My research focuses on the molecular mechanisms that control the Rac protein family, which regulates cell shape, cell movement, oxygen radical formation and gene expression, in particular, the proteins that activate Rac, so-called Rac-GEFs. A few years ago, my lab discovered a new type of Rac-GEF, the P-Rex family, and we have been studying the mechanisms that regulate their activity and their functional roles.
We found that P-Rex family Rac-GEFs are important for the ability of our white blood cells to defend us against bacterial and fungal infections, for the shape and electrical functions of nerve cells that control the coordination of our movements, and for the distribution of skin pigment cells during development. We also participated in studies which showed that the deregulation of the cellular amount or activity of P-Rex family Rac-GEFs contribute to cancer growth and metastasis.
Currently, I am investigating new functional roles of P-Rex and other Rac-GEFs, particularly in inflammatory cells, and exploring new ways of monitoring Rac-GEF activity.
The guanine-nucleotide exchange factor (GEF) P-Rex1 mediates G protein-coupled receptor (GPCR) signaling by activating the small GTPase Rac. We show here that P-Rex1 also controls GPCR trafficking. P-Rex1 inhibits the agonist-stimulated internalization of the GPCR S1PR1 independently of its Rac-GEF activity, through its PDZ, DEP, and inositol polyphosphate 4-phosphatase domains. P-Rex1 also limits the agonist-induced trafficking of CXCR4, PAR4, and GLP1R but does not control steady-state GPCR levels, nor the agonist-induced internalization of the receptor tyrosine kinases PDGFR and EGFR. P-Rex1 blocks the phosphorylation required for GPCR internalization. P-Rex1 binds G protein-coupled receptor kinase 2 (Grk2), both in vitro and in cells, but does not appear to regulate Grk2 activity. We propose that P-Rex1 limits the agonist-induced internalization of GPCRs through its interaction with Grk2 to maintain high levels of active GPCRs at the plasma membrane. Therefore, P-Rex1 plays a dual role in promoting GPCR responses by controlling GPCR trafficking through an adapter function as well as by mediating GPCR signaling through its Rac-GEF activity.
P-Rex1 is a guanine-nucleotide factor for the small GTPase Rac (Rac-GEF) that is known to mediate neutrophil migration and ROS production in response to the activation of GPCRs. These roles of P-Rex1 are assumed to require its activation of Rac.
We investigated the roles of Rac guanine-nucleotide exchange factor (Rac-GEF) P-Rex1 in glucose homeostasis using Prex1 and catalytically inactive Prex1 mice. P-Rex1 maintains fasting blood glucose levels and insulin sensitivity through its Rac-GEF activity but limits glucose clearance independently of its catalytic activity, throughout aging. Prex1 mice on a high-fat diet are protected from diabetes. The increased glucose clearance in Prex1 mice may stem in part from constitutively enhanced hepatic glucose uptake. P-Rex1 controls Glut2 surface levels and mitochondrial morphology, membrane potential, and ATP production in hepatocytes, independently of its catalytic activity. The inverse agonist GRA2 showed that P-Rex1 suppresses glucose uptake and mitochondrial ATP production in hepatocytes through the orphan GPCR Gpr21. Cell fractionation showed that P-Rex1 controls Gpr21 trafficking, independently of its catalytic activity. We propose that P-Rex1 limits hepatocyte glucose uptake by retaining Gpr21 at the plasma membrane. These findings delineate new strategies for controlling glucose homeostasis.