| PREX1, also known as phosphatidylinositol‑3,4,5‑trisphosphate‑dependent Rac exchanger 1, belongs to the Dbl family of Rho‑type guanine nucleotide exchange factors and functions as a Rac‑directed signal integrator downstream of phosphoinositide 3‑kinase and G protein‑coupled receptors. The protein contains an N‑terminal Dbl‑homology catalytic domain paired with a pleckstrin homology domain that senses phosphatidylinositol‑3,4,5‑trisphosphate, flanked by tandem DEP domains and C‑terminal PDZ and IP4P‑like regions that assemble regulatory and effector interactions and support long‑range allosteric control across a two‑layered autoinhibited architecture. Binding of phosphatidylinositol‑3,4,5‑trisphosphate to the pleckstrin homology domain and engagement of Gβγ subunits at defined regulatory surfaces release intramolecular restraints within PREX1, expose the Dbl‑homology active site, and permit efficient GDP–GTP exchange on Rac‑family GTPases, which elevates Rac‑GTP levels and couples receptor inputs to the core Rho GTPase network. Activated Rac then links PREX1 output to downstream effectors such as p21‑activated kinases and other Rac‑responsive kinases that remodel the actin cytoskeleton, regulate lamellipodia dynamics, and adjust adhesion complexes, placing PREX1 as a central controller of directed migration, invasion, and cell–matrix interactions in contexts where G protein‑coupled receptor and receptor tyrosine kinase signals converge. Structural analysis of full‑length PREX1 shows that the catalytic module packs against distal domains in an autoinhibitory configuration and that coincident lipid and Gβγ binding induces large conformational rearrangements across both layers of the molecule, aligning the Dbl‑homology domain with Rac substrates and stabilizing an active signaling conformation at the plasma membrane. Rac activation driven by PREX1 contributes to pathways that connect to ERK signaling and other mitogenic cascades, linking this exchange factor to regulation of proliferation and survival in addition to motility, and placing it within broader signaling circuits that integrate chemokine receptors, sphingosine‑1‑phosphate receptors, and growth factor receptors. Elevated PREX1 expression and activation are associated with increased invasive behavior and metastatic potential in cancers such as breast cancer, prostate cancer, melanoma, and glioblastoma, where PREX1–Rac signaling shapes cytoskeletal organization, directional migration, and matrix invasion, and where Rac‑dependent kinase outputs feed into transcriptional programs that support tumor progression. |
