DEXRAS1/RASD1/AGS1 was identified in three independent studies from 1998 to 2000. In 1998, Kemppainen and Behrend isolated a novel gene that was rapidly induced by the synthetic glucocorticoid, dexamethasone, in AtT-20 mouse pituitary tumor cells. They coined this new gene dexamethasone-inducible Ras protein 1 based on its homology to other members of the Ras superfamily of small GTPases (Kemppainen and Behrend 1998). A year later, Dexras1/Rasd1 was discovered in a yeast functional screen designed to identify mammalian genes that activate the pheromone response pathway in the absence of the pheromone receptor (Cismowski et al. 1999). It was given the name activator of G-protein signaling 1 (AGS1) based on its ability to activate G proteins in a G protein-coupled receptor (GPCR)-independent manner (Cismowski et al. 1999; Cismowski et al. 2000). Soon afterward, DEXRAS1/RASD1 was isolated from a yeast-2-hybrid screen as a binding partner of CAPON, an adaptor protein for neuronal nitric oxide synthase (nNOS) (Fang et al. 2000). These initial findings laid the foundation for future studies on this small GTPase known interchangeably as Dexras1, Rasd1, and AGS1.
Structure and Expression
DEXRAS1/RASD1 is a simple gene consisting of two exons and a short intervening intron. The human and murine Dexras1/Rasd1 genes are located on chromosomes 17 and 11, respectively, and share 89% nucleotide and 98% amino acid sequence identity. The promoter region of murine Dexras1/Rasd1 contains a putative retinoic acid-related orphan receptor response element (RORE) approximately 1.1 kb upstream of the gene, as well as a putative glucocorticoid responsive element (GRE) at position −1830 to −1816 from the transcription start site (Takahashi et al. 2003; Kim et al. 2016). The functional significance of the RORE is currently unknown; however, the promoter region encompassing the predicted GRE exhibits glucocorticoid receptor (GR) binding activity (Takahashi et al. 2003; Kim et al. 2016). In addition, the human Dexras1/Rasd1 gene contains a functional GRE approximately 2.3 kb downstream of the poly(A) signal (Kemppainen et al. 2003).
The expression of DEXRAS1/RASD1 is highly enriched in the murine brain, especially in the suprachiasmatic nucleus (SCN) and the hippocampus (Fang et al. 2000). Within the SCN, Dexras1/Rasd1 gene expression fluctuates in a circadian fashion, peaking in the night and reaching a trough in the day (Takahashi et al. 2003). Dexras1/Rasd1 expression is also observed in peripheral organs and tissues including the heart, liver, kidneys, and white adipose tissues. In terms of cellular compartmentalization, DEXRAS1/RASD1 protein has been detected in the cytoplasm and nucleus, as well as near the plasma membrane (Ong et al. 2011). Depending on the tissue type, the expression of Dexras1/Rasd1 is responsive to various physiological inputs including hormones (glucocorticoid, β-estradiol), amphetamines, traumatic injuries (spinal cord transection, sciatic nerve transection), and cardiac volume overload (Brogan et al. 2001; Li et al. 2008; Shen et al. 2008; Schwendt and McGinty 2010; McGrath et al. 2012; Kim et al. 2016).
Molecular and Cell Signaling
DEXRAS1/RASD1 is a binding partner for the cAMP-activated non-POU domain containing, octamer binding (NonO) transcription factor (Ong et al. 2011). DEXRAS1/RASD1 and NonO dually associate at the promoters of cAMP-responsive element (CRE)-regulated genes and repress their transcription (Ong et al. 2011). Lastly, DEXRAS1/RASD1 may also play a role in the amyloid precursor protein (APP) pathway. DEXRAS1/RASD1 can physically bind to FE65, a protein that can form a transcriptionally active complex with the APP intracellular domain (AICD) (Lau et al. 2008). The tripartite complex of DEXRAS1/RASD1, FE65, and APP inhibits FE65/APP-mediated transcriptional activation of the glycogen synthase kinase 3β (GSK3β) gene, resulting in reduced hyperphosphorylation of tau protein, a substrate of GSK3β (Lau et al. 2008). The interaction between DEXRAS1/RASD1 and FE65 is inhibited by phosphorylation of FE65 at tyrosine-547 (Lau et al. 2008).
DEXRAS1/RASD1 has been shown to regulate various physiological functions, many of which involve the abovementioned signaling cascades. DEXRAS1/RASD1 regulates the secretion of human growth hormone (hGH) and atrial natriuretic factor (ANF) in AtT-20 cells and cardiac cells, respectively, in a Gi/o-dependent manner (Graham et al. 2001; McGrath et al. 2012). In cardiac cells, DEXRAS1/RASD1 suppresses ANF release, but upon increased atrial distension by volume overload, DEXRAS1/RASD1 is rapidly inhibited, allowing ANF secretion and vascular vasodilation (McGrath et al. 2012). DEXRAS1/RASD1 is also involved in pancreatic β-cell insulin release in response to prolactin levels during late pregnancy and early lactation (Lellis-Santos et al. 2012). During late pregnancy, high levels of prolactin inhibit DEXRAS1/RASD1-mediated suppression of insulin secretion by pancreatic β-cells by abolishing GR-dependent transcription of the Dexras1/Rasd1 gene (Lellis-Santos et al. 2012). Decrease in prolactin levels during post-partum and early lactation allows GR-induced Dexras1/Rasd1 expression and subsequent inhibition of insulin secretion (Lellis-Santos et al. 2012) (Fig. 2). These results indicate a strong regulatory function of DEXRAS1/RASD1 in the control of peripartum maternal insulin secretion (Lellis-Santos et al. 2012).
