52 results found
Suwanmajo T, Krishnan J, 2018, Exploring the intrinsic behaviour of multisite phosphorylation systems as part of signalling pathways., J R Soc Interface, Vol: 15
Multisite phosphorylation is a basic way of chemically encoding substrate function and a recurring feature of cell signalling pathways. A number of studies have explored information processing characteristics of multisite phosphorylation, through studies of the intrinsic kinetics. Many of these studies focus on the module in isolation. In this paper, we build a bridge to connect the behaviour of multisite modification in isolation to that as part of pathways. We study the effect of activation of the enzymes (which are basic ways in which the module may be regulated), as well the effects of the modified substrates being involved in further modifications or exiting reaction compartments. We find that these effects can induce multiple kinds of transitions, including to behaviour not seen intrinsically in the multisite modification module. We then build on these insights to investigate how these multisite modification systems can be tuned by enzyme activation to realize a range of information processing outcomes for the design of synthetic phosphorylation circuits. Connecting the complexity of multisite modification kinetics, with the pathways in which they are embedded, serves as a basis for teasing out many aspects of their interaction, providing insights of relevance in systems biology, synthetic biology/chemistry and chemical information processing.
Menon G, Okeke C, Krishnan J, 2017, Modelling compartmentalization towards elucidation and engineering of spatial organization in biochemical pathways, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322
Menon G, Krishnan J, 2016, Bridging the gap between modules in isolation and as part of networks: A systems framework for elucidating interaction and regulation of signalling modules, JOURNAL OF CHEMICAL PHYSICS, Vol: 145, ISSN: 0021-9606
Seaton DD, Krishnan J, 2016, Model-Based Analysis of Cell Cycle Responses to Dynamically Changing Environments, PLOS COMPUTATIONAL BIOLOGY, Vol: 12, ISSN: 1553-734X
Zhao Y-B, Krishnan J, 2016, Probabilistic Boolean Network Modelling and Analysis Framework for mRNA Translation, IEEE-ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS, Vol: 13, Pages: 754-766, ISSN: 1545-5963
Alam-Nazki A, Krishnan J, 2015, Spatial Control of Biochemical Modification Cascades and Pathways, BIOPHYSICAL JOURNAL, Vol: 108, Pages: 2912-2924, ISSN: 0006-3495
Liu C, Krishnan J, Xu X-Y, 2015, Intrinsic and induced drug resistance mechanisms at the cellular and tissue scales, Integrative Biology, ISSN: 1757-9694
Liu C, Krishnan J, Xu XY, 2015, Intrinsic and induced drug resistance mechanisms: in silico investigations at the cellular and tissue scales, INTEGRATIVE BIOLOGY, Vol: 7, Pages: 1044-1060, ISSN: 1757-9694
Suwanmajo T, Krishnan J, 2015, Mixed mechanisms of multi-site phosphorylation, JOURNAL OF THE ROYAL SOCIETY INTERFACE, Vol: 12, ISSN: 1742-5689
Krishnan J, Liu C, 2014, An investigation of signal transduction and irreversible decision making through monostable and bistable switches, A Systems Theoretic Approach to Systems and Synthetic Biology II: Analysis and Design of Cellular Systems, Pages: 219-243, ISBN: 9789401790475
© 2014 Springer Science+Business Media Dordrecht. All rights reserved. Highly nonlinear signal transduction is ubiquitous in cell signalling pathways with switch-like behaviour encountered repeatedly. Monostable and bistable switches represent distinct basic switches which are encountered. A number of contexts in cellular signalling (e.g. apopotosis and cell cycle) involve essentially irreversible transitions and decision making. In this article we examine signal transduction through prototypical monostable and bistable switches with a view towards understanding how irreversible signal transduction may occur through them and also examine the similarities and differences in signal transduction and decision making to classes of experimentally employed inputs. The study provides insights into how irreversible transitions may be orchestrated through different switches in cell signalling, the underlying design characteristics, capabilities and constraints involved, and the extent to which these switches can be distinguished based on irreversible decision making to experimentally available classes of inputs.
