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Gene Section
Review
RGS2 (regulator of G-protein signaling 2, 24kDa)
Chau H Nguyen
Department of Physiology and Pharmacology, University of Western Ontario, London, ON, N6A 5C1,
Canada (CHN)
Published in Atlas Database: January 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/RGS2ID42102ch1q31.html
DOI: 10.4267/2042/44889
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Expression
Identity
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).
Other names: G0S8
HGNC (Hugo): RGS2
Location: 1q31.2
Note: RGS2 is a member of the RGS protein family of
GTPase accelerating proteins (GAPs) for heterotrimeric
G proteins. It is classified into the B/R4 subfamily.
DNA/RNA
Description
The gene spans 3,233 bases.
Localisation
Transcription
RGS2 is localized to the nucleus and the plasma
membrane (Roy et al., 2003; Gu et al., 2007).
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.
Function
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 proteineffector 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-
Protein
MTS = Membrane Targeting Sequence (residues 33-53). RGS
= Regulator of G protein Signaling Domain (residues 80-205).
Description
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).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11)
1036
RGS2 (regulator of G-protein signaling 2, 24kDa)
Nguyen CH
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).
alterations in proliferation and differentiation in these
cells.
Hypertension
Note
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).
Homology
References
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).
Siderovski DP, Heximer SP, Forsdyke DR. A human gene
encoding a putative basic helix-loop-helix phosphoprotein
whose mRNA increases rapidly in cycloheximide-treated blood
mononuclear cells. DNA Cell Biol. 1994 Feb;13(2):125-47
Heximer SP, Watson N, Linder ME, Blumer KJ, Hepler JR.
RGS2/G0S8 is a selective inhibitor of Gqalpha function. Proc
Natl Acad Sci U S A. 1997 Dec 23;94(26):14389-93
Implicated in
Ingi T, Krumins AM, Chidiac P, Brothers GM, Chung S, Snow
BE, Barnes CA, Lanahan AA, Siderovski DP, Ross EM, Gilman
AG, Worley PF. Dynamic regulation of RGS2 suggests a novel
mechanism in G-protein signaling and neuronal plasticity. J
Neurosci. 1998 Sep 15;18(18):7178-88
Colorectal cancer
Note
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.
Heximer SP, Srinivasa SP, Bernstein LS, Bernard JL, Linder
ME, Hepler JR, Blumer KJ. G protein selectivity is a
determinant of RGS2 function. J Biol Chem. 1999 Nov
26;274(48):34253-9
Kammermeier PJ, Ikeda SR. Expression of RGS2 alters the
coupling of metabotropic glutamate receptor 1a to M-type K+
and N-type Ca2+ channels. Neuron. 1999 Apr;22(4):819-29
Breast cancer
Song L, De Sarno P, Jope RS. Muscarinic receptor stimulation
increases regulators of G-protein signaling 2 mRNA levels
through a protein kinase C-dependent mechanism. J Biol
Chem. 1999 Oct 15;274(42):29689-93
Note
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.
Miles RR, Sluka JP, Santerre RF, Hale LV, Bloem L,
Boguslawski G, Thirunavukkarasu K, Hock JM, Onyia JE.
Dynamic regulation of RGS2 in bone: potential new insights
into
parathyroid
hormone
signaling
mechanisms.
Endocrinology. 2000 Jan;141(1):28-36
Oliveira-Dos-Santos AJ, Matsumoto G, Snow BE, Bai D,
Houston FP, Whishaw IQ, Mariathasan S, Sasaki T, Wakeham
A, Ohashi PS, Roder JC, Barnes CA, Siderovski DP,
Penninger JM. Regulation of T cell activation, anxiety, and
male aggression by RGS2. Proc Natl Acad Sci U S A. 2000
Oct 24;97(22):12272-7
Prostate cancer
Note
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.
Ross EM, Wilkie TM. GTPase-activating proteins for
heterotrimeric G proteins: regulators of G protein signaling
(RGS) and RGS-like proteins. Annu Rev Biochem.
