Journal articles: 'Two component signalling systems'

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Perraud, Anne-Laure, Verena Weiss, and Roy Gross. "Signalling pathways in two-component phosphorelay systems." Trends in Microbiology 7, no. 3 (March 1999): 115–20. http://dx.doi.org/10.1016/s0966-842x(99)01458-4.

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Macielag, Mark J., and Raul Goldschmidt. "Inhibitors of bacterial two-component signalling systems." Expert Opinion on Investigational Drugs 9, no. 10 (October 2000): 2351–69. http://dx.doi.org/10.1517/13543784.9.10.2351.

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Pawelczyk, Sonja, Kathryn A. Scott, Rebecca Hamer, Gareth Blades, Charlotte M. Deane, and George H. Wadhams. "Predicting Inter-Species Cross-Talk in Two-Component Signalling Systems." PLoS ONE 7, no. 5 (May 22, 2012): e37737. http://dx.doi.org/10.1371/journal.pone.0037737.

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Jacob-Dubuisson, Françoise, Ariel Mechaly, Jean-Michel Betton, and Rudy Antoine. "Structural insights into the signalling mechanisms of two-component systems." Nature Reviews Microbiology 16, no. 10 (July 15, 2018): 585–93. http://dx.doi.org/10.1038/s41579-018-0055-7.

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Puthiyaveetil, Sujith, and John F. Allen. "Chloroplast two-component systems: evolution of the link between photosynthesis and gene expression." Proceedings of the Royal Society B: Biological Sciences 276, no. 1665 (February 25, 2009): 2133–45. http://dx.doi.org/10.1098/rspb.2008.1426.

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Two-component signal transduction, consisting of sensor kinases and response regulators, is the predominant signalling mechanism in bacteria. This signalling system originated in prokaryotes and has spread throughout the eukaryotic domain of life through endosymbiotic, lateral gene transfer from the bacterial ancestors and early evolutionary precursors of eukaryotic, cytoplasmic, bioenergetic organelles—chloroplasts and mitochondria. Until recently, it was thought that two-component systems inherited from an ancestral cyanobacterial symbiont are no longer present in chloroplasts. Recent research now shows that two-component systems have survived in chloroplasts as products of both chloroplast and nuclear genes. Comparative genomic analysis of photosynthetic eukaryotes shows a lineage-specific distribution of chloroplast two-component systems. The components and the systems they comprise have homologues in extant cyanobacterial lineages, indicating their ancient cyanobacterial origin. Sequence and functional characteristics of chloroplast two-component systems point to their fundamental role in linking photosynthesis with gene expression. We propose that two-component systems provide a coupling between photosynthesis and gene expression that serves to retain genes in chloroplasts, thus providing the basis of cytoplasmic, non-Mendelian inheritance of plastid-associated characters. We discuss the role of this coupling in the chronobiology of cells and in the dialogue between nuclear and cytoplasmic genetic systems.

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Steel, Harrison, Aivar Sootla, Benjamin Smart, Nicolas Delalez, and Antonis Papachristodoulou. "Improving Orthogonality in Two-Component Biological Signalling Systems Using Feedback Control." IEEE Control Systems Letters 3, no. 2 (April 2019): 326–31. http://dx.doi.org/10.1109/lcsys.2018.2871663.

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Kothamachu, Varun B., Elisenda Feliu, Luca Cardelli, and Orkun S. Soyer. "Unlimited multistability and Boolean logic in microbial signalling." Journal of The Royal Society Interface 12, no. 108 (July 2015): 20150234. http://dx.doi.org/10.1098/rsif.2015.0234.

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The ability to map environmental signals onto distinct internal physiological states or programmes is critical for single-celled microbes. A crucial systems dynamics feature underpinning such ability is multistability. While unlimited multistability is known to arise from multi-site phosphorylation seen in the signalling networks of eukaryotic cells, a similarly universal mechanism has not been identified in microbial signalling systems. These systems are generally known as two-component systems comprising histidine kinase (HK) receptors and response regulator proteins engaging in phosphotransfer reactions. We develop a mathematical framework for analysing microbial systems with multi-domain HK receptors known as hybrid and unorthodox HKs. We show that these systems embed a simple core network that exhibits multistability, thereby unveiling a novel biochemical mechanism for multistability. We further prove that sharing of downstream components allows a system with n multi-domain hybrid HKs to attain 3 n steady states. We find that such systems, when sensing distinct signals, can readily implement Boolean logic functions on these signals. Using two experimentally studied examples of two-component systems implementing hybrid HKs, we show that bistability and implementation of logic functions are possible under biologically feasible reaction rates. Furthermore, we show that all sequenced microbial genomes contain significant numbers of hybrid and unorthodox HKs, and some genomes have a larger fraction of these proteins compared with regular HKs. Microbial cells are thus theoretically unbounded in mapping distinct environmental signals onto distinct physiological states and perform complex computations on them. These findings facilitate the understanding of natural two-component systems and allow their engineering through synthetic biology.

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Agrawal, Ruchi, Akancha Pandey, Mayooreshwar P. Rajankar, Narendra M. Dixit, and Deepak K. Saini. "The two-component signalling networks of Mycobacterium tuberculosis display extensive cross-talk in vitro." Biochemical Journal 469, no. 1 (June 19, 2015): 121–34. http://dx.doi.org/10.1042/bj20150268.

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Bacteria use two-component signalling systems (TCSs) to sense and respond to environmental changes. Currently, they are thought to be highly specific, with each TCS functioning independently. Here, unlike the prevalent paradigm, we show that the TCSs of M. tuberculosis cross-talk extensively, thereby proposing an alternative signalling scenario.

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Forsberg, J., M. Rosenquist, L. Fraysse, and J. F. Allen. "Redox signalling in chloroplasts and mitochondria: genomic and biochemical evidence for two-component regulatory systems in bioenergetic organelles." Biochemical Society Transactions 29, no. 4 (August 1, 2001): 403–7. http://dx.doi.org/10.1042/bst0290403.

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Redox chemistry is central to the primary functions of chloroplasts and mitochondria, that is, to energy conversion in photosynthesis and respiration. However, these bioenergetic organelles always contain very small, specialized genetic systems, relics of their bacterial origin. At huge cost, organellar genomes contain, typically, a mere 0.1 % of the genetic information in a eukaryotic cell. There is evidence that chloroplast and mitochondrial genomes encode proteins whose function and biogenesis are particularly tightly governed by electron transfer. We have identified nuclear genes for ‘bacterial’ histidine sensor kinases and aspartate response regulators that seem to be targeted to chloroplast and mitochondrial membranes. Sequence similarities to cyano-bacterial redox signalling components indicate homology and suggest conserved sensory and signalling functions. Two-component redox signalling pathways might be ancient, conserved mechanisms that permit endogenous control over the biogenesis, in situ, of bioenergetic complexes of chloroplasts and mitochondria.

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Rodrigue, Agnès, Yves Quentin, Andrée Lazdunski, Vincent Méjean, and Maryline Foglino. "Cell signalling by oligosaccharides. Two-component systems in Pseudomonas aeruginosa: why so many?" Trends in Microbiology 8, no. 11 (November 2000): 498–504. http://dx.doi.org/10.1016/s0966-842x(00)01833-3.

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Krueger, Beate, Torben Friedrich, Frank Förster, Jörg Bernhardt, Roy Gross, and Thomas Dandekar. "Different Evolutionary Modifications as a Guide to Rewire Two-Component Systems." Bioinformatics and Biology Insights 6 (January 2012): BBI.S9356. http://dx.doi.org/10.4137/bbi.s9356.

