Tuxworth, Richard Ian; (1999) The control of cell motility and differentiation by Ras pathways. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

The Ras Family of GTP-binding proteins have been implicated in the control of cellular growth, differentiation and motility. The regulation of proliferation by Ras has been extensively studied in mammalian cells but the control of cell motility has proved more difficult to study in these cells due to the dominant effects on cell proliferation that occur with the perturbation of Ras function. This thesis examines the functions of RasG and a putative Ras Exchange Factor Aimless, in the control of cell motility, and the functions of RasG in the control of the onset of differentiation of Dictyostelium discoideum. To understand the role of Ras in the control of motility 1 have investigated the effects of disrupting the rasG gene. Analysis of rasG null cells indicates that RasG plays an important role in the control of the cell motility and in the onset of early multicellular development, but is not required for proliferation. The rasG null cells show aberrant regulation of the actin cytoskeleton, a loss of polarity, reduced speed of motility and a failure in the final stages of cytokinesis. rasG null cells also exhibit a delay in the initiation of development. When development does occur, it is asynchronous. The aimless gene was previously identified in a genetic screen for signalling mutants. It is required for chemotaxis and implicates a Ras signalling pathway in this control of this process. However, the roles of Ras and a Ras signalling pathway in chemotaxis are unclear. By using dominant forms of the Aimless protein 1 have implicated Aimless in the regulation of localised actin polymerisation. Chemotaxis of rasG null cells is relatively normal, suggesting that Aimless does not activate RasG during chemotaxis or that another Ras protein can substitute for RasG during chemotaxis.

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