Signal transduction

About: Signal transduction is a research topic. Over the lifetime, 122628 publications have been published within this topic receiving 8209258 citations. The topic is also known as: GO:0007165.

G protein-coupled receptor kinases.

Abstract: G protein-coupled receptor kinases (GRKs) constitute a family of six mammalian serine/threonine protein kinases that phosphorylate agonist-bound, or activated, G protein-coupled receptors (GPCRs) as their primary substrates. GRK-mediated receptor phosphorylation rapidly initiates profound impairment of receptor signaling, or desensitization. This review focuses on the regulation of GRK activity by a variety of allosteric and other factors: agonist-stimulated GPCRs, beta gamma subunits of heterotrimeric GTP-binding proteins, phospholipid cofactors, the calcium-binding proteins calmodulin and recoverin, posttranslational isoprenylation and palmitoylation, autophosphorylation, and protein kinase C-mediated GRK phosphorylation. Studies employing recombinant, purified proteins, cell culture, and transgenic animal models attest to the general importance of GRKs in regulating a vast array of GPCRs both in vitro and in vivo.

Enhancing CD8 T-cell memory by modulating fatty acid metabolism.

Abstract: CD8 T cells, which have a crucial role in immunity to infection and cancer, are maintained in constant numbers, but on antigen stimulation undergo a developmental program characterized by distinct phases encompassing the expansion and then contraction of antigen-specific effector (T(E)) populations, followed by the persistence of long-lived memory (T(M)) cells. Although this predictable pattern of CD8 T-cell responses is well established, the underlying cellular mechanisms regulating the transition to T(M) cells remain undefined. Here we show that tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6), an adaptor protein in the TNF-receptor and interleukin-1R/Toll-like receptor superfamily, regulates CD8 T(M)-cell development after infection by modulating fatty acid metabolism. We show that mice with a T-cell-specific deletion of TRAF6 mount robust CD8 T(E)-cell responses, but have a profound defect in their ability to generate T(M) cells that is characterized by the disappearance of antigen-specific cells in the weeks after primary immunization. Microarray analyses revealed that TRAF6-deficient CD8 T cells exhibit altered expression of genes that regulate fatty acid metabolism. Consistent with this, activated CD8 T cells lacking TRAF6 display defective AMP-activated kinase activation and mitochondrial fatty acid oxidation (FAO) in response to growth factor withdrawal. Administration of the anti-diabetic drug metformin restored FAO and CD8 T(M)-cell generation in the absence of TRAF6. This treatment also increased CD8 T(M) cells in wild-type mice, and consequently was able to considerably improve the efficacy of an experimental anti-cancer vaccine.

TRAF6 is a signal transducer for interleukin-1

Abstract: Many cytokines signal through different cell-surface receptors to activate the transcription factor NF-kappaB. Members of the TRAF protein family have been implicated in the activation of NF-kappaB by the tumour-necrosis factor (TNF)-receptor superfamily. Here we report the identification of a new TRAF family member, designated TRAF6. When overexpressed in human 293 cells, TRAF6 activates NF-kappaB. A dominant-negative mutant of TRAF6 inhibits NF-kappaB activation signalled by interleukin-1 (IL-1) but not by TNF. IL-1 treatment of 293 cells induces the association of TRAF6 with IRAK, a serine/threonine kinase that is rapidly recruited to the IL-1 receptor after IL-1 induction. These findings indicate that TRAF proteins may function as signal transducers for distinct receptor families and that TRAF6 participates in IL-1 signalling.

The complexity of p53 modulation: emerging patterns from divergent signals

Abstract: Functional inactivation of p53 by gene mutation and deletion, protein degradation, or viral oncogene binding renders a mammalian cell susceptible to oncogenic stimuli and environmental insults that promote growth deregulation and malignant progression. Although a variety of mechanisms have been proposed for how p53 protects cells against neoplastic transformation, it is becoming clear that p53 integrates signals from the cell’s internal and external environment to respond to inappropriate growth promoting or growth inhibiting conditions (for review, see Gottleib and Oren 1995; Ko and Prives 1996; Levine 1997). This ‘‘sensor’’ function of p53 makes it unusual in the tumor suppressor gene family. The list of stimuli that alter p53 activity is increasing and our understanding of the signal transduction pathways used to signal to p53 are starting to become elucidated. The predominant regulation of p53 occurs at the protein level. Mutations in p53 that affect its conformation typically increase its half-life, in part by inhibiting degradation by the ubiquitin complex (Maki et al. 1996; Haupt et al. 1997; Kubbutat et al. 1997; Midgley and Lane 1997), and the majority of human tumor mutations decrease the sequence-specific DNA binding and transcriptional activity of p53 protein (Cho et al. 1994). In unstressed cells, p53 appears to be present at low levels and exists in a latent, inactive form that requires modification to become active. The types of modification that p53 is subjected to seem to be stress-, speciesand celltype-specific. Levels and/or activity of p53 increase in response to DNA damaging agents (Maltzman and Czyzyk 1984; Kastan et al. 1991; Nelson and Kastan 1994), decreased oxygen (Graeber et al. 1994), oncogenic stimuli (Debbas and White 1993; Lowe and Ruley 1993; Hermeking and Eick 1994; Wanger et al. 1994; Serrano et al. 1997), cell adhesion (Nigro et al. 1997), altered ribonucleotide pools (Linke et al. 1996), and redox stress (Hainaut and Milner 1993a; Hupp et al. 1993). Although all of these stresses signal the activation of p53 protein, unique pathways appear to be utilized by the different stresses. Is p53 protein accumulation needed for p53 activation or are modifications necessary for p53 activation separable from the modifications required for p53 protein accumulation? Both the modifiers and the types of modification will be important to sort out to understand the relationship between accumulation and activation. Although the two appear to be separable (Chernov et al. 1998; Hupp et al. 1995), it is possible that both are essential for full tumor suppressor function. The importance of p53 and modifications that affect its functions are not limited to malignant disease. The activity of p53 can increase in normal tissues when undergoing pathophysiological changes that result in oxidative or redox stress, such as ischemia and reperfusion injury of the brain, heart, and other tissues. Thus both oxidative stress generated by hydrogen peroxide, as well as reducing stresses generated by the lack of oxygen, appear to be potent stimulators of p53 activity. In addition, the link between p53 function and the modulation of angiogenesis further implicates p53 pathways in the processes of wound healing (Antoniades et al. 1994) and ischemic injury responses (Banasiak and Haddad 1998). At present little is known about the pathways that control p53 activity in response to ischemia and reperfusion in normal tissues, and this area should be fertile ground for research in future years. In this review, we discuss what is known about how various stressors signal to p53 and the various mechanisms utilized to modulate p53 activity. Because of the focus on signaling to p53, we will not attempt to discuss the ‘‘downstream’’ physiologic effects of p53 activation such as cell-cycle perturbations or cell death.