1, display enhanced tolerance to multiple environmental stress conditions without activating previously described drought, cold, and abscisic acid signaling pathways Thus, manipulation of key regulators of an oxidative stress signaling pathway, such as ANP1/NPK1, provides a strategy for engineering multiple stress tolerance that may greatly benefit agriculture
[...]
TL;DR: This article reviews recent developments in this field of research, with main emphasis on structure and expression of CD40 and its ligand; (2) CD40 signal transduction; (3) in vitro function ofCD40 on different cell types; and (4) in vivo functions of CD 40/CD40‐L interactions.
Abstract: CD40 is a cell surface receptor that belongs to the tumor necrosis factor-R (TNF-R) family, and that was first identified and functionally characterized on B lymphocytes. Its critical role in T cell-dependent humoral immune responses was demonstrated by patients with the hyper-IgM syndrome, as well as by gene targeting in mice. However, in recent years it has become clear that CD40 is expressed much more broadly, including expression on monocytes, dendritic cells, endothelial cells, and epithelial cells. In addition, the CD40-ligand (CD40-L/CD154), a member of the TNF family, is also expressed more widely than activated CD4+ T cells only. Therefore it is now thought that CD40-CD40-L interactions play a more general role in immune regulation. Collectively these studies have culminated in pre-clinical and clinical studies that are in progress. This article reviews recent developments in this field of research, with main emphasis on (1) structure and expression of CD40 and its ligand; (2) CD40 signal transduction; (3) in vitro function of CD40 on different cell types; and (4) in vivo functions of CD40/CD40-L interactions.
TL;DR: Results suggest that phosphorylation of serine 307 might mediate, at least partially, the inhibitory effect of proinflammatory cytokines like TNFα on IRS-1 function.