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Two-component systems (TCS) are short signalling pathways generally occurring in prokaryotes. They frequently regulate prokaryotic stimulus responses and thus are also of interest for engineering in biotechnology and synthetic biology. The aim of this study is to better understand and describe rewiring of TCS while investigating different evolutionary scenarios. Based on large-scale screens of TCS in different organisms, this study gives detailed data, concrete alignments, and structure analysis on three general modification scenarios, where TCS were rewired for new responses and functions: (i) exchanges in the sequence within single TCS domains, (ii) exchange of whole TCS domains; (iii) addition of new components modulating TCS function. As a result, the replacement of stimulus and promotor cassettes to rewire TCS is well defined exploiting the alignments given here. The diverged TCS examples are non-trivial and the design is challenging. Designed connector proteins may also be useful to modify TCS in selected cases.

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Wang, Baojun, Mauricio Barahona, Martin Buck, and Jörg Schumacher. "Rewiring cell signalling through chimaeric regulatory protein engineering." Biochemical Society Transactions 41, no. 5 (September 23, 2013): 1195–200. http://dx.doi.org/10.1042/bst20130138.

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Bacterial cells continuously sense and respond to their environment using their inherent signalling and gene regulatory networks. Cells are equipped with parallel signalling pathways, which can specifically cope with individual input signals, while interconnectivities between pathways lead to an enhanced complexity of regulatory responses that enable sophisticated adaptation. In principle, any cell signalling pathway may be rewired to respond to non-cognate signals by exchanging and recombining their underlying cognate signalling components. In the present article, we review the engineering strategies and use of chimaeric regulatory proteins in cell signalling pathways, especially the TCS (two-component signalling) system in bacteria, to achieve novel customized signalling or regulatory functions. We envisage that engineered chimaeric regulatory proteins can play an important role to aid both forward and reverse engineering of biological systems for many desired applications.

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Garg, Abhishek, Nimisha Khurana, Ananya Chugh, Kangna Verma, and Vandana Malhotra. "In silico evidence for extensive Ser/Thr phosphorylation of Mycobacterium tuberculosis two-component signalling systems." Current Science 123, no. 9 (November 10, 2022): 1164. http://dx.doi.org/10.18520/cs/v123/i9/1164-1169.

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Marchadier, Elodie, and Alistair M. Hetherington. "Involvement of two-component signalling systems in the regulation of stomatal aperture by light inArabidopsis thaliana." New Phytologist 203, no. 2 (April 24, 2014): 462–68. http://dx.doi.org/10.1111/nph.12813.

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Liu, Junli, Keith Lindsey, and Patrick J. Hussey. "Elucidating the regulation of complex signalling systems in plant cells." Biochemical Society Transactions 42, no. 1 (January 23, 2014): 219–23. http://dx.doi.org/10.1042/bst20130090.

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The pollen tube represents a model system for the study of tip growth, and the root provides a valuable system to study gene and signalling networks in plants. In the present article, using the two systems as examples, we discuss how to elucidate the regulation of complex signalling systems in plant cells. First, we discuss how hormones and related genes in plant root development form a complex interacting network, and their activities are interdependent. Therefore their roles in root development must be analysed as an integrated system, and elucidation of the regulation of each component requires the adaptation of a novel modelling methodology: regulation analysis. Secondly, hydrodynamics, cell wall and ion dynamics are all important properties that regulate plant cell growth. We discuss how regulation analysis can be applied to study the regulation of hydrodynamics, cell wall and ion dynamics, using pollen tube growth as a model system. Finally, we discuss future prospects for elucidating the regulation of complex signalling systems in plant cells.

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Brynildsen, M. P., W. W. Wong, and J. C. Liao. "Transcriptional regulation and metabolism." Biochemical Society Transactions 33, no. 6 (October 26, 2005): 1423–26. http://dx.doi.org/10.1042/bst0331423.

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Understanding organisms from a systems perspective is essential for predicting cellular behaviour as well as designing gene-metabolic circuits for novel functions. The structure, dynamics and interactions of cellular networks are all vital components of systems biology. To facilitate investigation of these aspects, we have developed an integrative technique called network component analysis, which utilizes mRNA expression and transcriptional network connectivity to determine network component dynamics, functions and interactions. This approach has been applied to elucidate transcription factor dynamics in Saccharomyces cerevisiae cell-cycle regulation, detect cross-talks in Escherichia coli two-component signalling pathways, and characterize E. coli carbon source transition. An ultimate test of system-wide understanding is the ability to design and construct novel gene-metabolic circuits. To this end, artificial feedback regulation, cell–cell communication and oscillatory circuits have been constructed, which demonstrate the design principles of gene-metabolic regulation in the cell.

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Larrieu, Antoine, and Teva Vernoux. "Comparison of plant hormone signalling systems." Essays in Biochemistry 58 (September 15, 2015): 165–81. http://dx.doi.org/10.1042/bse0580165.

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Plant growth and development are controlled by nine structurally distinct small molecules termed phytohormones. Over the last 20 years, the molecular basis of their signal transduction, from receptors to transcription factors, has been dissected using mainly Arabidopsis thaliana and rice as model systems. Phytohormones can be broadly classified into two distinct groups on the basis of whether the subcellular localization of their receptors is in the cytoplasm or nucleus, and hence soluble, or membrane-bound, and hence insoluble. Soluble receptors, which control the responses to auxin, jasmonates, gibberellins, strigolactones and salicylic acid, signal either directly or indirectly via the destruction of regulatory proteins. Responses to abscisic acid are primarily mediated by soluble receptors that indirectly regulate the phosphorylation of targeted proteins. Insoluble receptors, which control the responses to cytokinins, brassinosteroids and ethylene, transduce their signal through protein phosphorylation. This chapter provides a comparison of the different components of these signalling systems, and discusses the similarities and differences between them.

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Forsberg, J., M. Rosenquist, L. Fraysse, and J. F. Allen. "Redox signalling in chloroplasts and mitochondria: genomic and biochemical evidence for two-component regulatory systems in bioenergetic organelles." Biochemical Society Transactions 29, no. 3 (June 1, 2001): A49. http://dx.doi.org/10.1042/bst029a049b.

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PHALIP, Vincent, Jian-Hong LI, and Cheng-Cai ZHANG. "HstK, a cyanobacterial protein with both a serine/threonine kinase domain and a histidine kinase domain: implication for the mechanism of signal transduction." Biochemical Journal 360, no. 3 (December 10, 2001): 639–44. http://dx.doi.org/10.1042/bj3600639.

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Two distinct families of protein kinases are involved in signal transduction: Ser, Thr and Tyr kinases, which are predominantly found among eukaryotes, and His kinases, as part of bacterial two-component signalling systems. Genetic studies in Arabidopsis and Saccharomyces have demonstrated that bacterial-type two-component systems may act upstream of Ser/Thr kinases in the same signalling pathway, but how this coupling is accomplished remains unclear. In the present study, we report the characterization of a protein kinase, HstK, from the N2-fixing cyanobacterium Anabaena sp. PCC 7120, that possesses both a Ser/Thr kinase domain and a His kinase domain. Proteins with a structural architecture similar to that of HstK can be found in the eukaryote, Schizosaccharomyces pombe, and the bacterium, Rhodococcus sp. M5. HstK was present in cells grown with NH4+ or N2 as the nitrogen source, but was absent in cells grown with NO3−. The hstK gene was inactivated and the mutant phenotype was characterized. The catalytic domain of the Ser/Thr kinase of HstK functionally replaced that of Hog1p, a well-characterized protein kinase required for the response to high osmolarity in the S. cerevisiae heterologous system. The unusual multidomain structure of HstK suggests that a two-component system could be directly coupled to Ser/Thr kinases in the same signal transduction pathway.

