Guanine nucleotide exchange factor (GEF)

Guanine nucleotide exchange factors (GEFs) are a broad class of proteins that act as molecular switches to activate small GTPases, such as Ras, Rho, and Rab. They function by facilitating the release of guanosine diphosphate (GDP) from the GTPase, allowing guanosine triphosphate (GTP) to bind and trigger downstream signaling cascades involved in cell growth, motility, and survival (Bos et al., 2007, Cell). Because many GEFs, such as SOS1 and Epac, are upstream regulators of oncogenic pathways like the MAPK/ERK pathway, they have emerged as significant therapeutic targets in oncology and cardiovascular medicine. While historically considered difficult to drug due to their protein-protein interaction surfaces, recent advances have led to the development of small-molecule inhibitors that disrupt the GEF-GTPase interface or bind to allosteric sites. The term "Exchange factor" is a general functional designation; in a clinical or drug discovery context, it usually refers to specific members like Son of Sevenless homolog 1 (SOS1) or Exchange protein directly activated by cAMP (EPAC) (Hillig et al., 2019, PNAS).

Other names

GDP-GTP exchange factorGuanine nucleotide release factorGRFExchange proteinGuanine nucleotide dissociation stimulatorGDS

Guanine nucleotide exchange factors (GEFs) function by binding to inactive, GDP-bound small GTPases and promoting the dissociation of GDP. This allows the more abundant cellular GTP to bind, inducing a conformational change that activates the GTPase, enabling it to interact with downstream effectors in signaling pathways (Cherfils & Zeghouf, 2013, Physiological Reviews).