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The sensing and processing of multiple extracellular cues by living cells

Kuchenov, Dmitry

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Cells have an amazing ability to monitor complex extracellular environment, constantly deciding whether they, for example, migrate, survive, proliferate or differentiate. This ability is achieved through extremely dynamic cellular signaling networks that use the limited number of signaling components. Despite signaling networks of individual receptors are characterized in details, it is not fully understood how cells, employing shared signaling pathways, process and encode information from multiple cues that are physiologically common scenario.

In this study, I have first established a quantitative high-throughput FRET-based multi-parameter imaging platform (FMIP) which allows monitoring activity of multiple signaling pathways in living cells with high spatial and temporal resolution. The general applicability of this method was proven by profiling epidermal growth factor (EGF)-induced signaling network activity. FMIP was further employed in investigations of: (i) fatty acid dependent DAG signaling, (ii) the perturbation of EGF-induced signaling caused by the EGFR mutations; and (iii) the effects of an MEK inhibitor on EGF network activity. This platform will be a useful tool for investigating diverse signaling networks including growth factors, cytokines, hormones and GPCRs.

To understand the mechanisms underlying the signal integration and processing from multiple extracellular cues by living cells, I have further focused on receptor tyrosine kinases. Using FMIP I identified the dynamic signaling interactions (synergy, additivity, antagonism) between growth factors and cytokines at the system level. We find that those concentration dependent dynamic signaling interactions tune signaling network in the order of seconds or minutes to achieve specific activity state. While the signaling network state specifies unique gene expression the gene expression profile shapes signaling network state in the order of hours. We further showed the potentiation and the tuning of dynamic EGF signaling under quasi-physiological concentration in non-starved cells. Overall the results suggest that under physiological conditions, in the presence of multiple signaling cues of low concentrations, the cellular signaling network is pre-activated and tuned to achieve specific strong responses to low concentrations of ligands. Thus, we provide mechanistic understanding of specific cell adaptation to the extracellular environment in the presence of multiple cues.

Item Type: Dissertation
Supervisor: Schultz, Dr. Carsten
Place of Publication: Heidelberg, Germany
Date of thesis defense: 26 June 2017
Date Deposited: 12 Apr 2018 11:56
Date: 2019
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
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