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Attwood, Paul V. "Histidine kinases from bacteria to humans." Biochemical Society Transactions 41, no. 4 (July 18, 2013): 1023–28. http://dx.doi.org/10.1042/bst20130019.

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It is more than 50 years since protein histidine phosphorylation was first discovered in 1962 by Boyer and co-workers; however, histidine kinases are still much less well recognized than the serine/threonine and tyrosine kinases. The best-known histidine kinases are the two-component signalling kinases that occur in bacteria, fungi and plants. The mechanisms and functions of these kinases, their cognate response regulators and associated phosphorelay proteins are becoming increasingly well understood. When genomes of higher eukaryotes began to be sequenced, it did not appear that they contained two-component histidine kinase system homologues, apart from a couple of related mitochondrial enzymes that were later shown not to function as histidine kinases. However, as a result of the burgeoning sequencing of genomes from a wide variety of eukaryotic organisms, it is clear that there are proteins that correspond to components of the two-component histidine kinase systems in higher eukaryotes and that operational two-component kinase systems are likely to occur in these organisms. There is unequivocal direct evidence that protein histidine phosphorylation does occur in mammals. So far, only nucleoside diphosphate kinases have been shown to be involved in protein histidine phosphorylation, but their mechanisms of action are not well understood. It is clear that other, yet to be identified, histidine kinases also exist in mammals and that protein histidine phosphorylation may play important roles in higher eukaryotes.

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Somers, David E. "Clock-associated genes in Arabidopsis : a family affair." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 356, no. 1415 (November 29, 2001): 1745–53. http://dx.doi.org/10.1098/rstb.2001.0965.

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The identification of components of the plant circadian clock has been advanced recently with the success of two forward genetics approaches. The ZEITLUPE and TOC1 loci were cloned and each was found to be part of two separate, larger gene families with intriguing domain structures. The ZTL family of proteins contains a subclass of the PAS domain coupled to an F box and kelch motifs, suggesting that they play a role in a novel light–regulated ubiquitination mechanism. TOC1 shares similarity to the receiver domain of the well–known two–component phosphorelay signalling systems, combined with a strong similarity to a region of the CONSTANS transcription factor, which is involved in controlling flowering time. When added to the repertoire of previously identified clock–associated genes, it is clear that both similarities and differences with other circadian systems will emerge in the coming years.

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Henner, D. J., M. Yang, and E. Ferrari. "Localization of Bacillus subtilis sacU(Hy) mutations to two linked genes with similarities to the conserved procaryotic family of two-component signalling systems." Journal of Bacteriology 170, no. 11 (1988): 5102–9. http://dx.doi.org/10.1128/jb.170.11.5102-5109.1988.

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Bolanos-Garcia, Victor M., Qian Wu, Takashi Ochi, Dimitri Y. Chirgadze, Bancinyane Lynn Sibanda, and Tom L. Blundell. "Spatial and temporal organization of multi-protein assemblies: achieving sensitive control in information-rich cell-regulatory systems." Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences 370, no. 1969 (June 28, 2012): 3023–39. http://dx.doi.org/10.1098/rsta.2011.0268.

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The regulation of cellular processes in living organisms requires signalling systems that have a high signal-to-noise ratio. This is usually achieved by transient, multi-protein complexes that assemble cooperatively. Even in the crowded environment of the cell, such assemblies are unlikely to form by chance, thereby providing a sensitive regulation of cellular processes. Furthermore, selectivity and sensitivity may be achieved by the requirement for concerted folding and binding of previously unfolded components. We illustrate these features by focusing on two essential signalling pathways of eukaryotic cells: first, the monitoring and repair of DNA damage by non-homologous end joining, and second, the mitotic spindle assembly checkpoint, which detects and corrects defective attachments of chromosomes to the kinetochore. We show that multi-protein assemblies moderate the full range of functional complexity and diversity in the two signalling systems. Deciphering the nature of the interactions is central to understanding the mechanisms that control the flow of information in cell signalling and regulation.

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Dower, S. K., and E. E. Qwarnstrom. "Signalling networks, inflammation and innate immunity." Biochemical Society Transactions 31, no. 6 (December 1, 2003): 1462–71. http://dx.doi.org/10.1042/bst0311462.

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We have been analysing the signalling systems that couple to receptors of the TIR (Toll/interleukin-1 receptor) family, which signal through a common cytoplasm region; the TIR domain. These systems are of both practical and fundamental biological significance, being central to the pathogenesis of chronic inflammatory diseases such as atherosclerosis, to host defence throughout the biological world, and are ancient in the context of life on earth, having originated more than 1 billion years ago: prior to the divergence of plants and animals. TIR domain receptors couple to at least two sets of well-characterized pathways: those leading to the activation of inhibitory κB kinase complexes/nuclear factor κB, and those leading to the activation of mitogen-activated protein kinase/AP-1/ATF-2 etc. We have been investigating these systems using a combination of expression screening methods to identify new components, and real-time green fluorescent protein-based techniques to observe execution of signalling programmes in real time. Our data reveal that there is a very large level of cell-to-cell variation in signal programme execution even in clonal populations and that at least one mechanism for dealing with this heterogeneity is the assembly of signal transduction components into large multiprotein complexes.

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Shrivastava, Rashmi, Ananta Kumar Ghosh, and Amit Kumar Das. "Intra- and intermolecular domain interactions among novel two-component system proteins coded by Rv0600c, Rv0601c and Rv0602c of Mycobacterium tuberculosis." Microbiology 155, no. 3 (March 1, 2009): 772–79. http://dx.doi.org/10.1099/mic.0.019059-0.

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Two-component signal transduction pathways comprising a histidine kinase and its cognate response regulator play a dominant role in the adaptation of Mycobacterium tuberculosis to its host, and its virulence, pathogenicity and latency. Autophosphorylation occurs at a conserved histidine of the histidine kinase and subsequently the phosphoryl group is transferred to the conserved aspartate of its cognate response regulator. Among the twelve two-component systems of M. tuberculosis, Rv0600c (HK1), Rv0601c (HK2) and Rv0602c (TcrA) are annotated as a unique three-protein two-component system. HK1 contains an ATP-binding domain, and HK2, a novel Hpt mono-domain protein, contains the conserved phosphorylable histidine residue. HK1 and HK2 complement each other's functions. Interactions among different domains of the HK1, HK2 and TcrA proteins were studied using a yeast two-hybrid system. Self-interaction was observed for HK2 but not for HK1 or TcrA. HK2 was found to interact reasonably well with both HK1 and TcrA, but HK1 interacted weakly with TcrA. The conserved aspartate-containing receiver domain of TcrA interacted well with HK2 but not with HK1. These results suggest the existence of a novel signalling mechanism amongst HK1–HK2–TcrA, and a model for this mechanism is proposed.

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Bowman, W. C. "Second messenger systems as sites of drug action." Proceedings of the Royal Society of Edinburgh. Section B. Biological Sciences 99, no. 1-2 (1992): 1–17. http://dx.doi.org/10.1017/s0269727000013002.

