RGS2 (regulator of G-protein signaling 2, 24kDa)

2010-01-01   Chau H Nguyen 

Department of Physiology, Pharmacology, University of Western Ontario, London, ON, N6A 5C1, Canada





The gene spans 3,233 bases.


6 alternatively spliced mRNA variants have been reported; 1 unspliced form. The best characterized mRNA variant is 1355bp long arising from 5 exons: 32bp 5 UTR, 636bp coding sequence, 687 bp 3 UTR.


Atlas Image
MTS = Membrane Targeting Sequence (residues 33-53). RGS = Regulator of G protein Signaling Domain (residues 80-205).


Primary protein product is a 211 amino acid hydrophilic, basic protein (pI 9.6) with a calculated molecular weight of 24.4 kD (Siderovski et al., 1994).
Possibly three additional functional proteins arising from alternative translation initiation of AUG codons corresponding to amino acid residues 5, 16, and 33 of full-length protein (Gu et al., 2008).
RGS2 can be phosphorylated by PKC and PKGIalpha (Cunningham et al., 2001; Tang et al., 2003).


RGS2 is ubiquitously expressed and its mRNA is found at medium to high levels in brain, heart, lung, kidney, intestine, lymphocytes, placenta, and testis (Larminie et al., 2004).
RGS2 expression (mRNA and protein) can be upregulated in response to Gs- and Gq-mediated signals (Song et al., 1999; Miles et al., 2000; Roy et al., 2006b; Zou et al., 2006), as well as a variety of stressful stimuli including heat shock (Zmijewski et al., 2001), oxidative stress (Zmijewski et al., 2001), DNA damage (Song and Jope, 2006), and infection (McCaffrey et al., 2004).


RGS2 is localized to the nucleus and the plasma membrane (Roy et al., 2003; Gu et al., 2007).


Canonical functions: RGS proteins bind to heterotrimeric G proteins by way of their RGS domain and act as GAPs (GTPase accelerating protein) to turn off G protein coupled receptor (GPCR) signals (Ross and Wilkie, 2000). RGS2 is unique in its selective GAP activity toward Galphaq and its low affinity for Galphai/o subunits (Heximer et al., 1997; Heximer et al., 1999; Cladman and Chidiac, 2002). RGS2 has also been shown to regulate Galphas-mediated signals in a GAP-independent manner, which likely reflects its ability to interact with other components of the G protein signaling machinery to interfere with G protein-effector interactions. These include adenylyl cyclase (Salim et al., 2003; Roy et al., 2006a), select GPCRs (Bernstein et al., 2004; Hague et al., 2005; Roy et al., 2006a), and the GPCR-scaffolding protein, spinophilin (Wang et al., 2005). RGS2 has been implicated in the control of vascular and neurological functions (Ingi et al., 1998; Kammermeier and Ikeda, 1999; Oliveira-Dos-Santos et al., 2000; Heximer et al., 2003; Tang et al., 2003).
Noncanonical functions: RGS2 has been shown to bind and regulate the activity of proteins outside the realm of GPCR signaling networks including tubulin (Heo et al., 2006), the TRPV6 calcium channel (Schoeber et al., 2006), and the eukaryotic initation factor, eIF2B (Nguyen et al., 2009).


All RGS proteins share a homologous (45-80%) 120 amino acid RGS domain that confers their binding to heterotrimeric G protein alpha subunits. RGS2 shares highest homology to other members of the B/R4 subfamily (Ross and Wilkie, 2000; Sierra et al., 2002).

