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PubMed1991

Signal transduction by the T cell antigen receptor.

The T cell antigen receptor (TCR) must recognize antigen, and translate this recognition event into intracellular signal transduction events. Two signal transduction events are regulated by the TCR: the activation of a protein tyrosine kinase (PTK) and phospholipase C (PLC). Recent studies suggest that the TCR-activated PTK regulates PLC activation by the phosphorylation of tyrosine residues of PLC gamma 1. The complex structure of the TCR is now being related to its signal transduction function. Studies with chimeric receptors reveal that the antigen binding Ti heterodimer communicates with the subunits involved with signal transduction, the CD3 chains and zeta dimers, through the carboxy-terminal regions of the Ti chains that surround and include the transmembrane domains. Other chimeras have helped demonstrate that the zeta chain family of dimers function to couple the TCR to intracellular signal transduction mechanisms. The signal transduction function of the TCR can be regulated in a number of ways and by other T cell surface molecules. The plasma membrane tyrosine phosphatase CD45, plays a critical role to specifically regulate TCR-mediated activation of PTK's and PLC. Thus, an understanding of the complex structure of the TCR and the intricacies of its signal transduction function is rapidly emerging.

Animals↗

PubMed2005

Understanding signal transduction through functional proteomics.

The study of signal transduction provides fundamental information regarding the regulation of all biologic processes that support the normal function of life. Functional proteomics, a rapidly emerging discipline that aims to understand the expression, function and regulation of the entire set of proteins in a given cell type, tissue or organism, offers unprecedented opportunity for signal transduction research in terms of understanding cellular behavior and regulation at the systems level. Indeed, swift progress in the area of proteomics has demonstrated the major impact of proteomic approaches on signal transduction and biomedical research. In this review, recent and innovative applications of functional proteomics in determining changes in protein contents, modifications, activities and interactions underpinning signaling transduction pathways are discussed.

Electrophoresis, Gel, Two-Dimensional↗

PubMed2004

The role of A-Kinase anchoring proteins in cAMP-mediated signal transduction pathways.

Compartmentalization of signal transduction enzymes is an important mechanism of cellular signaling specificity. This occurs through the interaction of enzymes with scaffolding or anchoring proteins. To date, one of the best-studied examples of kinase anchoring is the targeting of protein kinase A to cellular locations through its association with A-kinase anchoring proteins (AKAPs). AKAPs mediate a high-affinity interaction with the type II regulatory subunit of protein kinase A for the purpose of localizing the kinase to pools of cyclic adenosine monophosphate and within proximity of preferred substrates. Furthermore, AKAPs can organize entire signaling complexes made up of kinases, phosphatases, signaling enzymes, and additional regulatory proteins.

A Kinase Anchor Proteins↗

PubMed2003

[Future perspectives. From basic research to the development of new therapies aimed at the inhibition of the different stages of signal transduction: applications in breast cancer].

The mechanism implicated in the carcinogenesis are better understood and the transduction of signal is a potential target for new agents. In this review, we describe the different pathways implicated in the transduction of signal and the potential target for new agents in breast cancer.

Antibodies, Monoclonal↗

PubMed2003

Signal transduction networks in rheumatoid arthritis.

Signal transduction pathways regulate cellular responses to stress and play a critical role in inflammation. The complexity and specificity of signalling mechanisms represent major hurdles for developing effective, safe therapeutic interventions that target specific molecules. One approach is to dissect the pathways methodically to determine their hierarchy in various cell types and diseases. This approach contributed to the identification and prioritisation of specific kinases that regulate NF-kappa B and the mitogen activated protein (MAP) kinase cascade as especially attractive targets. Although significant issues remain with regard to the discovery of truly selective kinase inhibitors, the risks that accompany inhibition of fundamental signal transduction mechanisms can potentially be decreased by careful dissection of the pathways and rational target selection.

Antirheumatic Agents↗

PubMed1998

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.