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Synopsis:Transmembrane signalling from cell surface receptors occurs by two broad mechanisms: (i) the rapid (ms) direct opening of an ion channel, where the ion channel is a component of the receptor complex (e.g. the nicotinic acetylcholine receptor); and (ii) the more slow (s) modulation of a membrane enzyme or more distant ion channel. Most of the examples of this second mechanism involve a GTP-binding protein or so–called G-protein, and the production of a second messenger. The production of nitric oxide is a special case in that it is eventually produced as a result of the activity of the second messenger ïnositol trisphosphate. The nitric oxide then diffuses into a second cell to give rise to the production of an additional ‘second’ messenger, cyclic GMP.All of the surface receptors themselves exist as a number of subtypes. Additionally, most of the components of the second messenger systems – G-proteins, adenylyl cyclase, guanylyl cyclase, phosphoinositidase, C, inositol trisphosphate receptors, protein kinase A, protein kinase G, protein kinase C, cyclic nucleotide phosphodiesterases, and the enzymes involved in phosphatidylinositol resynthesis – occur in a number of isoforms. Furthermore, all the enzymes are controlled in their activity by a number of co-factors and other modulators. This diversity provides the potential for selective drug action, a potential which is already being exploited and which will be increasingly so in the near future.

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Berridge, Michael J. "Vitamin D: a custodian of cell signalling stability in health and disease." Biochemical Society Transactions 43, no. 3 (June 1, 2015): 349–58. http://dx.doi.org/10.1042/bst20140279.

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There is increasing evidence that a deficiency in vitamin D contributes to many human diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), hypertension and cardiovascular disease. The ability of vitamin D to maintain healthy cells seems to depend on its role as a guardian of phenotypic stability particularly with regard to the reactive oxygen species (ROS) and Ca2+ signalling systems. Vitamin D maintains the expression of those signalling components responsible for stabilizing the low-resting state of these two signalling pathways. This vitamin D signalling stability hypothesis proposes that vitamin D, working in conjunction with klotho and Nrf2 (nuclear factor-erythroid-2-related factor 2), acts as a custodian to maintain the normal function of the ROS and Ca2+ signalling pathways. A decline in vitamin D levels will lead to an erosion of this signalling stability and may account for why so many of the major diseases in man, which have been linked to vitamin D deficiency, are associated with a dysregulation in both ROS and Ca2+ signalling.

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Ahmed, Zamal, Annika C. Schüller, Klaus Suhling, Carolyn Tregidgo, and John E. Ladbury. "Extracellular point mutations in FGFR2 elicit unexpected changes in intracellular signalling." Biochemical Journal 413, no. 1 (June 12, 2008): 37–49. http://dx.doi.org/10.1042/bj20071594.

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An understanding of cellular signalling from a systems-based approach has to be robust to assess the effects of point mutations in component proteins. Outcomes of these perturbations should be predictable in terms of downstream response, otherwise a holistic interpretation of biological processes or disease states cannot be obtained. Two single, proximal point mutations (S252W and P253R) in the extracellular region of FGFR2 (fibroblast growth factor receptor 2) prolong growth factor engagement resulting in dramatically different intracellular phenotypes. Following ligand stimulation, the wild-type receptor undergoes rapid endocytosis into lysosomes, whereas SWFGFR2 (the S252W FGFR2 point mutation) and PRFGFR2 (the P253R FGFR2 point mutation) remain on the cell membrane for an extended period of time, modifying protein recruitment and elevating downstream ERK (extracellular-signal-regulated kinase) phosphorylation. FLIM (fluorescent lifetime imaging microscopy) reveals that direct interaction of FRS2 (FGFR substrate 2) with wild-type receptor occurs primarily at the vesicular membrane, whereas the interaction with the P253R receptor occurs exclusively at the plasma membrane. These observations suggest that the altered FRS2 recruitment by the mutant receptors results in an abnormal cellular signalling mechanism. In the present study these profound intracellular phenotypes resulting from extracellular receptor modification reveal a new level of complexity which will challenge a systems biology interpretation.

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Reading, Nicola C., David Rasko, Alfredo G. Torres, and Vanessa Sperandio. "A transcriptome study of the QseEF two-component system and the QseG membrane protein in enterohaemorrhagic Escherichia coli O157 : H7." Microbiology 156, no. 4 (April 1, 2010): 1167–75. http://dx.doi.org/10.1099/mic.0.033027-0.

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QseE is a sensor kinase that responds to epinephrine, sulfate and phosphate. QseE constitutes a two-component signalling system together with the QseF σ 54-dependent response regulator. Encoded within the same operon as qseEF is the qseG gene, which encodes a membrane protein involved in the translocation of a type III secretion effector protein of enterohaemorrhagic Escherichia coli (EHEC) into epithelial cells. The qseEGF genes also form an operon with the glnB gene, which encodes the E. coli nitrogen sensor PII protein. Here we report a transcriptome analysis comparing qseE, qseF andqseG single mutants with the wild-type strain. This study revealed that the proteins encoded by these genes play a modest but significant role in iron uptake. Although QseEFG regulate genes involved in nitrogen utilization, these proteins do not play a notable role in nitrogen metabolism. In addition, QseEFG regulate transcription of the rcsBC and phoPQ two-component systems, linking several signal transduction pathways. The similarity of the microarray profiles of these mutants also indicates that these proteins work together. These data indicate that QseEFG are involved in the regulation of virulence and metabolism in EHEC.

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Taff, Conor C., Gail L. Patricelli, and Corey R. Freeman-Gallant. "Fluctuations in neighbourhood fertility generate variable signalling effort." Proceedings of the Royal Society B: Biological Sciences 281, no. 1796 (December 7, 2014): 20141974. http://dx.doi.org/10.1098/rspb.2014.1974.

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Studies of sexual signalling generally focus on interactions between dyadic pairs, yet communication in natural populations often occurs in the context of complex social networks. The ability to survey social environments and adjust signal production appropriately should be a critical component of success in these systems, but has rarely been documented empirically. Here, we used autonomous recording devices to identify 118 472 songs produced by 26 male common yellowthroats ( Geothlypis trichas ) over two breeding seasons, coupled with detailed surveys of social conditions on each territory. We found strong evidence that common yellowthroat males adjusted their total song production in response to both changes in within-pair social context and changes in the fertility of neighbouring females up to 400 m away. Within the social pair, males drastically reduced their song production when mated, but the magnitude of this reduction depended on both the time of day and on the fertility status of the social mate. By contrast, when fertile females were present on nearby territories, males increased their song output, especially during daytime singing. At this time, it is unclear whether males actively gathered information on neighbouring female fertility or whether the patterns that we observed were driven by changes in social interactions that varied with neighbourhood fertility. Regardless of the mechanism employed, however, subtle changes in the social environment generated substantial variation in signalling effort.

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Csikász-Nagy, Attila, Luca Cardelli, and Orkun S. Soyer. "Response dynamics of phosphorelays suggest their potential utility in cell signalling." Journal of The Royal Society Interface 8, no. 57 (August 11, 2010): 480–88. http://dx.doi.org/10.1098/rsif.2010.0336.

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Phosphorelays are extended two-component signalling systems found in diverse bacteria, lower eukaryotes and plants. Only few of these systems are characterized, and we still lack a full understanding of their signalling abilities. Here, we aim to achieve a global understanding of phosphorelay signalling and its dynamical properties. We develop a generic model, allowing us to systematically analyse response dynamics under different assumptions. Using this model, we find that the steady-state concentration of phosphorylated protein at the final layer of a phosphorelay is a linearly increasing, but eventually saturating function of the input. In contrast, the intermediate layers can display ultrasensitivity. We find that such ultrasensitivity is a direct result of the phosphorelay biochemistry; shuttling of a single phosphate group from the first to the last layer. The response dynamics of the phosphorelay results in tolerance of cross-talk, especially when it occurs as cross-deactivation. Further, it leads to a high signal-to-noise ratio for the final layer. We find that a relay length of four, which is most commonly observed, acts as a saturating point for these dynamic properties. These findings suggest that phosphorelays could act as a mechanism to reduce noise and effects of cross-talk on the final layer of the relay and enforce its input–response relation to be linear. In addition, our analysis suggests that middle layers of phosphorelays could embed thresholds. We discuss the consequence of these findings in relation to why cells might use phosphorelays along with enzymatic kinase cascades.

