The Rho guanine nucleotide exchange factor P-Rex1 as a potential drug target for cancer metastasis and inflammatory diseases.

Phosphatidylinositol 3,4,5-trisphosphate (PIP₃)-dependent Rac exchanger 1 (P-Rex1) is a guanine nucleotide exchange factor (GEF) for Rac small GTPases and the Rac-related GTPase RhoG. P-Rex1 plays an important role in cell migration and relays intracellular signals generated through activation of G protein-coupled receptors and receptor tyrosine kinases. Studies of mouse models have found that P-Rex1 expression and activation is associated with tumor cell migration, brain development and pathological changes such as lung edema. Since its initial discovery, P-Rex1 has been known for its large size and multiple activation mechanisms that involve not only PIP₃ but also the βγ subunits of heterotrimeric G proteins and a regulatory subunit of cyclic AMP-dependent kinase, PKA RIα. At the core of the GEF activity is the tandem Dbl homology domain and the pleckstrin homology domain (DH/PH domains) that are masked until activation signals unwind the P-Rex1 structure. Understanding the activation mechanisms will help designing therapeutics that target P-Rex1 for cancer and other diseases.