Betson, Martha Elizabeth; (2001) Regulation of cell-cell adhesion in keratinocytes: The reciprocal relationship between cadherins and Rho family GTPases. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Cadherins are transmembrane receptors, which mediate adhesion between adjacent cells. They play an essential role in development and maintenance of tissue architecture. The RHO GTPases modulate actin cytoskeletal architecture in different cell types. Two family members in particular, RhoA and Rad, have been found to regulate the stability of cadherin receptors at intercellular junctions. In this thesis I set out to study in more detail the relationship between cadherin-mediated adhesion and the small GTPase Rac in keratinocytes. Previous work has shown that while Rac is necessary for cell-cell contact formation, it can also disrupt cadherin-dependent adhesion when its activity is sustained. I have mapped the domain of Rac that is required for breakdown of intercellular junctions. In addition, I have shown that Rac mediates perturbation of cell-cell adhesion induced by oncogenic H-Ras. I have also investigated which Rac effectors may mediate Rac-induced disassembly of cell-cell contacts. To look for new Rac targets that may regulate cadherin-mediated adhesion, I performed a yeast two-hybrid screen of a keratinocyte library and identified a novel Rac-binding clone. Ligand binding to a variety of cell surface receptors has been found to induce Rac activation. I have found that calcium-induced cell-cell contact formation can also activate Rac. Cadherin function is necessary for Rac activation, and clustering of the cadherin receptors is sufficient to activate Rac. Initial activation of Rac is dependent on signalling from the EGF receptor but not PI 3-kinase activity. At later time-points, Rac is activated by an alternative EGF-receptor-independent mechanism. In conclusion, this work focuses on the relationship between Rac and cadherin-mediated adhesion in epithelia. This could shed light on the regulation of epithelial morphogenesis under normal conditions and potentially lead to an understanding of how this is subverted during tumorigenesis.

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