Identification of novel G protein-dependent activators of Rho-family GTPases Rho-family GTPases control cell morphology and migration. Their deregulation drives pathological conditions such as inflammatory disorders and cancer metastasis1. They are activated by GEFs which are tightly controlled through various mechanisms. Our lab identified P Rex-family GEFs, important regulators of many cell types, but also drivers of cancer progression and metastasis3-12. Uniquely, they are activated by the G subunits of heterotrimeric G proteins upon GPCR stimulation8,13-15. The catalytic DH domain of P-Rex1 is sufficient for G stimulation13,14. which is surprising because these domains are conserved, suggesting that G may regulate more GEFs. The PhD student will employ two approaches test this hypothesis: i) test the effects of G on the GEF activities of a range of recombinant DH domains. ii) purify G-dependent GEFs through their effects on GTPase activity, clone and characterise them in vitro and in cells3-15. This may identify novel signalling pathways from GPCR to GTPases that may regulate cell migration and could be targeted in inflammatory conditions or cancer metastasis. 1Heasman & Ridley (2008) NatRevMolCellBiol.2Rossman et al (2005) NatRevMolCellBiol. 3Welch et al (2002) Cell. 4Welch et al (2005) CurrBiol. 5Donald et al (2008) PNAS. 6Jackson et al (2010) PLoSOne. 7Fine et al (2009) Science. 8Sosa et al (2010) MolCell. 9Lawson et al (2011) JImmunol. 10Lindsay et al (2011) NatCommun. 11Berger et al (2012) Nature. 12Herter et al (2013) Blood. 13Hill et al (2005) JBiolChem 280. 14Barber et al (2007) JBiolChem. 15 Barber et al (2012) BiochemJ.
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