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Bienz M.,Medical Research Council MRC Laboratory of Molecular Biology
Trends in Biochemical Sciences | Year: 2014

A key mechanism for guarding against inappropriate activation of signaling molecules is their weak affinity for effectors, which prevents them from undergoing accidental signal-transducing interactions due to fluctuations in their cellular concentration. The molecular devices that overcome these weak affinities are the signalosomes: dynamic clusters of transducing molecules assembled typically at signal-activated receptors. Signalosomes contain high local concentrations of protein-binding sites, and thus have a high avidity for their low-affinity ligands that generate signal responses. This review focuses on three domains - DIX (dishevelled and axin), PB1 (Phox and Bem1), and SAM (sterile alpha motif) - that undergo dynamic head-to-tail polymerization to assemble signalosomes and similar particles that require transient high local concentrations of protein-binding sites. © 2014 Elsevier Ltd. Source

Eberl G.,Institute Pasteur Paris | Colonna M.,University of Washington | Di Santo J.P.,French Institute of Health and Medical Research | McKenzie A.N.,Medical Research Council MRC Laboratory of Molecular Biology
Science (New York, N.Y.) | Year: 2015

Innate lymphoid cells (ILCs) are a growing family of immune cells that mirror the phenotypes and functions of T cells. However, in contrast to T cells, ILCs do not express acquired antigen receptors or undergo clonal selection and expansion when stimulated. Instead, ILCs react promptly to signals from infected or injured tissues and produce an array of secreted proteins termed cytokines that direct the developing immune response into one that is adapted to the original insult. The complex cross-talk between microenvironment, ILCs, and adaptive immunity remains to be fully deciphered. Only by understanding these complex regulatory networks can the power of ILCs be controlled or unleashed in order to regulate or enhance immune responses in disease prevention and therapy. Copyright © 2015, American Association for the Advancement of Science. Source

Zhang M.,University of California at San Diego | Zhang M.,Harvard University | Schafer W.R.,University of California at San Diego | Schafer W.R.,Medical Research Council MRC Laboratory of Molecular Biology | And 2 more authors.
BMC Systems Biology | Year: 2010

Background: Egg-laying behavior in the nematode C. elegans displays a distinct clustered temporal pattern: egg-laying events occur primarily in bursts or active phases, separated by inactive phases during which eggs are retained. The onset of the active phase can be modeled as a Poisson process with a time constant of approximately 20 minutes, while egg-laying events within an active phase occur with a faster time constant of approximately 20 seconds. Here we propose a cellular model for how the temporal pattern of egg-laying might be generated, based on genetic and cell-biological experiments and statistical analyses.Results: We suggest that the HSN neuron is the executive neuron driving egg-laying events. We propose that the VC neurons act as "single egg counters" that inhibit HSN activity for short periods in response to individual egg-laying events. We further propose that the uv1 neuroendocrine cells are "cluster counters", which inhibit HSN activity for longer periods and are responsible for the time constant of the inactive phase. Together they form an integrated circuit that drives the clustered egg-laying pattern.Conclusions: The detailed predictions derived from this model can now be tested by straightforward validation experiments. © 2010 Zhang et al; licensee BioMed Central Ltd. Source

Burke J.E.,University of Victoria | Williams R.L.,Medical Research Council MRC Laboratory of Molecular Biology
Trends in Biochemical Sciences | Year: 2015

•Input-selective mutations make apparent complex synergy in PI3K signaling.•Each class IA PI3K isoform has a different capacity to be activated by upstream inputs.•p110β is synergistically activated by inputs from RTKs, GPCRs, and Rac.•p110δ inhibitors may have broad utility in cancer therapies through immunomodulation.•Oncogenic mutations in PIK3CA and PIK3R1 promote growth through multiple mechanisms. The class I phosphoinositide 3-kinases (PI3Ks) are lipid kinases that transduce a host of cellular signals and regulate a broad range of essential functions including growth, proliferation, and migration. As such, PI3Ks have pivotal roles in diseases such as cancer, diabetes, primary immune disorders, and inflammation. These enzymes are activated downstream of numerous activating stimuli including receptor tyrosine kinases, G protein-coupled receptors (GPCRs), and the Ras superfamily of small G proteins. A major challenge is to decipher how each PI3K isoform is able to successfully synergize these inputs into their intended signaling function. This article highlights recent progress in characterizing the molecular mechanisms of PI3K isoform-specific activation pathways, as well as novel roles for PI3Ks in human diseases, specifically cancer and immune diseases. © 2014. Source

Scherrer T.,ETH Zurich | Mittal N.,Medical Research Council MRC Laboratory of Molecular Biology | Mittal N.,National Institute of Pharmaceutical Education and Research | Janga S.C.,Medical Research Council MRC Laboratory of Molecular Biology | Gerber A.P.,ETH Zurich
PLoS ONE | Year: 2010

Hundreds of RNA-binding proteins (RBPs) control diverse aspects of post-transcriptional gene regulation. To identify novel and unconventional RBPs, we probed high-density protein microarrays with fluorescently labeled RNA and selected 200 proteins that reproducibly interacted with different types of RNA from budding yeast Saccharomyces cerevisiae. Surprisingly, more than half of these proteins represent previously known enzymes, many of them acting in metabolism, providing opportunities to directly connect intermediary metabolism with posttranscriptional gene regulation. We mapped the RNA targets for 13 proteins identified in this screen and found that they were associated with distinct groups of mRNAs, some of them coding for functionally related proteins. We also found that overexpression of the enzyme Map1 negatively affects the expression of experimentally defined mRNA targets. Our results suggest that many proteins may associate with mRNAs and possibly control their fates, providing dense connections between different layers of cellular regulation. © 2010 Scherrer et al. Source

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