Krishnan J, Mois K, Suwanmajo T, 2014, The behaviour of basic autocatalytic signalling modules in isolation and embedded in networks, JOURNAL OF CHEMICAL PHYSICS, Vol: 141, ISSN: 0021-9606
Liu C, Krishnan, Xu XY, 2014, Towards an integrated systems-based modelling framework for drug transport and its effect on tumour cells, JOURNAL OF BIOLOGICAL ENGINEERING, Vol: 8, ISSN: 1754-1611
Zhao Y-B, Krishnan J, 2014, mRNA translation and protein synthesis: an analysis of different modelling methodologies and a new PBN based approach, BMC SYSTEMS BIOLOGY, Vol: 8, ISSN: 1752-0509
Alam-Nazki A, Krishnan J, 2013, Covalent Modification Cycles through the Spatial Prism, BIOPHYSICAL JOURNAL, Vol: 105, Pages: 1720-1731, ISSN: 0006-3495
Krishnan J, Alam-Nazki A, 2013, Elucidating design principles underlying attractive and repulsive gradient sensing in eukaryotic chemotaxis
Liu C, Krishnan J, Xu XY, 2013, Investigating the effects of ABC transporter-based acquired drug resistance mechanisms at the cellular and tissue scale, INTEGRATIVE BIOLOGY, Vol: 5, Pages: 555-568, ISSN: 1757-9694
Suwanmajo T, Krishnan J, 2013, Biphasic responses in multi-site phosphorylation systems, JOURNAL OF THE ROYAL SOCIETY INTERFACE, Vol: 10, ISSN: 1742-5689
Alam-Nazki A, Krishnan J, 2012, An investigation of spatial signal transduction in cellular networks, BMC SYSTEMS BIOLOGY, Vol: 6, ISSN: 1752-0509
Betney R, de Silva E, Mertens C, et al., 2012, Regulation of release factor expression using a translational negative feedback loop: A systems analysis, RNA-A PUBLICATION OF THE RNA SOCIETY, Vol: 18, Pages: 2320-2334, ISSN: 1355-8382
Liu C, Krishnan J, Xu XY, 2012, Investigation of the effect of drugs on solid tumours within a systems-based mathematical modelling framework, Pages: 131-135
The study develops a skeletal modeling framework to systematically evaluate the effect of anticancer drugs on solid tumors, especially from the perspective of cellular signaling. The modeling framework incorporates interstitial drug transport, intracellular apoptosis signaling and the dynamics of tumor cell density, which are regarded as the essentially minimal elements. The study deliberately starts with coarse grained descriptions of the cellular signaling, which nevertheless are capable of correctly capturing the qualitative dynamics involved. A series of simulations have been performed to provide mechanistic and predictive insights into cellular response towards different forms of drug stimuli. It is found qualitatively different intracellular signaling models can give rise to similar tissue behavior. Within the context, validating the models must be performed with care by considering a variety of drug stimuli.
Seaton DD, Krishnan J, 2012, Multispecific interactions in enzymatic signalling cascades, Pages: 67-73, ISSN: 0302-9743
The reversible postranslational modification of proteins is a ubiquitous feature of cellular signal transduction networks. In these systems, signalling is typically seen as resulting from the interaction between an active enzyme and a downstream unmodified substrate. However, it is known that in some cases the inactive form of an enzyme is also capable of binding the unmodified substrate, and that in other cases the active enzyme is capable of binding modified substrate. In this paper, we analyse the behaviour of a two-stage enzymatic cascade in which these additional protein-protein interactions are possible. Without the additional interactions, the model produces the standard ultrasensitive switch-like behaviour. We find that inactive enzyme binding to unmodified substrate increases the ultrasensitivity of this switch, while active enzyme binding to modified substrate results in the switch becoming biphasic. These results indicate how important the rules governing the occurrence of protein-protein interactions can be in determining the signalling behaviour of a pathway, even when particular protein-protein interactions have no clear functional role. © 2012 Springer-Verlag.
Seaton DD, Krishnan J, 2012, Effects of multiple enzyme-substrate interactions in basic units of cellular signal processing, PHYSICAL BIOLOGY, Vol: 9, ISSN: 1478-3967
Krishnan J, 2011, Effects of saturation and enzyme limitation in feedforward adaptive signal transduction, IET SYSTEMS BIOLOGY, Vol: 5, Pages: 208-219, ISSN: 1751-8849
Krishnan J, 2011, Chemical Engineering at the Cellular Scale: Cellular Signal Processing, INDUSTRIAL & ENGINEERING CHEMISTRY RESEARCH, Vol: 50, Pages: 13236-13243, ISSN: 0888-5885
Krishnan J, Alam-Nazki A, 2011, An investigation of design principles underlying repulsive and attractive gradient sensing and their switching, JOURNAL OF THEORETICAL BIOLOGY, Vol: 273, Pages: 80-99, ISSN: 0022-5193
Liu C, Krishnan J, Stebbing J, et al., 2011, Use of mathematical models to understand anticancer drug delivery and its effect on solid tumors, PHARMACOGENOMICS, Vol: 12, Pages: 1337-1348, ISSN: 1462-2416
Liu C, Krishnan J, Xu XY, 2011, A systems-based mathematical modelling framework for investigating the effect of drugs on solid tumours, THEORETICAL BIOLOGY AND MEDICAL MODELLING, Vol: 8, ISSN: 1742-4682
Seaton D, Krishnan J, 2011, Modular systems approach to understanding the interaction of adaptive and monostable and bistable threshold processes, IET SYSTEMS BIOLOGY, Vol: 5, Pages: 81-U25, ISSN: 1751-8849
Seaton DD, Krishnan J, 2011, The coupling of pathways and processes through shared components, BMC SYSTEMS BIOLOGY, Vol: 5, ISSN: 1752-0509
Seaton DD, Krishnan J, 2011, Modelling the influence of allostery on crosstalk in the phosphatidylinositol signalling pathway, Pages: 392-398
The phosphatidylinositol signalling pathway is responsible for regulating a wide variety of processes in the cell via its regulation of intracellular calcium levels. This pathway is known to respond synergistically to certain combinations of signals. Key components in this pathway are the isoforms of PLCβ, which are capable of binding two upstream effectors, Gaq and Gβγ, and may do this in an allosteric way. We present a modelling investigation into how two different isoforms of PLCβ, PLCβ2 and PLCβ3, displaying different degrees of allostery, may interact with one another to modify the overall pathway synergy. We show how the synergy depends on both the absolute and relative concentrations of the two isoforms, and explain these effects mechanistically through the uptake of Gaq and Gβγ by PLCβ2 and PLCβ3. From a systems perspective, this illustrates how synergy, which is present at a single-molecule level through allostery, is modified in the context of a pathway. Furthermore, it allows consideration of how this effect may be significant in the wider system, which consists of many other downstream interconnections and feedbacks.
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