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Aier, Imlimaong, and Pritish K. Varadwaj. "Understanding the Mechanism of Cell Death in Gemcitabine Resistant Pancreatic Ductal Adenocarcinoma: A Systems Biology Approach." Current Genomics 20, no. 7 (January 1, 2020): 483–90. http://dx.doi.org/10.2174/1389202920666191025102726.

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Background: Gemcitabine is the standard chemotherapeutic drug administered in advanced Pancreatic Ductal Adenocarcinoma (PDAC). However, due to drug resistance in PDAC patients, this treatment has become less effective. Over the years, clinical trials for the quest of finding novel compounds that can be used in combination with gemcitabine have met very little success. Objective: To predict the driving factors behind pancreatic ductal adenocarcinoma, and to understand the effect of these components in the progression of the disease and their contribution to cell growth and proliferation. Methods: With the help of systems biology approaches and using gene expression data, which is generally found in abundance, dysregulated elements in key signalling pathways were predicted. Prominent dysregulated elements were integrated into a model to simulate and study the effect of gemcitabine- induced hypoxia. Results: In this study, several transcription factors in the form of key drivers of cancer-related genes were predicted with the help of CARNIVAL, and the effect of gemcitabine-induced hypoxia on the apoptosis pathway was shown to have an effect on the downstream elements of two primary pathway models; EGF/VEGF and TNF signalling pathway. Conclusion: It was observed that EGF/VEGF signalling pathway played a major role in inducing drug resistance through cell growth, proliferation, and avoiding cell death. Targeting the major upstream components of this pathway could potentially lead to successful treatment.

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Sim, Jee-Hyun, Wenyuan Shi, and Renate Lux. "Protein–protein interactions in the chemotaxis signalling pathway of Treponema denticola." Microbiology 151, no. 6 (June 1, 2005): 1801–7. http://dx.doi.org/10.1099/mic.0.27622-0.

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Motile bacteria employ sophisticated chemotaxis signal transduction systems to transform environmental cues into corresponding behavioural responses. The proteins involved in this signalling pathway have been extensively studied on a molecular level in various model organisms, including enterobacteria and Bacillus subtilis, and specific protein–protein interactions have been identified. The chemotaxis operon of spirochaetes encodes a novel chemotaxis protein, CheX, in addition to homologues to the central components of established chemotaxis systems. Interestingly, the closest functionally characterized homologue of CheX is CheC of the complex B. subtilis chemotaxis pathway. In this study, the yeast two-hybrid system was applied to investigate protein–protein interactions within the chemotaxis signalling pathway of Treponema denticola, with special focus on CheX. CheX was found to interact with CheA and with itself. The other chemotaxis proteins exhibited interactions comparable to their homologues in known chemotaxis systems. Based on these findings, a model integrating CheX in the chemotaxis signal transduction pathway of T. denticola is proposed.

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De Maeyer, K., J. D'aes, G. K. H. Hua, M. Perneel, L. Vanhaecke, H. Noppe, and M. Höfte. "N-Acylhomoserine lactone quorum-sensing signalling in antagonistic phenazine-producing Pseudomonas isolates from the red cocoyam rhizosphere." Microbiology 157, no. 2 (February 1, 2011): 459–72. http://dx.doi.org/10.1099/mic.0.043125-0.

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Forty fluorescent Pseudomonas strains isolated from white and red cocoyam roots were tested for their ability to synthesize N-acyl-l-homoserine lactones (acyl-HSLs). Remarkably, only isolates from the red cocoyam rhizosphere that were antagonistic against the cocoyam root rot pathogen Pythium myriotylum and synthesized phenazine antibiotics produced acyl-HSLs. This supports the assumption that acyl-HSL production is related to the antagonistic activity of the strains. After detection, the signal molecules were identified through TLC-overlay and liquid chromatography-multiple MS (LC-MS/MS) analysis. In our representative strain, Pseudomonas CMR12a, production of the signal molecules could be assigned to two quorum-sensing (QS) systems. The first one is the QS system for phenazine production, PhzI/PhzR, which seemed to be well conserved, since it was genetically organized in the same way as in the well-described phenazine-producing Pseudomonas strains Pseudomonas fluorescens 2-79, Pseudomonas chlororaphis PCL1391 and Pseudomonas aureofaciens 30-84. The newly characterized genes cmrI and cmrR make up the second QS system of CMR12a, under the control of the uncommon N-3-hydroxy-dodecanoyl-homoserine lactone (3-OH-C12-HSL) and with low similarity to other Pseudomonas QS systems. No clear function could yet be assigned to the CmrI/CmrR system, although it contributes to the biocontrol capability of CMR12a. Both the PhzI/PhzR and CmrI/CmrR systems are controlled by the GacS/GacA two-component regulatory system.

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Puthiyaveetil, Sujith, Iskander M. Ibrahim, and John F. Allen. "Evolutionary rewiring: a modified prokaryotic gene-regulatory pathway in chloroplasts." Philosophical Transactions of the Royal Society B: Biological Sciences 368, no. 1622 (July 19, 2013): 20120260. http://dx.doi.org/10.1098/rstb.2012.0260.

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Photosynthetic electron transport regulates chloroplast gene transcription through the action of a bacterial-type sensor kinase known as chloroplast sensor kinase (CSK). CSK represses photosystem I (PS I) gene transcription in PS I light and thus initiates photosystem stoichiometry adjustment. In cyanobacteria and in non-green algae, CSK homologues co-exist with their response regulator partners in canonical bacterial two-component systems. In green algae and plants, however, no response regulator partner of CSK is found. Yeast two-hybrid analysis has revealed interaction of CSK with sigma factor 1 (SIG1) of chloroplast RNA polymerase. Here we present further evidence for the interaction between CSK and SIG1. We also show that CSK interacts with quinone. Arabidopsis SIG1 becomes phosphorylated in PS I light, which then specifically represses transcription of PS I genes. In view of the identical signalling properties of CSK and SIG1 and of their interactions, we suggest that CSK is a SIG1 kinase. We propose that the selective repression of PS I genes arises from the operation of a gene-regulatory phosphoswitch in SIG1. The CSK-SIG1 system represents a novel, rewired chloroplast-signalling pathway created by evolutionary tinkering. This regulatory system supports a proposal for the selection pressure behind the evolutionary stasis of chloroplast genes.

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Zhai, Ya-Jun, Hua-Run Sun, Xing-Wei Luo, Jian-Hua Liu, Yu-Shan Pan, Hua Wu, Li Yuan, Jun Liang, Dan-Dan He, and Gong-Zheng Hu. "CpxR regulates the colistin susceptibility of Salmonella Typhimurium by a multitarget mechanism." Journal of Antimicrobial Chemotherapy 75, no. 10 (July 4, 2020): 2780–86. http://dx.doi.org/10.1093/jac/dkaa233.

