Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101764


Historical Background

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 Dexras1/Rasd1 gene encodes a 31.6 kDa small GTPase and is the founding member of a subfamily of Ras-related proteins to which DEXRAS2 and RHES also belong. The protein structure of DEXRAS1/RASD1 contains four highly conserved GTP binding and hydrolysis pockets (Σ1-Σ4), as well as an effector loop (Fig. 1). The Σ1 and Σ2 pockets contain phosphate-magnesium binding domains (GXXXXGK(S/T) and DXXG), whereas Σ3 and Σ4 contain guanine nucleotide binding loops (NKXD and EXSAK) (Graham et al. 2001; Thapliyal et al. 2014). Σ1 has been shown to confer GTP/GDP binding and GTP hydrolysis activities; however, purified DEXRAS/RASD1 exhibits weak binding to both GTP and GDP, suggesting that in vivo other proteins may be needed to facilitate nucleotide binding and/or exchange (Cismowski et al. 2000). The Σ1 and Σ4 domains harbor residues that are critical to the activity of DEXRAS1/RASD1. Mutation of glycine-31 to valine (G31V) in the Σ1 domain abolishes the effects of DEXRAS1/RASD1 on GPCR-Gi/o signaling (Cismowski et al. 1999; Takesono et al. 2002). Mutation of alanine-178 to valine (A178V) in the Σ4 loop renders DEXRAS1/RASD1 constitutively active by increasing the rate of GTP/GDP exchange (Graham et al. 2001). The C-terminal region of DEXRAS1/RASD1 also contains a cationic CAAX-domain. Two post-translational modifications have so far been identified. The first is S-nitrosylation of cysteine-11 (C11) by neuronal nitric oxide synthase (nNOS), an event that requires formation of a ternary complex involving DEXRAS1/RASD1, nNOS, and CAPON. This modification enhances the dissociation of guanosine diphosphate (GDP) from DEXRAS1/RASD1 and the binding of guanosine triphosphate (GTP) (Jaffrey et al. 2002). The second is farnesylation of cysteine-277 (C277) within the CAAX cationic domain. Farnesylation, which is a type of prenylation, enables DEXRAS1/RASD1 to anchor to the inner leaflet of the plasma membrane (Cismowski et al. 2000; Graham et al. 2001).
RASD1, Fig. 1

DEXRAS1/RASD1 protein structure. Positions of conserved GTP binding and hydrolysis domains (blue), the effector loop domain (red) and the cationic domain (yellow) of the murine DEXRAS1/RASD1 protein. Numbers below each domain indicate the positions of the flanking amino acids. Green lines indicate post-translational modifications on cysteine-11 (s-nitrosylation) and cysteine-277 (prenylation). Red lines indicate point mutations that abolish the ability of DEXRAS1/RASD1 to bind to GTP/GDP (G31V) or that generate a constitutively active protein (A178V)

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

The Dexras1/Rasd1 gene expression is induced by GR activation, likely via GREs in the promoter region and 3′ region (Fig. 2). In pancreatic β-cells, GR and STAT5 act in a cooperative manner to transactivate the Dexras1/Rasd1 gene, which in turn inhibits the protein kinase C (PKC), cAMP-dependent protein kinase (PKA), and mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) pathways (Lellis-Santos et al. 2012). In 3T3-L1 adipocyte precursor cells, following GR induction, DEXRAS1/RASD1 translocates to the plasma membrane in response to insulin where it associates with Src homology 2 domain containing (Shc) adaptor protein and Raf kinase to activate the MAPK/ERK pathway (Cha et al. 2013; Kim et al. 2016). Insulin-activated DEXRAS1/RASD1 in these cells ultimately leads to the enhancement of CCAAT/enhancer binding protein β (C/EBPβ)-mediated transcription (Cha et al. 2013; Kim et al. 2016).
RASD1, Fig. 2

DEXRAS1/RASD1 and GR-mediated signaling pathways. Following cellular uptake, glucocorticoids bind to GRs and enable their homo- or hetero-dimerization with transcriptional coactivators. In adipocytes, the GR homodimer transcriptionally activates Dexras1/Rasd1 via its 5′ glucocorticoid receptor element (GRE). Activation of insulin-like growth factor 1 (IGF-1) receptor (IGF1R) by IGF-1/insulin enables the translocation of DEXRAS1/RASD1 to the plasma membrane. DEXRAS1/RASD1 may then activate MAPK signaling via its direct interaction with the Shc-Grb2-Raf complex. Phospho-active MAPK, in turn, phosphorylates the transcription factor C/EBPβ, which transcriptionally targets key mitogenic genes essential for adipogenesis. In pancreatic β-cells, GR/STAT5 heterodimerization transcriptionally activates Dexras1/Rasd1, inhibiting the signaling pathways involved in insulin secretion. Prolactin receptor (PRLR) activation inhibits GR/STAT5 heterodimerization by enhancing STAT5 homodimerization, thus inhibiting Dexras1/Rasd1 transcriptional activation

