Ags1

AGS1 (activator of G-protein signaling 1; also known as RASD1 or Dexras1) is a member of the Ras family of monomeric GTPases. AGS1 has all of the conserved domains of the Ras superfamily required for guanine nucleotide and hydrolysis and effector interaction, as well as for C-terminal prenylation and membrane association. AGS1 is distinguished from most Ras family members by unique N- and C-terminal extensions, a short internal insert region and by specific differences in amino acids within domains involved in nucleotide binding and hydrolysis that are consistent with constitutive activity. AGS1 shares strongest homology with Rhes (62% amino-acid identity), another Ras-related protein with unique insert regions. After Rhes, AGS1 is most closely related to Rap2 proteins (approximately 36% amino-acid identity within the conserved domains). Expression of AGS1 is regulated by glucocorticoids, antiproliferative stimuli, desiccative and hypertonic stress, ischemia/reperfusion injury and embryonic alcohol exposure.

Though not as extensively characterized as many Ras family members, AGS1 appears to regulate signal transduction directly at the level of the heterotrimeric G protein. In transiently transfected cell lines AGS1 activates ERK1/2, blocks ADP-ribosylation of G_αi by pertussis toxin, inhibits cyclic AMP (cAMP) accumulation in response to forskolin or constitutively active G_αs, and inhibits cAMP-dependent peptide hormone secretion. Each of these functions is consistent with AGS1 acting as a direct Gα activator. In vitro, AGS1 binds to purified G_αi but not Gβγ and increases GTPγS binding to purified Gα_i1 and Gα_i2. However, when transiently co-transfected with a G_αi-coupled receptor, AGS1 blocks Gβγ-mediated signaling after agonist activation of that G-protein-coupled receptor (GPCR), and AGS1 blocks receptor-mediated heterologous sensitization of adenylyl cyclase. The seemingly contradictory effects of AGS1 on G_αi signaling may result from competition between AGS1 and GPCRs for a limited pool of heterotrimeric G proteins, from alteration of GPCR/G-protein coupling, or the interaction of AGS1 with more than one signaling component (i.e. direct interaction with Gβγ). Indeed, AGS1 interacts with Gβγ in a yeast two-hybrid assay.

In vivo AGS1 functions downstream of N-methyl-D-aspartate (NMDA) receptors to regulate neuronal iron homeostasis, as well as to suppress tumor growth in athymic mice. Mice lacking AGS1 expression exhibit altered regulation of both photic and non-photic responses in the mammalian circadian clock.