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Using High-Precision Signaling Activity Imaging to Personalize Ras Pathway Inhibition Strategies in Neurofibromatosis

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Technical Report,01 Jun 2018,31 May 2019

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University of California, Davis Davis United States

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The goal of this project is to characterize differences in Ras pathway signaling, using live cell activity measurements in cell types and genetic contexts relevant to NF1. In our previous reports, we described the completed data collection for single-cell measurements of ERK activity in both cell lines and in patient-derived fibroblasts. In this reporting period, we performed additional experiments and quantitative analysis to confirm our findings and to collate our data into a unified model of signal transmission by the RasERK cascade. This model explains the finding that NF1-deficient cells, similar to Ras mutant cells, have an increased baseline of ERK activity in the absence of growth factors, but no increase in ERK amplitude upon growth factor stimulation. We show that the mechanism for this effect is distributed and includes regulation of phosphatase activity and a cryptic saturation point at Ras-Raf . Altogether, our results answer the central question of our project by demonstrating that the primary signaling defect in NF1-deficient cells is one of increased tonic ERK signaling, not of increased intensity.

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  • Medicine and Medical Research

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