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Abstract Background The two-component signalling systems PmrAB and PhoPQ of Salmonella have been extensively studied with regard to colistin resistance. We previously showed that overexpressed CpxR could significantly increase the colistin susceptibility (16-fold compared with the WT strain) of Salmonella enterica serovar Typhimurium (Salmonella Typhimurium) through PmrAB and PhoPQ. Objectives To identify the potential target genes of CpxR in PmrAB- and PhoPQ-related signalling pathways. Methods His6-CpxR was prokaryotically expressed and purified by Ni-NTA resin affinity chromatography. β-Galactosidase activity assays were conducted to investigate whether CpxR could regulate the promoters of colistin resistance-related genes (CRRGs). Electrophoretic mobility shift assays (EMSAs) were used to further detect His6-CpxR complexes with promoters of CRRGs. Results We demonstrated for the first time (to the best of our knowledge) that CpxR and the AcrAB–TolC efflux pump have reciprocal effects on CRRG transcription. Additionally, CpxR could regulate the colistin susceptibility of Salmonella Typhimurium by binding directly to the promoters of phoPQ, pmrC, pmrH and pmrD at the CpxR box-like sequences or indirectly through other regulators including pmrAB and mgrB. Conclusions CpxR could regulate the colistin susceptibility of Salmonella Typhimurium by a multitarget mechanism.

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Tanaka, Kousei, Kazuo Kobayashi, and Naotake Ogasawara. "The Bacillus subtilis YufLM two-component system regulates the expression of the malate transporters MaeN (YufR) and YflS, and is essential for utilization of malate in minimal medium." Microbiology 149, no. 9 (September 1, 2003): 2317–29. http://dx.doi.org/10.1099/mic.0.26257-0.

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The Gram-positive bacterium Bacillus subtilis has a complete set of enzymes for the tricarboxylic acid (TCA) cycle and can grow aerobically using most of the TCA cycle intermediates (malate, fumarate, succinate and citrate) as a sole carbon source. The B. subtilis genome sequence contains three paralogous two-component regulatory systems, CitST, DctSR and YufLM. CitST and DctSR activate the expression of a transporter of the Mg2+–citrate complex (CitM) and a fumarate and succinate transporter (DctP), respectively. These findings prompted an investigation of whether the YufL sensor and its cognate regulator, YufM, play a role in malate uptake. This paper reports that the YufM regulator shows in vitro binding to the promoter region of two malate transporter genes, maeN and yflS, and is responsible for inducing their expression in vivo. It was also found that inactivation of the yufM or maeN genes resulted in bacteria that could not grow in a minimal salts medium containing malate as a sole carbon source, indicating that the induction of the MaeN transporter by the YufM regulator is essential for the utilization of malate as a carbon source. Inactivation of the yufL gene resulted in the constitutive expression of MaeN. This expression was suppressed by reintroduction of the kinase domain of YufL, indicating that the YufL sensor is required for proper signal detection and signalling specificity. The authors propose that a phosphatase activity of YufL plays an important role in the YufLM two-component regulatory system. The studies reported here have revealed that members of a set of paralogous two-component regulatory systems in B. subtilis, CitST, DctSR and YufLM, are involved in a related function – uptake (and metabolism) of the TCA cycle intermediates – but with distinct substrate specificities.

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Krishnan, J., Lingjun Lu, and Aiman Alam Nazki. "The interplay of spatial organization and biochemistry in building blocks of cellular signalling pathways." Journal of The Royal Society Interface 17, no. 166 (May 2020): 20200251. http://dx.doi.org/10.1098/rsif.2020.0251.

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Biochemical pathways and networks are central to cellular information processing. While a broad range of studies have dissected multiple aspects of information processing in biochemical pathways, the effect of spatial organization remains much less understood. It is clear that space is central to intracellular organization, plays important roles in cellular information processing and has been exploited in evolution; additionally, it is being increasingly exploited in synthetic biology through the development of artificial compartments, in a variety of ways. In this paper, we dissect different aspects of the interplay between spatial organization and biochemical pathways, by focusing on basic building blocks of these pathways: covalent modification cycles and two-component systems, with enzymes which may be monofunctional or bifunctional. Our analysis of spatial organization is performed by examining a range of ‘spatial designs’: patterns of localization or non-localization of enzymes/substrates, theoretically and computationally. Using these well-characterized in silico systems, we analyse the following. (i) The effect of different types of spatial organization on the overall kinetics of modification, and the role of distinct modification mechanisms therein. (ii) How different information processing characteristics seen experimentally and studied from the viewpoint of kinetics are perturbed, or generated. (iii) How the activity of enzymes (bifunctional enzymes in particular) may be spatially manipulated, and the relationship between localization and activity. (iv) How transitions in spatial organization (encountered either through evolution or through the lifetime of cells, as seen in multiple model organisms) impacts the kinetic module (and pathway) behaviour, and how transitions in chemistry may be impacted by prior spatial organization. The basic insights which emerge are central to understanding the role of spatial organization in biochemical pathways in both bacteria and eukaryotes, and are of direct relevance to engineering spatial organization of pathways in bottom-up synthetic biology in cellular and cell-free systems.

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Ashton, Anna, Jason Clark, Julia Fedo, Angelo Sementilli, Yara D. Fragoso, and Peter McCaffery. "Retinoic Acid Signalling in the Pineal Gland Is Conserved across Mammalian Species and Its Transcriptional Activity Is Inhibited by Melatonin." Cells 12, no. 2 (January 11, 2023): 286. http://dx.doi.org/10.3390/cells12020286.

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The pineal gland is integral to the circadian timing system due to its role in nightly melatonin production. Retinoic acid (RA) is a potent regulator of gene transcription and has previously been found to exhibit diurnal changes in synthesis and signalling in the rat pineal gland. This study investigated the potential for the interaction of these two systems. PCR was used to study gene expression in mouse and human pineal glands, ex-vivo organotypic cultured rat pineal gland and cell lines. The mouse and human pineal glands were both found to express the necessary components required for RA signalling. RA influences the circadian clock in the brain, therefore the short-term effect of RA on clock gene expression was determined in ex vivo rat pineal glands but was not found to rapidly regulate Per1, Per2, Bmal1, or Cry1. The interaction between RA and melatonin was also investigated and, unexpectedly, melatonin was found to suppress the induction of gene transcription by RA. This study demonstrates that pineal expression of the RA signalling system is conserved across mammalian species. There is no short-term regulation of the circadian clock but an inhibitory effect of melatonin on RA transcriptional activity was demonstrated, suggesting that there may be functional cross-talk between these systems.

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Liu, Jiwei, Jianguo Yang, Jin Wen, Yun Yang, Xiaolu Wei, Xiaodong Zhang, and Yi-Ping Wang. "Mutational analysis of dimeric linkers in peri- and cytoplasmic domains of histidine kinase DctB reveals their functional roles in signal transduction." Open Biology 4, no. 6 (June 2014): 140023. http://dx.doi.org/10.1098/rsob.140023.

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Membrane-associated histidine kinases (HKs) in two-component systems respond to environmental stimuli by autophosphorylation and phospho-transfer. HK typically contains a periplasmic sensor domain that regulates the cytoplasmic kinase domain through a conserved cytoplasmic linker. How signal is transduced from the ligand-binding site across the membrane barrier remains unclear. Here, we analyse two linker regions of a typical HK, DctB. One region connects the first transmembrane helix with the periplasmic Per-ARNT-Sim domains, while the other one connects the second transmembrane helix with the cytoplasmic kinase domains. We identify a leucine residue in the first linker region to be essential for the signal transduction and for maintaining the delicate balance of the dimeric interface, which is key to its activities. We also show that the other linker, belonging to the S-helix coiled-coil family, plays essential roles in signal transduction inside the cell. Furthermore, by combining mutations with opposing activities in the two regions, we show that these two signalling transduction elements are integrated to produce a combined effect on the final activity of DctB.