2000;69:795-827
Cunningham ML, Waldo GL, Hollinger S, Hepler JR, Harden
TK. Protein kinase C phosphorylates RGS2 and modulates its
capacity for negative regulation of Galpha 11 signaling. J Biol
Chem. 2001 Feb 23;276(8):5438-44
Acute myeloid leukemia
Zmijewski JW, Song L, Harkins L, Cobbs CS, Jope RS.
Oxidative stress and heat shock stimulate RGS2 expression in
1321N1 astrocytoma cells. Arch Biochem Biophys. 2001 Aug
15;392(2):192-6
Note
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
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11)
Cladman W, Chidiac P. Characterization and comparison of
RGS2 and RGS4 as GTPase-activating proteins for m2
muscarinic receptor-stimulated G(i). Mol Pharmacol. 2002
Sep;62(3):654-9
Sierra DA, Gilbert DJ, Householder D, Grishin NV, Yu K,
Ukidwe P, Barker SA, He W, Wensel TG, Otero G, Brown G,
1037
RGS2 (regulator of G-protein signaling 2, 24kDa)
Nguyen CH
Copeland NG, Jenkins NA, Wilkie TM. Evolution of the
regulators of G-protein signaling multigene family in mouse
and human. Genomics. 2002 Feb;79(2):177-85
androgen-independent activation of androgen receptor in
prostate cancer cells. Oncogene. 2006 Jun 22;25(26):3719-34
Heo K, Ha SH, Chae YC, Lee S, Oh YS, Kim YH, Kim SH, Kim
JH, Mizoguchi A, Itoh TJ, Kwon HM, Ryu SH, Suh PG. RGS2
promotes formation of neurites by stimulating microtubule
polymerization. Cell Signal. 2006 Dec;18(12):2182-92
Heximer SP, Knutsen RH, Sun X, Kaltenbronn KM, Rhee MH,
Peng N, Oliveira-dos-Santos A, Penninger JM, Muslin AJ,
Steinberg TH, Wyss JM, Mecham RP, Blumer KJ.
Hypertension and prolonged vasoconstrictor signaling in
RGS2-deficient mice. J Clin Invest. 2003 Feb;111(4):445-52
Roy AA, Baragli A, Bernstein LS, Hepler JR, Hébert TE,
Chidiac P. RGS2 interacts with Gs and adenylyl cyclase in
living cells. Cell Signal. 2006 Mar;18(3):336-48
Roy AA, Lemberg KE, Chidiac P. Recruitment of RGS2 and
RGS4 to the plasma membrane by G proteins and receptors
reflects functional interactions. Mol Pharmacol. 2003
Sep;64(3):587-93
Roy AA, Nunn C, Ming H, Zou MX, Penninger J, Kirshenbaum
LA, Dixon SJ, Chidiac P. Up-regulation of endogenous RGS2
mediates cross-desensitization between Gs and Gq signaling
in osteoblasts. J Biol Chem. 2006 Oct 27;281(43):32684-93
Salim S, Sinnarajah S, Kehrl JH, Dessauer CW. Identification
of RGS2 and type V adenylyl cyclase interaction sites. J Biol
Chem. 2003 May 2;278(18):15842-9
Schoeber JP, Topala CN, Wang X, Diepens RJ, Lambers TT,
Hoenderop JG, Bindels RJ. RGS2 inhibits the epithelial Ca2+
channel TRPV6. J Biol Chem. 2006 Oct 6;281(40):29669-74
Tang KM, Wang GR, Lu P, Karas RH, Aronovitz M, Heximer
SP, Kaltenbronn KM, Blumer KJ, Siderovski DP, Zhu Y,
Mendelsohn ME. Regulator of G-protein signaling-2 mediates
vascular smooth muscle relaxation and blood pressure. Nat
Med. 2003 Dec;9(12):1506-12
Song L, Jope RS. Cellular stress increases RGS2 mRNA and
decreases RGS4 mRNA levels in SH-SY5Y cells. Neurosci
Lett. 2006 Jul 24;402(3):205-9
Zou MX, Roy AA, Zhao Q, Kirshenbaum LA, Karmazyn M,