DEXRAS1/RASD1 is highly expressed in both the suprachiasmatic nucleus (SCN) and the hippocampus of the murine brain. In the SCN, several studies have revealed a role of DEXRAS1/RASD1 in the regulation of multiple receptor-dependent signaling pathways that are activated by photic or nonphotic stimuli. Dexras1/Rasd1-ablated mice exhibit deficits in time-of-day-dependent clock resetting in response to light: specifically, they show smaller NMDAR-dependent phase delays in the early night and larger PAC1-dependent phase advances in the late night (Cheng et al. 2004; Cheng et al. 2006). Dexras1/Rasd1 deletion also unmasks NPY-dependent nonphotic responses in mice, a species that is refractory to nonphotic stimulations (Cheng et al. 2004; Koletar et al. 2011; Bouchard-Cannon and Cheng 2012). The effects of DEXRAS1/RASD1 on NMDA and NPY signaling in the SCN are sensitive to pertussis toxin, implicating an involvement of heterotrimeric Gi/o proteins (Cheng et al. 2004). The suppressive effects of DEXRAS1/RASD1 on PAC1/GS signaling may be indirect and the result of enhanced Gi/o-mediated inhibition of AC (Cheng et al. 2006).
DEXRAS1/RASD1 in the murine hippocampus has been suggested to mediate anxiety-related behaviors following NMDA receptor activation (Zhu et al. 2014; Carlson et al. 2016). Dexras1/Rasd1-deficient mice do not display any significant difference in hippocampal-dependent memory and learning or baseline anxiety-like behavior compared with wild-type mice, but demonstrate an increase in prepulse inhibition and corresponding reduction in startle response indicative of elevated sensorimotor gating (Carlson et al. 2016). Additional data suggest that DEXRAS1/RASD1 enhances anxiogenic behaviors in mice by controlling the expression of NMDA subunit NR2A in the hippocampus (Carlson et al. 2016). NR2A abundance is elevated in the brains of Dexras1/Rasd1-deficient mice (Carlson et al. 2016). An alternative explanation for the anxiogenic effects of DEXRAS1/RASD1 proposes that NMDA receptor activation leads to nNOS/CAPON-dependent, DEXRAS1/RASD1-mediated inhibition of an anxiolytic MAPK/ERK pathway in the hippocampus (Zhu et al. 2014).
DEXRAS1/RASD1 has a crucial function in the enhancement of adipogenesis in mice. Dexras1/Rasd1-deficient mice are resistant to high-fat diet-induced obesity, exhibiting reduced accumulation of white adipose tissue mass under these conditions (Cha et al. 2013). In 3T3-L1 cells, Dexras1/Rasd1 silencing or deletion of the prenylation-targeted C-terminal domain of DEXRAS1/RASD1 abolishes hormone-induced adipocyte differentiation (Cha et al. 2013; Kim et al. 2016).
Finally, DEXRAS1/RASD1 has been shown to play a role in cell proliferation and apoptotic cell death (Vaidyanathan et al. 2004). In cancer cell lines, the basal expression of DEXRAS1/RASD1 is significantly dampened compared to noncancerous cell lines. Its over-expression in these cell lines leads to a delay in cell cycle progression and an increase in apoptosis (Vaidyanathan et al. 2004). Both effects depend on the GTP/GDP binding activity of DEXRAS1/RASD1, as they are abrogated by the G31V mutation (Vaidyanathan et al. 2004).
DEXRAS1/RASD1 is a highly conserved member of the Ras superfamily of small GTPases and was first studied in the late 1990s for its glucocorticoid inducibility, activation of G protein signaling, and association with the nNOS-CAPON complex. The structure of DEXRAS1/RASD1 displays multiple GTP binding and hydrolysis pockets as well as a C-terminal end targeted for prenylation. The GTP-binding activity of DEXRAS1/RASD1 may be enhanced via its association with the nNOS-CAPON complex. The current literature demonstrates a highly complex role of DEXRAS1/RASD1 in the modulation of signaling cascades downstream of various receptors, including glucocorticoid receptors, NMDA receptors, and GS- and Gi/o-coupled GPCRs. In addition to its roles in signaling, DEXRAS1/RASD1 can complex with scaffolds or other proteins (e.g., CAPON, FE65, DMT1) and alter effector protein function. Dexras1/Rasd1 expression is induced by a wide range of physiological stimuli and has many biological effects including the regulation of circadian timekeeping, anxiety-related behavior, adipocyte differentiation, and hormone release.
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