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Bela, Krisztina, Riyazuddin Riyazuddin, and Jolán Csiszár. "Plant Glutathione Peroxidases: Non-Heme Peroxidases with Large Functional Flexibility as a Core Component of ROS-Processing Mechanisms and Signalling." Antioxidants 11, no. 8 (August 21, 2022): 1624. http://dx.doi.org/10.3390/antiox11081624.

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Glutathione peroxidases (GPXs) are non-heme peroxidases catalyzing the reduction of H2O2 or organic hydroperoxides to water or corresponding alcohols using glutathione (GSH) or thioredoxin (TRX) as a reducing agent. In contrast to animal GPXs, the plant enzymes are non-seleno monomeric proteins that generally utilize TRX more effectively than GSH but can be a putative link between the two main redox systems. Because of the substantial differences compared to non-plant GPXs, use of the GPX-like (GPXL) name was suggested for Arabidopsis enzymes. GPX(L)s not only can protect cells from stress-induced oxidative damages but are crucial components of plant development and growth. Due to fine-tuning the H2O2 metabolism and redox homeostasis, they are involved in the whole life cycle even under normal growth conditions. Significantly new mechanisms were discovered related to their transcriptional, post-transcriptional and post-translational modifications by describing gene regulatory networks, interacting microRNA families, or identifying Lys decrotonylation in enzyme activation. Their involvement in epigenetic mechanisms was evidenced. Detailed genetic, evolutionary, and bio-chemical characterization, and comparison of the main functions of GPXs, demonstrated their species-specific roles. The multisided involvement of GPX(L)s in the regulation of the entire plant life ensure that their significance will be more widely recognized and applied in the future.

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Moroz, Leonid L., and Andrea B. Kohn. "Independent origins of neurons and synapses: insights from ctenophores." Philosophical Transactions of the Royal Society B: Biological Sciences 371, no. 1685 (January 5, 2016): 20150041. http://dx.doi.org/10.1098/rstb.2015.0041.

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There is more than one way to develop neuronal complexity, and animals frequently use different molecular toolkits to achieve similar functional outcomes. Genomics and metabolomics data from basal metazoans suggest that neural signalling evolved independently in ctenophores and cnidarians/bilaterians. This polygenesis hypothesis explains the lack of pan-neuronal and pan-synaptic genes across metazoans, including remarkable examples of lineage-specific evolution of neurogenic and signalling molecules as well as synaptic components. Sponges and placozoans are two lineages without neural and muscular systems. The possibility of secondary loss of neurons and synapses in the Porifera/Placozoa clades is a highly unlikely and less parsimonious scenario. We conclude that acetylcholine, serotonin, histamine, dopamine, octopamine and gamma-aminobutyric acid (GABA) were recruited as transmitters in the neural systems in cnidarian and bilaterian lineages. By contrast, ctenophores independently evolved numerous secretory peptides, indicating extensive adaptations within the clade and suggesting that early neural systems might be peptidergic. Comparative analysis of glutamate signalling also shows numerous lineage-specific innovations, implying the extensive use of this ubiquitous metabolite and intercellular messenger over the course of convergent and parallel evolution of mechanisms of intercellular communication. Therefore: (i) we view a neuron as a functional character but not a genetic character, and (ii) any given neural system cannot be considered as a single character because it is composed of different cell lineages with distinct genealogies, origins and evolutionary histories. Thus, when reconstructing the evolution of nervous systems, we ought to start with the identification of particular cell lineages by establishing distant neural homologies or examples of convergent evolution. In a corollary of the hypothesis of the independent origins of neurons, our analyses suggest that both electrical and chemical synapses evolved more than once.

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Ay, Nihat, Jessica Flack, and David C. Krakauer. "Robustness and complexity co-constructed in multimodal signalling networks." Philosophical Transactions of the Royal Society B: Biological Sciences 362, no. 1479 (January 11, 2007): 441–47. http://dx.doi.org/10.1098/rstb.2006.1971.

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In animal communication, signals are frequently emitted using different channels (e.g. frequencies in a vocalization) and different modalities (e.g. gestures can accompany vocalizations). We explore two explanations that have been provided for multimodality: (i) selection for high information transfer through dedicated channels and (ii) increasing fault tolerance or robustness through multichannel signals. Robustness relates to an accurate decoding of a signal when parts of a signal are occluded. We show analytically in simple feed-forward neural networks that while a multichannel signal can solve the robustness problem, a multimodal signal does so more effectively because it can maximize the contribution made by each channel while minimizing the effects of exclusion. Multimodality refers to sets of channels where within each set information is highly correlated. We show that the robustness property ensures correlations among channels producing complex, associative networks as a by-product. We refer to this as the principle of robust overdesign . We discuss the biological implications of this for the evolution of combinatorial signalling systems; in particular, how robustness promotes enough redundancy to allow for a subsequent specialization of redundant components into novel signals.

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Sailem, Heba, Vicky Bousgouni, Sam Cooper, and Chris Bakal. "Cross-talk between Rho and Rac GTPases drives deterministic exploration of cellular shape space and morphological heterogeneity." Open Biology 4, no. 1 (January 2014): 130132. http://dx.doi.org/10.1098/rsob.130132.

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One goal of cell biology is to understand how cells adopt different shapes in response to varying environmental and cellular conditions. Achieving a comprehensive understanding of the relationship between cell shape and environment requires a systems-level understanding of the signalling networks that respond to external cues and regulate the cytoskeleton. Classical biochemical and genetic approaches have identified thousands of individual components that contribute to cell shape, but it remains difficult to predict how cell shape is generated by the activity of these components using bottom-up approaches because of the complex nature of their interactions in space and time. Here, we describe the regulation of cellular shape by signalling systems using a top-down approach. We first exploit the shape diversity generated by systematic RNAi screening and comprehensively define the shape space a migratory cell explores. We suggest a simple Boolean model involving the activation of Rac and Rho GTPases in two compartments to explain the basis for all cell shapes in the dataset. Critically, we also generate a probabilistic graphical model to show how cells explore this space in a deterministic, rather than a stochastic, fashion. We validate the predictions made by our model using live-cell imaging. Our work explains how cross-talk between Rho and Rac can generate different cell shapes, and thus morphological heterogeneity, in genetically identical populations.

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Creasey, Elizabeth A., Robin M. Delahay, Sarah J. Daniell, and Gad Frankel. "Yeast two-hybrid system survey of interactions between LEE-encoded proteins of enteropathogenic Escherichia coli." Microbiology 149, no. 8 (August 1, 2003): 2093–106. http://dx.doi.org/10.1099/mic.0.26355-0.

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Many Gram-negative pathogens employ a specific secretion pathway, termed type III secretion, to deliver virulence effector proteins directly to the membranes and cytosol of host eukaryotic cells. Subsequent functions of many effector proteins delivered in this manner result in subversion of host-signalling pathways to facilitate bacterial entry, survival and dissemination to neighbouring cells and tissues. Whereas the secreted components of type III secretion systems (TTSSs) from different pathogens are structurally and functionally diverse, the structural components and the secretion apparatus itself are largely conserved. TTSSs are large macromolecular assemblies built through interactions between protein components of hundreds of individual subunits. The goal of this project was to screen, using the standard yeast two-hybrid system, pair-wise interactions between components of the enteropathogenic Escherichia coli TTSS. To this end 37 of the 41 genes encoded by the LEE pathogenicity island were cloned into both yeast two-hybrid system vectors and all possible permutations of interacting protein pairs were screened for. This paper reports the identification of 22 novel interactions, including interactions between inner-membrane structural TTSS proteins; between the type III secreted translocator protein EspD and structural TTSS proteins; between established and putative chaperones and their cognate secreted proteins; and between proteins of undefined function.