DEXRAS1/RASD1 is also functionally linked to NMDA receptors (NMDARs) via its association with nNOS and CAPON (Fig. 3). NMDAR-mediated calcium influx activates the catalytic activity of nNOS. Activated nNOS forms a ternary complex with CAPON and DEXRAS1/RASD1. The C-terminal domain of DEXRAS1/RASD1 interacts directly with the N-terminal phosphotyrosine binding (PTB) domain of CAPON. This ternary complex enables nNOS to S-nitrosylate DEXRAS1/RASD1 on Cys-11, resulting in enhanced GTP binding in the Σ1 pocket (Fang et al. 2000; Jaffrey et al. 2002). S-nitrosylated DEXRAS1/RASD1 may also bind to the divalent metal transporter 1 (DMT1) via the scaffold protein, peripheral benzodiazepine receptor-associated protein 7 (PAP7), and enhance NMDAR-induced extracellular iron uptake (Cheah et al. 2006). More recently, DEXRAS1/RASD1 has been shown to mediate NMDAR-triggered release of lysosomal stores of iron (White et al. 2016). Cytosolic iron suppresses subsequent NMDAR activity by inhibiting a PKC/Src signaling pathway that otherwise positively regulates NMDARs (White et al. 2016).
RASD1, Fig. 3

DEXRAS1/RASD1 and NMDA-mediated iron trafficking. Glutamate-induced activation of NMDA receptors (NMDAR) triggers calcium influx into the cell. The scaffold protein CAPON recruits nNOS to the NMDAR, enabling calcium/calmodulin (CaM)-dependent activation of nNOS. The nNOS-CAPON heterodimer is released from the NMDAR complex and a new, ternary complex is formed with DEXRAS1/RASD1. nNOS mediates the S-nitrosylation of DEXRAS1/RASD1 by generating NO from L-arginine (Arg) and conjugating it to cysteine-11 (C11-SNO). S-nitrosylated DEXRAS1/RASD1 can then bind to the divalent transporter DMT1 via the scaffold protein PAP7, leading to a rise in cytosolic iron levels from extracellular uptake or release of lysosomal iron stores. Lysosomal iron release may negatively feed back onto the NMDAR by inhibiting PKC-mediated phosphorylation of Src

However, the most documented function of DEXRAS1/RASD1 is the regulation of GPCR-G protein signaling. Biochemical studies using purified proteins showed that DEXRAS1/RASD1 has guanine nucleotide exchange (GEF) activity selectively toward Gi and Go proteins, both in their heterotrimeric state as well as their monomeric Gi/oα form (Cismowski et al. 2000). This GEF activity would explain the ability of DEXRAS1/RASD1 to activate G protein-dependent signaling pathways in the absence of GPCR activation (Cismowski et al. 1999) (Fig. 4a). DEXRAS1/RASD1 can also directly associate with the Gβ1 subunit, although the functional consequence of this interaction on Gβγ signaling remains unknown (Hiskens et al. 2005). Paradoxically, DEXRAS1/RASD1 has been shown to suppress receptor-activated Gi/o signaling; this has been demonstrated for the N-formyl peptide receptor, dopamine D2L receptor, neuropeptide Y (NPY) receptor, and M2 muscarinic receptor (Graham et al. 2002; Takesono et al. 2002; Cheng et al. 2004; Nguyen and Watts 2006). In this context, DEXRAS1/RASD1 may be competing with the activated GPCR for the available pool of heterotrimeric G proteins, resulting in the suppression of Gi/o signaling (Fig. 4b). In most studies, activation of Gβγ signaling effectors such as MAPK/ERK and G protein-coupled inward-rectifying potassium channels (GIRKs) have been used as a proxy of Gi/o signaling (Takesono et al. 2002). Only one study has directly investigated the effects of DEXRAS1/RASD1 on both the Gα and Gβγ arms of receptor-activated Gi/o signaling. Nguyen and Watts found that DEXRAS1/RASD1 does not impact acute D2L receptor-mediated inhibition of adenylyl cyclase 1 (AC1) activity, which is mediated by the Gα arm, but does abrogate Gβγ-dependent heterologous sensitization of AC1 (Nguyen and Watts 2005). Lastly, DEXRAS1/RASD1 has been shown to suppress AC-mediated cAMP production downstream of GPCRs (e.g., dopamine D1, PAC1) that are coupled to GS signaling (Harrison and He, 2011; Cheng et al., 2006) (Fig. 4c). Whether these are direct effects on heterotrimeric GS proteins or indirect effects due to modulation of Giα monomers as suggested by Harrison and He remain to be clarified.
RASD1, Fig. 4

DEXRAS1/RASD1 and G-protein signaling. The role of DEXRAS1/RASD1 in GPCR-independent (a) and GPCR-dependent G-protein signaling (b, c). (a) In the absence of GPCR stimulation, DEXRAS1/RASD1 activates heterotrimeric Gi/o proteins via its GEF activity, facilitating signaling downstream of both the Gα and Gβγ arms. Gi/oα represses the AC-cAMP pathway, whereas Gβγ activates downstream effectors such as the MAPK pathway. (b) DEXRAS1/RASD1 inhibits Gi/o signaling downstream of agonist-activated Gi/o-GPCRs, presumably by competing for the available pool of heterotrimeric Gi/o proteins, leading to the suppression of Gβγ-targeted pathways. According to this model, DEXRAS1/RASD1 activity should also influence Gi/oα-mediated inhibition of AC, although this is not the case for acute D2L-mediated AC1 inhibition. (c) DEXRAS1/RASD1 inhibits GS-dependent cAMP accumulation following GS-GPCR stimulation; this inhibition is purported to be indirect through DEXRAS1/RASD1’s interaction with Gi/o

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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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Pascale Bouchard-Cannon
    • 1
    • 2
  • Hai-Ying Mary Cheng
    • 1
    • 2
  1. 1.Department of BiologyUniversity of Toronto MississaugaMississaugaCanada
  2. 2.Department of Cell and Systems BiologyUniversity of TorontoTorontoCanada