Adaptor Proteins, Signal Transducing↗

PubMedDate not supplied

Gravity perception and signal transduction in single cells.

Cellular signal processing in multi-, as well as in unicellular organisms, has to rely on fundamentally similar mechanisms. Free-living single cells often use the gravity vector for their spatial orientation (gravitaxis) and show distinct gravisensitivities. In this investigation the gravisensitive giant ameboid cell Physarum polycephalum (Myxomycetes, acellular slime molds) is used. Its gravitaxis and the modulation of its intrinsic rhythmic contraction activity by gravity was demonstrated in 180 degrees-turn experiments and in simulated, as well as in actual, near-weightlessness studies (fast-rotating clinostat; Spacelab D1, IML-1). The stimulus perception was addressed in an IML-2 experiment, which provided information on the gravireceptor itself by the determination of the cell's acceleration-sensitivity threshold. Ground-based experiments designed to elucidate the subsequent steps in signal transduction leading to a motor response, suggest that an acceleration stimulus induces changes in the level of second messenger, adenosine 3',5'-cyclic monophosphate (cAMP), indicating also that the acceleration-stimulus signal transduction chain of Physarum uses an ubiquitous second messenger pathway.

Acceleration↗

PubMed2001

Novel domains of the prokaryotic two-component signal transduction systems.

The archetypal two-component signal transduction systems include a sensor histidine kinase and a response regulator, which consists of a receiver CheY-like domain and a DNA-binding domain. Sequence analysis of the sensor kinases and response regulators encoded in complete bacterial and archaeal genomes revealed complex domain architectures for many of them and allowed the identification of several novel conserved domains, such as PAS, GAF, HAMP, GGDEF, EAL, and HD-GYP. All of these domains are widely represented in bacteria, including 19 copies of the GGDEF domain and 17 copies of the EAL domain encoded in the Escherichia coli genome. In contrast, these novel signaling domains are much less abundant in bacterial parasites and in archaea, with none at all found in some archaeal species. This skewed phyletic distribution suggests that the newly discovered complexity of signal transduction systems emerged early in the evolution of bacteria, with subsequent massive loss in parasites and some horizontal dissemination among archaea. Only a few proteins containing these domains have been studied experimentally, and their exact biochemical functions remain obscure; they may include transformations of novel signal molecules, such as the recently identified cyclic diguanylate. Recent experimental data provide the first direct evidence of the participation of these domains in signal transduction pathways, including regulation of virulence genes and extracellular enzyme production in the human pathogens Bordetella pertussis and Borrelia burgdorferi and the plant pathogen Xanthomonas campestris. Gene-neighborhood analysis of these new domains suggests their participation in a variety of processes, from mercury and phage resistance to maintenance of virulence plasmids. It appears that the real picture of the complexity of phosphorelay signal transduction in prokaryotes is only beginning to unfold.

Bacterial Proteins↗

PubMed2001

Arabidopsis genomes uncoupled 5 (GUN5) mutant reveals the involvement of Mg-chelatase H subunit in plastid-to-nucleus signal transduction.

A plastid-derived signal plays an important role in the coordinated expression of both nuclear- and chloroplast-localized genes that encode photosynthesis-related proteins. Arabidopsis GUN (genomes uncoupled) loci have been identified as components of plastid-to-nucleus signal transduction. Unlike wild-type plants, gun mutants have nuclear Lhcb1 expression in the absence of chloroplast development. We observed a synergistic phenotype in some gun double-mutant combinations, suggesting there are at least two independent pathways in plastid-to-nucleus signal transduction. There is a reduction of chlorophyll accumulation in gun4 and gun5 mutant plants, and a gun4gun5 double mutant shows an albino phenotype. We cloned the GUN5 gene, which encodes the ChlH subunit of Mg-chelatase. We also show that gun2 and gun3 are alleles of the known photomorphogenic mutants, hy1 and hy2, which are required for phytochromobilin synthesis from heme. These findings suggest that certain perturbations of the tetrapyrrole biosynthetic pathway generate a signal from chloroplasts that causes transcriptional repression of nuclear genes encoding plastid-localized proteins. The comparison of mutant phenotypes of gun5 and another Mg-chelatase subunit (ChlI) mutant suggests a specific function for ChlH protein in the plastid-signaling pathway.

