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Title: Mechanisms of P-Rex1 regulation
Author: Barber, M. A.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2010
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First, regulation of its subcellular localisation: the upstream activators of P-Rex1, Gβγs and PI(3,4,5)P3, as well as its downstream effector Rac, are all intrinsically associated with the plasma membrane. Yet in resting cells P-Rex1 is mainly cytosolic. Here, it is shown that Gβγ and PI3K together synergistically cause a robust increase in membrane-localised P-Rex1. The isolated DH/PH domains of P-Rex1 are sufficient for synergistic Gβγ- and PI3K-driven membrane localisation. Furthermore, membrane-derived purified P-Rex1 has a higher basal activity than cytosol-derived P-Rex1. Second, regulation by, and of, protein binding partners: regulation of GEF activity can be achieved by interactions between GEFs and other cellular proteins. Few protein binding partners (aside from Rac) are currently known for P-Rex family GEFs. Five new potential P-Rex1 binding partners have been identified here. The interaction of P-Rex1 with one of these novel binding partners, neurochondrin, has been confirmed and further characterised. Coexpression of P-Rex1 and neurochondrin affects both their subcellular localisation and causes characteristic changes in membrane ruffling. Third, P-Rex1 GEF activity is known to be inhibited through phosphorylation by PKA. Here, an activating phosphatase for P-Rex1 has been identified for the first time, the serine/threonine phosphatase Protein Phosphatase 1α (PP1α). The interaction between P-Rex1 and PP1α as well as the PP1α-dependent dephosphorylation of P-Rex1 and the activation of P-Rex1 Rac-GEF activity by PP1α has been characterised both in vitro and in vivo.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available