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Jessus, Catherine, Catriona Munro, and Evelyn Houliston. "Managing the Oocyte Meiotic Arrest—Lessons from Frogs and Jellyfish." Cells 9, no. 5 (May 7, 2020): 1150. http://dx.doi.org/10.3390/cells9051150.

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During oocyte development, meiosis arrests in prophase of the first division for a remarkably prolonged period firstly during oocyte growth, and then when awaiting the appropriate hormonal signals for egg release. This prophase arrest is finally unlocked when locally produced maturation initiation hormones (MIHs) trigger entry into M-phase. Here, we assess the current knowledge of the successive cellular and molecular mechanisms responsible for keeping meiotic progression on hold. We focus on two model organisms, the amphibian Xenopus laevis, and the hydrozoan jellyfish Clytia hemisphaerica. Conserved mechanisms govern the initial meiotic programme of the oocyte prior to oocyte growth and also, much later, the onset of mitotic divisions, via activation of two key kinase systems: Cdk1-Cyclin B/Gwl (MPF) for M-phase activation and Mos-MAPkinase to orchestrate polar body formation and cytostatic (CSF) arrest. In contrast, maintenance of the prophase state of the fully-grown oocyte is assured by highly specific mechanisms, reflecting enormous variation between species in MIHs, MIH receptors and their immediate downstream signalling response. Convergence of multiple signalling pathway components to promote MPF activation in some oocytes, including Xenopus, is likely a heritage of the complex evolutionary history of spawning regulation, but also helps ensure a robust and reliable mechanism for gamete production.

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Conradi, Carsten, and Maya Mincheva. "Catalytic constants enable the emergence of bistability in dual phosphorylation." Journal of The Royal Society Interface 11, no. 95 (June 6, 2014): 20140158. http://dx.doi.org/10.1098/rsif.2014.0158.

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Dual phosphorylation of proteins is a principal component of intracellular signalling. Bistability is considered an important property of such systems and its origin is not yet completely understood. Theoretical studies have established parameter values for multistationarity and bistability for many types of proteins. However, up to now no formal criterion linking multistationarity and bistability to the parameter values characterizing dual phosphorylation has been established. Deciding whether an unclassified protein has the capacity for bistability, therefore requires careful numerical studies. Here, we present two general algebraic conditions in the form of inequalities. The first employs the catalytic constants, and if satisfied guarantees multistationarity (and hence the potential for bistability). The second involves the catalytic and Michaelis constants, and if satisfied guarantees uniqueness of steady states (and hence absence of bistability). Our method also allows for the direct computation of the total concentration values such that multistationarity occurs. Applying our results yields insights into the emergence of bistability in the ERK–MEK–MKP system that previously required a delicate numerical effort. Our algebraic conditions present a practical way to determine the capacity for bistability and hence will be a useful tool for examining the origin of bistability in many models containing dual phosphorylation.

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Naug, Dhruba, and H. S. Arathi. "Receiver bias for exaggerated signals in honeybees and its implications for the evolution of floral displays." Biology Letters 3, no. 6 (October 2, 2007): 635–37. http://dx.doi.org/10.1098/rsbl.2007.0436.

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Mechanistic models of animal signals posit the occurrence of biases on the part of receivers that could be potentially exploited by signallers. Such biases are most obvious when animals are confronted with exaggerated versions of signals they normally encounter. Signalling systems operating in plant–pollinator interactions are among the most highly coevolved, with plants using a variety of floral signals to attract pollinators. A number of observations suggest that pollinators preferentially visit larger floral displays although the benefit of this to either the plant or the pollinator is not always clear. We use a standard dual-choice experimental protocol to show that honeybees display a receiver bias for exaggerated size and colour contrast—two important components of floral signals—even when such signals do not indicate quality. We discuss the implications of this receiver bias for the evolution of floral displays and its possible exploitation by invading alien plants.

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Langer, Ingrid, Jérôme Jeandriens, Alain Couvineau, Swapnil Sanmukh, and Dorota Latek. "Signal Transduction by VIP and PACAP Receptors." Biomedicines 10, no. 2 (February 9, 2022): 406. http://dx.doi.org/10.3390/biomedicines10020406.

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Homeostasis of the human immune system is regulated by many cellular components, including two neuropeptides, VIP and PACAP, primary stimuli for three class B G protein-coupled receptors, VPAC1, VPAC2, and PAC1. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) regulate intestinal motility and secretion and influence the functioning of the endocrine and immune systems. Inhibition of VIP and PACAP receptors is an emerging concept for new pharmacotherapies for chronic inflammation and cancer, while activation of their receptors provides neuroprotection. A small number of known active compounds for these receptors still impose limitations on their use in therapeutics. Recent cryo-EM structures of VPAC1 and PAC1 receptors in their agonist-bound active state have provided insights regarding their mechanism of activation. Here, we describe major molecular switches of VPAC1, VPAC2, and PAC1 that may act as triggers for receptor activation and compare them with similar non-covalent interactions changing upon activation that were observed for other GPCRs. Interhelical interactions in VIP and PACAP receptors that are important for agonist binding and/or activation provide a molecular basis for the design of novel selective drugs demonstrating anti-inflammatory, anti-cancer, and neuroprotective effects. The impact of genetic variants of VIP, PACAP, and their receptors on signalling mediated by endogenous agonists is also described. This sequence diversity resulting from gene splicing has a significant impact on agonist selectivity and potency as well as on the signalling properties of VIP and PACAP receptors.

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Ma, Pikyee, and Mary K. Phillips-Jones. "Membrane Sensor Histidine Kinases: Insights from Structural, Ligand and Inhibitor Studies of Full-Length Proteins and Signalling Domains for Antibiotic Discovery." Molecules 26, no. 16 (August 23, 2021): 5110. http://dx.doi.org/10.3390/molecules26165110.

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There is an urgent need to find new antibacterial agents to combat bacterial infections, including agents that inhibit novel, hitherto unexploited targets in bacterial cells. Amongst novel targets are two-component signal transduction systems (TCSs) which are the main mechanism by which bacteria sense and respond to environmental changes. TCSs typically comprise a membrane-embedded sensory protein (the sensor histidine kinase, SHK) and a partner response regulator protein. Amongst promising targets within SHKs are those involved in environmental signal detection (useful for targeting specific SHKs) and the common themes of signal transmission across the membrane and propagation to catalytic domains (for targeting multiple SHKs). However, the nature of environmental signals for the vast majority of SHKs is still lacking, and there is a paucity of structural information based on full-length membrane-bound SHKs with and without ligand. Reasons for this lack of knowledge lie in the technical challenges associated with investigations of these relatively hydrophobic membrane proteins and the inherent flexibility of these multidomain proteins that reduces the chances of successful crystallisation for structural determination by X-ray crystallography. However, in recent years there has been an explosion of information published on (a) methodology for producing active forms of full-length detergent-, liposome- and nanodisc-solubilised membrane SHKs and their use in structural studies and identification of signalling ligands and inhibitors; and (b) mechanisms of signal sensing and transduction across the membrane obtained using sensory and transmembrane domains in isolation, which reveal some commonalities as well as unique features. Here we review the most recent advances in these areas and highlight those of potential use in future strategies for antibiotic discovery. This Review is part of a Special Issue entitled “Interactions of Bacterial Molecules with Their Ligands and Other Chemical Agents” edited by Mary K. Phillips-Jones.

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Journal articles on the topic 'Two component signalling systems'

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