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 P-Rex family proteins P-Rex1 and P-Rex2 are Dbl-type guanine-nucleotide exchange factors (GEFs) that activate Rac small GTPases upon synergistic stimulation by PIP and G尾纬, acting as coincidence detectors for PI3K and GPCR signalling. P-Rex Rac-GEFs control physiological responses ranging from inflammation, innate and adaptive immunity to GPCR trafficking, glucose homeostasis, and the function of the vascular endothelium, nervous system, and adipose tissue. P-Rex2 also increases PI3K-signalling through its catalysis-independent inhibition of the tumour suppressor PTEN. Deregulated levels of P-Rex1 are linked to fibrotic diseases, asthma, and autism spectrum disorders, and both P-Rex1 and P-Rex2 are deregulated in metabolic diseases. Upregulation of P-Rex1 and P-Rex2 as well as activating P-Rex2 mutations also occur in many types of cancer, including breast, prostate, lung, liver and colorectal cancer, as well as in melanoma and glioma. and contribute to tumour growth or metastasis depending on the P-Rex protein and cancer type. Deregulation of P-Rex1 in cancer typically promotes tumour growth or metastasis, whereas upregulation or mutation of P-Rex2 in cancer is mostly associated with tumour growth. Recently, structural data have increased our understanding of P-Rex regulation, the first P-Rex inhibitors have been developed, and GEF-activity independent functions of P-Rex proteins in GPCR trafficking, neutrophil-responses, innate immunity, and glucose homeostasis have been described. This review summarises the P-Rex literature from the discovery of the P-Rex protein family in 2002 to the present, with a focus on recent advances.
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.