Guanine nucleotide exchange factor

[1] A variety of unrelated structural domains have been shown to exhibit guanine nucleotide exchange activity.

Small GTPases act as molecular switches in intracellular signaling pathways and have many downstream targets.

[7] GAPs (GTPase-activating protein) act antagonistically to inactivate GTPases by increasing their intrinsic rate of GTP hydrolysis.

When the Ran GAP catalyzes conversion of RanGTP to RanGDP in the cytosol, the protein cargo is released.

GEF binding induces conformational changes in the P loop and switch regions of the GTPase while the rest of the structure is largely unchanged.

While different subfamilies of Ras superfamily GTPases have a conserved GTP binding domain, this is not the case for GEFs.

The CDC25 domain comprises approximately 500 amino acids and was first identified in the CDC25 protein in budding yeast (Saccharomyces cerevisiae).

[10] Dbl-like RhoGEFs were present at the origin of eukaryotes and evolved as highly adaptive cell signaling mediators.

Many of the mammalian Dbl family proteins are tissue-specific and their number in Metazoa varies in proportion of cell signaling complexity.

It is generally thought to modulate membrane binding through interactions with phospholipids, but its function has been shown to vary in different proteins.

For example, SOS1, the Ras GEF in the MAPK/ERK pathway, is recruited by the adaptor protein GRB2 in response to EGF receptor activation.

[14] GEFs are potential target for cancer therapy due to their role in many signaling pathways, particularly cell proliferation.

[6][13] The Rho GTPase Vav1, which can be activated by the GEF receptor, has been shown to promote tumor proliferation in pancreatic cancer.

[18] GEFs represent possible therapeutic targets as they can potentially play a role in regulating these pathways through their activation of GTPases.