Kitsou, E.; (2006) Characterisation of the physical and functional interaction of DRhoGEF2 with DMec2 via its PDZ domain. Doctoral thesis , University of London.

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Abstract

Morphogenesis is the process which will define the final form of an organism by a series of complex cellular events such as cell division, shape changes and migration, events that require the coordinated modification of the cytoskeleton. The cytoskeleton is mainly regulated by the Rho family of small GTPases. The Guanine Nucleotide Exchange Factor, DRhoGEF2, is an activator of Rho 1 and it is essential for morphogenetic cell shape changes. Signalling through DRhoGEF2 seems to be restricted to a specific area in the cell. One major question in the field is the mechanism by which the activity of RhoGEFs is spatially and temporally limited. The multidomain nature of DRhoGEF2 provides the framework for a tight regulation and the participation in a protein network. The activity of the distinct structural elements of DRhoGEF2 has not been completely elucidated. This thesis investigates the role of the PDZ domain for the function of DRhoGEF2. Preliminary results indicate that the PDZ domain acts as a positive regulator. In addition, an interaction has recently been discovered between the DRhoGEF2 PDZ domain and the novel protein DMec2. This thesis explores the functional significance of DMec2 and in particular its putative contribution to morphogenesis through its interaction with DRhoGEF2. Overexpression and elimination of DMec2 does not alter the actin nor microtubule cytoskeleton and ectopic expression does not produce any obvious phenotypes therefore its role remains obscure. Furthermore, DMec2 binds to the PDZ domain however there is no indication of a functional relevance of this interaction. This work suggests further study to explore the integration of signals by the PDZ domain of DRhoGEF2.

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