Implicated in

Entity name
Colorectal cancer
The correlation between RGS2 expression and survival time of patients with colorectal cancer was studied (Jiang et al., 2009). The authors determined that RGS2 mRNA levels were lower in tissues from patients with recurring colorectal cancer in comparison to those patients without recurrence; however, this study did not identify any causal relationship between RGS2 expression and colorectal cancer.
Entity name
Breast cancer
RGS2 mRNA expression was examined in a number of breast cancer cell lines and solid breast cancers (Smalley et al., 2007). The authors found that RGS2 was expressed at higher levels in the majority of solid breast cancers in comparison to control mammary cells. No causal relationship between RGS2 expression and breast cancer was identified.
Entity name
Prostate cancer
RGS2 expression was found to be selectively decreased in androgen-independent prostate cancer cells compared to androgen-dependent cancer cells, as well as in human prostate tumor samples (Cao et al., 2006). The authors show that exogenous RGS2 is sufficient to inhibit androgen-independent receptor signaling and clonogenic growth of androgen-independent prostate cancer cells.
RGS2 expression was found to be repressed by an activating mutation of the fetal liver tyrosine kinase 3 (Flt3-ITD), which is associated with acute myeloid leukemia (Schwable et al., 2005). The authors demonstrate that exogenous RGS2 is sufficient to modulate Flt3-ITD-mediated signaling in myeloid cells. Further, RGS2 is able to reverse the Flt3-ITD-induced alterations in proliferation and differentiation in these cells.
Entity name
Studies using RGS2 knockout mice have identified a role for RGS2 in vascular function and blood pressure regulation (Heximer et al., 2003; Tang et al., 2003).


Pubmed IDLast YearTitleAuthors
149761832004RGS2 binds directly and selectively to the M1 muscarinic acetylcholine receptor third intracellular loop to modulate Gq/11alpha signaling.Bernstein LS et al
164499652006Regulator of G-protein signaling 2 (RGS2) inhibits androgen-independent activation of androgen receptor in prostate cancer cells.Cao X et al
121814422002Characterization and comparison of RGS2 and RGS4 as GTPase-activating proteins for m2 muscarinic receptor-stimulated G(i).Cladman W et al
110637462001Protein kinase C phosphorylates RGS2 and modulates its capacity for negative regulation of Galpha 11 signaling.Cunningham ML et al
179011992008Alternative translation initiation of human regulators of G-protein signaling-2 yields a set of functionally distinct proteins.Gu S et al
178485752007Unique hydrophobic extension of the RGS2 amphipathic helix domain imparts increased plasma membrane binding and function relative to other RGS R4/B subfamily members.Gu S et al
159172352005Selective inhibition of alpha1A-adrenergic receptor signaling by RGS2 association with the receptor third intracellular loop.Hague C et al
168202812006RGS2 promotes formation of neurites by stimulating microtubule polymerization.Heo K et al
125888822003Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice.Heximer SP et al
97366411998Dynamic regulation of RGS2 suggests a novel mechanism in G-protein signaling and neuronal plasticity.Ingi T et al
200019672010Analysis of RGS2 expression and prognostic significance in stage II and III colorectal cancer.Jiang Z et al
102308011999Expression of RGS2 alters the coupling of metabotropic glutamate receptor 1a to M-type K+ and N-type Ca2+ channels.Kammermeier PJ et al
149928132004Selective expression of regulators of G-protein signaling (RGS) in the human central nervous system.Larminie C et al
152693472004A specific gene expression program triggered by Gram-positive bacteria in the cytosol.McCaffrey RL et al
106146202000Dynamic regulation of RGS2 in bone: potential new insights into parathyroid hormone signaling mechanisms.Miles RR et al
197363202009Translational control by RGS2.Nguyen CH et al
110273162000Regulation of T cell activation, anxiety, and male aggression by RGS2.Oliveira-Dos-Santos AJ et al
109664762000GTPase-activating proteins for heterotrimeric G proteins: regulators of G protein signaling (RGS) and RGS-like proteins.Ross EM et al
160958802006RGS2 interacts with Gs and adenylyl cyclase in living cells.Roy AA et al
129201942003Recruitment of RGS2 and RGS4 to the plasma membrane by G proteins and receptors reflects functional interactions.Roy AA et al
169507882006Up-regulation of endogenous RGS2 mediates cross-desensitization between Gs and Gq signaling in osteoblasts.Roy AA et al
126046042003Identification of RGS2 and type V adenylyl cyclase interaction sites.Salim S et al
168959082006RGS2 inhibits the epithelial Ca2+ channel TRPV6.Schoeber JP et al
155361492005RGS2 is an important target gene of Flt3-ITD mutations in AML and functions in myeloid differentiation and leukemic transformation.Schwäble J et al
81798201994A human gene encoding a putative basic helix-loop-helix phosphoprotein whose mRNA increases rapidly in cycloheximide-treated blood mononuclear cells.Siderovski DP et al
118294882002Evolution of the regulators of G-protein signaling multigene family in mouse and human.Sierra DA et al
180676752007Regulator of G-protein signalling 2 mRNA is differentially expressed in mammary epithelial subpopulations and over-expressed in the majority of breast cancers.Smalley MJ et al
105144401999Muscarinic receptor stimulation increases regulators of G-protein signaling 2 mRNA levels through a protein kinase C-dependent mechanism.Song L et al
167330812006Cellular stress increases RGS2 mRNA and decreases RGS4 mRNA levels in SH-SY5Y cells.Song L et al
146083792003Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure.Tang KM et al
157935682005Spinophilin regulates Ca2+ signalling by binding the N-terminal domain of RGS2 and the third intracellular loop of G-protein-coupled receptors.Wang X et al
114885922001Oxidative stress and heat shock stimulate RGS2 expression in 1321N1 astrocytoma cells.Zmijewski JW et al
165171242006RGS2 is upregulated by and attenuates the hypertrophic effect of alpha1-adrenergic activation in cultured ventricular myocytes.Zou MX et al