Amino Acid Sequence↗

PubMed1990

Roles of protein kinases and phosphatases in signal transduction.

Most, if not all, signal transduction at cell surface receptors in animal cells appears to occur by one of four basic mechanisms, 1) cyclic nucleotide systems; 2) phosphoinositidase systems; 3) ion channel systems; 4) tyrosine kinase systems. The end effects of all four signal transduction systems are largely mediated by protein (serine/threonine) kinases and/or phosphatases. Thus, the only known high affinity intracellular receptors for cyclic nucleotides and diacylglycerol are cyclic nucleotide-dependent protein kinases and protein kinase C respectively, while activation of tyrosine kinase systems causes concomitant activation of several different protein (serine/threonine) kinases. Many, although not all, effects of elevated Ca2+ are also mediated by calmodulin-dependent protein kinases. Initial tests of the involvement of any of these kinases in control of a physiological system can be made using cell-permeable kinase activators or inhibitors, e.g. cyclic nucleotide analogues, phorbol esters or Ca2+ ionophores. A family of four protein (serine/threonine) phosphatases account for dephosphorylation of all known cytosolic or nuclear substrates phosphorylated by these protein kinases. Two of these (PP1 and PP2A) have a broad substrate specificity and appear to be highly conserved during evolution, being present in both animal and plant kingdoms. PP1 is potently inhibited by protein inhibitors-1 and -2, while the marine toxin and tumour promoter, okadaic acid, inhibits PP2A with extreme potency and PP1 less potently. Okadaic acid provides a novel cell-permeable probe for examining the role of protein phosphorylation, and PP1 and PP2A in particular, in any physiological process. Recent examples of its use are discussed. These approaches can provide initial evidence that a particular protein is regulated in response to an extracellular signal by protein phosphorylation. Confirmation of this hypothesis may be obtained by showing that the precise residue(s) phosphorylated by the protein kinase in a cell-free system are also phosphorylated in intact cells in response to the extracellular signal. Sensitive methods are now available for the analysis of phosphorylation sites by gas phase sequencing and Fast Atom Bombardment (FAB) mass spectrometry. Sequencing of phosphorylation sites also allows the development of synthetic peptide assays for the various kinases involved. These methods will be illustrated using the author's own studies on phosphorylation of enzymes of lipid metabolism.

Animals↗

PubMed2004

Signal transduction in rheumatoid arthritis.

PURPOSE: Signal transduction pathways are the intracellular mechanism by which cells respond and adapt to environmental stress. Understanding the critical networks in diseases like rheumatoid arthritis can potentially identify novel therapeutic targets. RECENT FINDINGS: Dissecting the complex pathways involved in rheumatoid synovitis, including mitogen-activated protein kinases, NF-kB, tumor suppressors, Janus kinases, the signal transducer and activator of transcription, suppressors of cytokine stimulation, and toll-like receptors may lead to new approaches to inflammatory arthritis. For instance, targeting NF-kB via IkB kinase 2 with specific inhibitors may block an array of proinflammatory cytokines that contribute to synovitis. Inhibition of Janus kinases and p38 could block metalloproteinase expression and protect the extracellular matrix. Overexpression of suppressors of cytokine stimulation and inhibition of signal transducer and activator of transcription are additional approaches that have demonstrated efficacy in animal models of arthritis. Tumor suppressor proteins and cell cycle inhibitors represent additional targets with unexpected anti-inflammatory activities. Recent evidence also suggests that targeting toll-like receptors may regulate cytokine expression in rheumatoid arthritis. SUMMARY: Multiple signal transduction pathways have been implicated in rheumatoid arthritis, and preclinical models have confirmed the therapeutic potential of small molecule inhibitors. Orally bioavailable inhibitors of the mitogen-activated protein kinase and NF-kB pathways have been designed and are currently being evaluated. Many other pathways could be targeted and offer new therapeutic options for rheumatoid arthritis.

