RapGEF

Rap guanine nucleotide exchange factors, or RapGEFs, are regulatory proteins that activate the small GTPases Rap1 and Rap2 by catalyzing GDP-to-GTP exchange. By switching Rap proteins to their active GTP-bound state, RapGEFs influence processes such as cell adhesion, integrin activation, cytoskeletal dynamics, neuronal development, and vesicular trafficking.

Mechanistically, most RapGEFs share a catalytic CDC25 homology domain, which performs nucleotide exchange, often following an adjacent REM domain that supports catalytic activity. Regulatory modules determine localization, interaction partners, and stimuli responsiveness. A major subset, the Epac family, is directly regulated by cyclic AMP (cAMP). Epac proteins contain cAMP-binding domains that relieve autoinhibition and promote Rap1 activation in response to increases in intracellular cAMP, linking hormonal and neurotransmitter signals to Rap signaling.

Other RapGEFs include C3G, which is activated downstream of Crk adaptor proteins and Src-family kinases, and PDZGEF proteins, which possess PDZ-domain–based interactions. Collectively, RapGEFs integrate signals from growth factors, calcium, lipids, and second messengers to spatially and temporally regulate Rap GTPases.

Biological roles of RapGEFs are diverse and cell-type dependent, contributing to endothelial barrier function, synaptic development, immune cell trafficking, and platelet function. Dysregulation of RapGEF signaling has been implicated in cancer progression, cardiovascular disease, and neurological disorders. The discovery of Epac in the late 1990s highlighted a direct, cAMP-dependent path from second messengers to Rap activation, complementing the older Ras-like GEF paradigm.

See also: Rap GTPases, guanine nucleotide exchange factors (GEFs), cAMP signaling, Crk adaptor proteins.