GEFs

GEFs, or guanine nucleotide exchange factors, are proteins that activate small GTPases by promoting GDP release and allowing GTP binding. They regulate members of the Ras superfamily, including Ras, Rho, Rab, Arf, and Ran. GEFs function in opposition to GAPs, which stimulate GTP hydrolysis, and help control when GTPases switch from inactive (GDP-bound) to active (GTP-bound) states.

Mechanism and domains: Most GEFs facilitate the nucleotide exchange by stabilizing the nucleotide-free form of the GTPase and inducing conformational changes that release GDP. Many GEFs use a DH (Dbl homology) domain paired with a PH (pleckstrin homology) domain to activate Rho-family GTPases; Rab GEFs often contain DENN domains; Arf GEFs use Sec7 domains; Ran GEFs include RCC1-type proteins. Membrane localization and protein interactions frequently regulate their activity.

Examples: Ras GEFs include SOS1 and SOS2 and RasGRPs; Rho and Rac GEFs include Tiam1, Vav family members, and other DH/PH proteins; Rab GEFs include Rabex-5 and DENN-domain proteins; Arf GEFs include GBF1 and BIG1/2; Ran GEFs include RCC1.

Biological roles and disease: GEFs control signaling pathways governing cell proliferation, differentiation, cytoskeletal dynamics, and vesicle trafficking. Precise regulation is essential, and dysregulation of GEF activity is implicated in cancers, developmental disorders, and immune dysfunction. Regulation occurs through phosphorylation, localization, lipid interactions, autoinhibition, and feedback from GTPases.

In research and medicine, GEFs are studied to map signaling networks and as potential targets to modulate GTPase activity in disease contexts.