Arthritis, Rheumatoid↗

PubMed2004

Efficacy in CB1 receptor-mediated signal transduction.

CB(1) receptor cellular signal transduction is dependent on the expression of G proteins to which the receptor couples, the potential for precoupling of particular G proteins to the receptors either by scaffolding mechanisms or colocalization in lipid raft domains, and the effector mechanisms that these transducer molecules regulate. This discourse will evaluate studies of efficacy for CB(1) receptor-Gi/o activation at the molecular level. Evidence for brain regional differences in CB(1) receptor signal transduction efficacy and agonist selectivity for G proteins will be summarized. The possibility that CB(1) receptors interact with Gs or Gq will be evaluated, and questions with regard to the constitutive activity and G protein sequestration will be posed.

Animals↗

PubMed1990

Analysis of T cell signaling by class I MHC molecules: the cytoplasmic domain is not required for signal transduction.

The structural requirements for signal transduction by class I major histocompatibility complex (MHC) molecules were examined. Native or mutant HLA-A2 or HLA-B27 constructs lacking most of their cytoplasmic domains were co-transfected with pSV2neo into Jurkat cells. Transfection of either native or mutant constructs resulted in a comparable expression of the gene products. Stimulation of transfectants expressing either native or truncated A2 or B27 molecules with specific mAb evoked an increase in [Ca2+]i upon crosslinking. Moreover, crosslinking native or truncated A2 or B27 induced IL-2 production upon co-stimulation with phorbol myristate acetate. These results confirm that crosslinking class I MHC molecules transduces an activation signal to human T cells. Effective signaling was observed when all but four of the intracytoplasmic residues were deleted, indicating that signal transduction does not require this portion of the molecule.

Animals↗

PubMed1991

Effects of farnesylcysteine analogs on protein carboxyl methylation and signal transduction.

Several proteins associated with signal transduction in eukaryotes are carboxyl methylated at COOH-terminal S-farnesylcysteine residues. These include members of the Ras superfamily and gamma-subunits of heterotrimeric G-proteins. The enzymes that catalyze the carboxyl methylation reaction also methylate small molecules such as N-acetyl-S-trans, trans-farnesyl-L-cysteine (AFC). AFC inhibits carboxyl methylation of p21ras and related proteins both in vitro and in vivo. Saturating concentrations of AFC cause a greater than 80% inhibition of chemotactic responses of mouse peritoneal macrophages. Our results suggest that carboxyl methylation may play a role in the regulation of receptor-mediated signal transduction processes in eukaryotic cells.

Alkyl and Aryl Transferases↗

PubMed2006

Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells.

Sterol synthesis is required for Sonic hedgehog (Shh) signal transduction. Errors in Shh signal transduction play important roles in the formation of human tumors, including medulloblastoma (MB). It is not clear which products of sterol synthesis are necessary for Shh signal transduction or how they act. Here we show that cholesterol or specific oxysterols are the critical products of sterol synthesis required for Shh pathway signal transduction in MB cells. In MB cells, sterol synthesis inhibitors reduce Shh target gene transcription and block Shh pathway-dependent proliferation. These effects of sterol synthesis inhibitors can be reversed by exogenous cholesterol or specific oxysterols. We also show that certain oxysterols can maximally activate Shh target gene transcription through the Smoothened (Smo) protein as effectively as the known Smo full agonist, SAG. Thus, sterols are required and sufficient for Shh pathway activation. These results suggest that oxysterols may be critical regulators of Smo, and thereby Shh signal transduction. Inhibition of Shh signaling by sterol synthesis inhibitors may offer a novel approach to the treatment of MB and other Shh pathway-dependent human tumors.

