The role of phosphoinositide 3-kinases in neutrophil chemotaxis

• Main Author: Ferguson, G. J.
• Published: University of Cambridge 2007
• Subjects: 571.6
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.598984

There are four class I phosphoinositide 3-kine4ase (PI3K) isoforms (α, β, γ and δ) which are responsible for the production of the signalling molecule PtdIns(3,4,5)P₃ at the plasma membrane. Class I PI3Ks have been shown to be required for neutrophil chemotaxis, however their exact function is unknown. They may play a role in action reorganisation, the regulation of adhesion or by acting as a compass molecule that is required for a neutrophils sense of direction. This thesis presents work using isoform selective PI3K inhibitors and genetic modifications in mice to assess the potential role of PI3K isoforms in chemotaxis of both human and murine neutrophils under a variety of different contexts. Although inhibition or deletion of PI3Kγ indicates it can play a significant role in the migration of neutrophils towards chemoattractants it is not essential as its requirement is content dependent. In addition, there is also a role for the class Ia PI3Ks in neutrophil chemotaxis, however these play a smaller role, which is also context dependent. A more detailed analysis of neutrophil migration indicates that the role for PI3Kγ in chemotaxis was not, as previously speculated, in sensing the gradient but was instead in controlling motility. This work also demonstrates that one of the mechanisms through which PI3Kγ may regulate neutrophil migration is through the modulation of adhesion.