Other Information

Locus ID:

NCBI: 5997
MIM: 600861
HGNC: 9998
Ensembl: ENSG00000116741


dbSNP: 5997
ClinVar: 5997
TCGA: ENSG00000116741


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Olfactory transductionKEGGko04740
Olfactory transductionKEGGhsa04740
Oxytocin signaling pathwayKEGGhsa04921
Oxytocin signaling pathwayKEGGko04921
cGMP-PKG signaling pathwayKEGGhsa04022
cGMP-PKG signaling pathwayKEGGko04022
Signal TransductionREACTOMER-HSA-162582
Signaling by GPCRREACTOMER-HSA-372790
GPCR downstream signalingREACTOMER-HSA-388396
G alpha (q) signalling eventsREACTOMER-HSA-416476
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907


Entity IDNameTypeEvidenceAssociationPKPDPMIDs


Pubmed IDYearTitleCitations
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
257662352015Control of mammalian G protein signaling by N-terminal acetylation and the N-end rule pathway.51
172203562007N-terminal residues control proteasomal degradation of RGS2, RGS4, and RGS5 in human embryonic kidney 293 cells.48
210416082011Family-based analysis of genetic variation underlying psychosis-inducing effects of cannabis: sibling analysis and proband follow-up.48
157935682005Spinophilin regulates Ca2+ signalling by binding the N-terminal domain of RGS2 and the third intracellular loop of G-protein-coupled receptors.47
233498322013MicroRNA-22 (miR-22) overexpression is neuroprotective via general anti-apoptotic effects and may also target specific Huntington's disease-related mechanisms.46
123565772002Regulator of G-protein signaling protein 2 modulates purinergic calcium and ciliary beat frequency responses in airway epithelia.43
183166762008Influence of RGS2 on anxiety-related temperament, personality, and brain function.43
126046042003Identification of RGS2 and type V adenylyl cyclase interaction sites.41
164499652006Regulator of G-protein signaling 2 (RGS2) inhibits androgen-independent activation of androgen receptor in prostate cancer cells.41


Chau H Nguyen

RGS2 (regulator of G-protein signaling 2, 24kDa)

Atlas Genet Cytogenet Oncol Haematol. 2010-01-01

Online version: http://atlasgeneticsoncology.org/gene/42102/rgs2