Use of elicitor sets to characterize cellular signal transduction networks Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/ns064908t

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  • Intracellular signaling cascades can no longer be viewed as linear pathways that relay and amplify information. Often, components of different pathways interact, resulting in signaling networks. The interactions of different pathways and the dynamic modulation of the activities of the components within signaling pathways can create a multitude of biological outputs. The cell appears to use these pathways as a way of integrating multiple inputs to shape a uniquely defined output. These outputs allow the cell to respond to and adapt to an ever-changing environment. Understanding how biological systems receive, process and respond to complex data inputs has important implications for the design and utilization of sensors for a variety of applications, including toxicology, pharmacology, medical diagnostics, and environmental monitoring. This study uses the elicitor sets method, which is an experimental framework designed to monitor information flows through signal transduction pathways. The elicitor set approach has been used to derive mechanistic interpretations from the action of Phenylmethylsulfonyl Fluoride (PMSF), a serine protease inhibitor and nerve agent analog. The elicitor panel comprises of signal transduction network effectors namely forskolin, clonidine, cirazoline and H89, each of which targets the signaling pathway at known specific points. The elicitor set experiments enable compartmentalization of the cAMP signaling pathway, examining the role played by each segment and identifying possible cross-talk mechanisms. Our experiments substantiate that selection of adenyl cyclase as the reference node and 10 [mu]M forskolin as the primary elicitor, segments the upper portion of the G-Protein Coupled Receptor (GPCR) pathway associated with the G[sub q] and G[sub i] proteins. Application of the secondary elicitors, 100 nM clonidine (a2-adrenergic receptor agonist), 1 pM and 100 pM cirazoline (al-adrenergic receptor agonists), and 1 [mu]M and 100 [mu]M H-89 (PKA inhibitor) fortifies the decoupling, as the system is unresponsive to clonidine and cirazoline in the presence of forskolin, while continuing to respond to H-89. Exposure of the cells to 1 mM PMSF subsequent to forskolin addition restricted the quantifiable impact of PMSF to regions of the signaling pathways below adenyl cyclase. Triggering the system by use of secondary elicitors augmented the information resolution which is reinforced by the increased sensitivity of cells to 100 [mu]M H-89 that acts at an important checkpoint below adenyl cyclase.
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