Animals↗

PubMed2004

Global transcription profiling reveals multiple sugar signal transduction mechanisms in Arabidopsis.

Complex and interconnected signaling networks allow organisms to control cell division, growth, differentiation, or programmed cell death in response to metabolic and environmental cues. In plants, it is known that sugar and nitrogen are critical nutrient signals; however, our understanding of the molecular mechanisms underlying nutrient signal transduction is very limited. To begin unraveling complex sugar signaling networks in plants, DNA microarray analysis was used to determine the effects of glucose and inorganic nitrogen source on gene expression on a global scale in Arabidopsis thaliana. In whole seedling tissue, glucose is a more potent signal in regulating transcription than inorganic nitrogen. In fact, other than genes associated with nitrate assimilation, glucose had a greater effect in regulating nitrogen metabolic genes than nitrogen itself. Glucose also regulated a broader range of genes, including genes associated with carbohydrate metabolism, signal transduction, and metabolite transport. In addition, a large number of stress responsive genes were also induced by glucose, indicating a role of sugar in environmental responses. Cluster analysis revealed significant interaction between glucose and nitrogen in regulating gene expression because glucose can modulate the effects of nitrogen and vise versa. Intriguingly, cycloheximide treatment appeared to disrupt glucose induction more than glucose repression, suggesting that de novo protein synthesis is an intermediary event required before most glucose induction can occur. Cross talk between sugar and ethylene signaling may take place on the transcriptional level because several ethylene biosynthetic and signal transduction genes are repressed by glucose, and the repression is largely unaffected by cycloheximide. Collectively, our global expression data strongly support the idea that glucose and inorganic nitrogen act as both metabolites and signaling molecules.

Arabidopsis↗

PubMed1992

In vivo efficacy of a novel inhibitor of selected signal transduction pathways including calcium, arachidonate, and inositol phosphates.

Aberrant signal transduction has been implicated in malignant transformation, growth, and progression. This has led to the proposal to use inhibitors of signal transduction pathways to treat cancer. One approach to circumventing potential toxicity and improving efficacy would be to target pathways upon which cancer cells selectively depend. Pathways associated with the malignant process involve calcium fluxes, the release of arachidonic acid, and the generation of phosphoinositides. In this report, CAI (L651582, NSC 609974), a substituted carboxyamido-imidazole and novel inhibitor of these selected signal transduction pathways, inhibits anchorage-dependent and -independent growth in a large series of human cancer cell lines. CAI pretreatment of HT-29 human colon cancer and 5R ras-transfected rat embryo fibroblast cells inhibits the formation and growth of experimental pulmonary metastases in nude mice. Oral administration of CAI in PEG-400 vehicle arrests growth and metastasis of transplanted human melanoma and ovarian cancer xenografts. No significant gross or histological toxicity was observed at CAI doses yielding blood levels in the concentration range demonstrated to inhibit select signal transduction pathways in vitro. These data indicate the feasibility and demonstrate a potential selectivity and sensitivity of using specific signal transduction inhibitors for the experimental treatment of cancer.

Aminoimidazole Carboxamide↗

PubMed1996

Where the outside meets the inside: integrins as activators and targets of signal transduction cascades.

In fibroblasts, signaling through the adhesion receptors known as integrins synergizes with other cellular stimulators such as the growth factors. There is currently great interest in the details of the ensuing 'outside in' signal transduction mechanisms, and the focal adhesion kinase in particular, has been a focus of attention. Less is understood of signalling through integrins on leukocytes which also perform a costimulator role. The activity of these leukocyte integrins is not constitutive but is initiated via signalling through other receptors, termed 'inside out' signalling. These signals cause movement and clustering of integrins in the membrane leading to strengthened adhesion between cells.

Cell Adhesion↗