THESIS
2021
1 online resource (x, 53 pages) : illustrations (some color)
Abstract
Microtubules are an essential component of the cytoskeleton, helping cells to divide, transport components, change or maintain their morphology, and migrate. Microtubules typically grow atop a cone-shaped protein complex called the γ-tubulin ring complex (γ-TuRC), which initiates microtubule growth in response to cell signalling proteins. Not all factors that regulate microtubule growth have been identified, but a protein kinase called phosphatidylinositol 3-kinase (PI3K), which is overactive in many cancers, can bind to γ-tubulin and has been shown to regulate microtubule growth at the plasma membrane. However, most microtubules do not grow at the plasma membrane; rather, most microtubules grow at microtubule-organising centres such as the centrosome and the Golgi, and in the cytosol....[
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Microtubules are an essential component of the cytoskeleton, helping cells to divide, transport components, change or maintain their morphology, and migrate. Microtubules typically grow atop a cone-shaped protein complex called the γ-tubulin ring complex (γ-TuRC), which initiates microtubule growth in response to cell signalling proteins. Not all factors that regulate microtubule growth have been identified, but a protein kinase called phosphatidylinositol 3-kinase (PI3K), which is overactive in many cancers, can bind to γ-tubulin and has been shown to regulate microtubule growth at the plasma membrane. However, most microtubules do not grow at the plasma membrane; rather, most microtubules grow at microtubule-organising centres such as the centrosome and the Golgi, and in the cytosol. In this study, I provide evidence by chemical inhibition, knockdown, or overexpression of PI3K, in different cell lines, that the catalytic subunit of PI3K, p110α (and not its kinase-dead mutant), increases microtubule nucleation at the centrosome and Golgi, and in the cytosol. Moreover, I was surprised to find that cells overexpressing PI3K p110α increase microtubule nucleation in surrounding cells, and this provides evidence for a question posed in the literature that, clinically, cells with mutations in PI3K exert a greater influence on tissue than the proportion of mutated cells alone would suggest. The present study demonstrates a role for PI3K in regulating microtubule growth initiation by the principal microtubule nucleator, γ-TuRC. This is a contribution to cell biology and has clinical implications given the dominance of PI3K in cancer and overgrowth syndromes, and the fact that most chemotherapies target microtubules.
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