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Please use this identifier to cite or link to this item: http://arks.princeton.edu/ark:/88435/dsp01p5547v350
Title: Development of optogenetic tools to investigate the mechanism of cytoplasmic receptor tyrosine kinase signaling
Development of optogenetic tools to investigate the mechanism of cytoplasmic receptor tyrosine kinase signaling
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Authors: Uribe, Giselle
Advisors: Toettcher, Jared E.
Department: Molecular Biology
Class Year: 2020
Abstract: Receptor tyrosine kinases (RTKs) are a family of transmembrane receptors that activate signaling cascades to control cell proliferation, differentiation and growth. Upon ligand binding, RTKs dimerize leading to autophosphorylation and recruitment of downstream effectors that activate various signaling pathways, including the Ras/Erk pathway. In cancer, chromosomal translocations can lead to changes in receptor localization: turning a membrane kinase into an active cytosolic-localized kinase due to its fusion with a higher-order oligomer clustering partner. Yet, it remains a question how these cytosolic receptors activate the Ras/Erk pathway when Ras itself localizes to the membrane. To answer this question, we engineered cytosolic RTKs that oligomerize in response to blue light. Using these light-sensitive constructs we find that some RTKs, namely Fibroblast Growth Factor Receptor (FGFR) and Tropomyosin-Related Kinase A (TrkA) signal when clustered both on the membrane and in the cytosol, while others, namely epidermal growth factor receptor (EGFR) only signal when bound to the plasma membrane. Although EGFR does not trigger downstream signaling, it auto-phosphorylates and recruits Grb2 in response to oligomerization; the first step in Ras-Erk pathway activation. Through a series of experiments, we demonstrate that these differences in signaling arise from FGFR kinase activity on unknown substrates that activate Ras. Overall our results highlight the presence of unknown downstream effectors that selectively transmit signals from cytosolic RTKs to activate downstream pathways.
URI: http://arks.princeton.edu/ark:/88435/dsp01p5547v350
Type of Material: Princeton University Senior Theses
Language: en
Appears in Collections:Molecular Biology, 1954-2020

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