3 research outputs found
The sensing and processing of multiple extracellular cues by living cells
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
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Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms.
The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a grave threat to public health and the global economy. SARS-CoV-2 is closely related to the more lethal but less transmissible coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). Here, we have carried out comparative viral-human protein-protein interaction and viral protein localization analyses for all three viruses. Subsequent functional genetic screening identified host factors that functionally impinge on coronavirus proliferation, including Tom70, a mitochondrial chaperone protein that interacts with both SARS-CoV-1 and SARS-CoV-2 ORF9b, an interaction we structurally characterized using cryo-electron microscopy. Combining genetically validated host factors with both COVID-19 patient genetic data and medical billing records identified molecular mechanisms and potential drug treatments that merit further molecular and clinical study