Chidiac P. RGS2 is upregulated by and attenuates the
hypertrophic effect of alpha1-adrenergic activation in cultured
ventricular myocytes. Cell Signal. 2006 Oct;18(10):1655-63
Bernstein LS, Ramineni S, Hague C, Cladman W, Chidiac P,
Levey AI, Hepler JR. RGS2 binds directly and selectively to the
M1 muscarinic acetylcholine receptor third intracellular loop to
modulate Gq/11alpha signaling. J Biol Chem. 2004 May
14;279(20):21248-56
Gu S, He J, Ho WT, Ramineni S, Thal DM, Natesh R, Tesmer
JJ, Hepler JR, Heximer SP. Unique hydrophobic extension of
the RGS2 amphipathic helix domain imparts increased plasma
membrane binding and function relative to other RGS R4/B
subfamily members. J Biol Chem. 2007 Nov 9;282(45):3306475
Larminie C, Murdock P, Walhin JP, Duckworth M, Blumer KJ,
Scheideler MA, Garnier M. Selective expression of regulators
of G-protein signaling (RGS) in the human central nervous
system. Brain Res Mol Brain Res. 2004 Mar 17;122(1):24-34
McCaffrey RL, Fawcett P, O'Riordan M, Lee KD, Havell EA,
Brown PO, Portnoy DA. A specific gene expression program
triggered by Gram-positive bacteria in the cytosol. Proc Natl
Acad Sci U S A. 2004 Aug 3;101(31):11386-91
Smalley MJ, Iravani M, Leao M, Grigoriadis A, Kendrick H,
Dexter T, Fenwick K, Regan JL, Britt K, McDonald S, Lord CJ,
Mackay A, Ashworth A. Regulator of G-protein signalling 2
mRNA is differentially expressed in mammary epithelial
subpopulations and over-expressed in the majority of breast
cancers. Breast Cancer Res. 2007;9(6):R85
Hague C, Bernstein LS, Ramineni S, Chen Z, Minneman KP,
Hepler JR. Selective inhibition of alpha1A-adrenergic receptor
signaling by RGS2 association with the receptor third
intracellular loop. J Biol Chem. 2005 Jul 22;280(29):27289-95
Gu S, Anton A, Salim S, Blumer KJ, Dessauer CW, Heximer
SP. Alternative translation initiation of human regulators of Gprotein signaling-2 yields a set of functionally distinct proteins.
Mol Pharmacol. 2008 Jan;73(1):1-11
Schwäble J, Choudhary C, Thiede C, Tickenbrock L, Sargin B,
Steur C, Rehage M, Rudat A, Brandts C, Berdel WE, MüllerTidow C, Serve H. RGS2 is an important target gene of Flt3ITD mutations in AML and functions in myeloid differentiation
and leukemic transformation. Blood. 2005 Mar 1;105(5):210714
Nguyen CH, Ming H, Zhao P, Hugendubler L, Gros R, Kimball
SR, Chidiac P. Translational control by RGS2. J Cell Biol. 2009
Sep 7;186(5):755-65
Jiang Z, Wang Z, Xu Y, Wang B, Huang W, Cai S. Analysis of
RGS2 expression and prognostic significance in stage II and III
colorectal cancer. Biosci Rep. 2010 Dec;30(6):383-90
Wang X, Zeng W, Soyombo AA, Tang W, Ross EM, Barnes
AP, Milgram SL, Penninger JM, Allen PB, Greengard P,
Muallem S. Spinophilin regulates Ca2+ signalling by binding
the N-terminal domain of RGS2 and the third intracellular loop
of G-protein-coupled receptors. Nat Cell Biol. 2005
Apr;7(4):405-11
This article should be referenced as such:
Nguyen CH. RGS2 (regulator of G-protein signaling 2, 24kDa).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):10361038.
Cao X, Qin J, Xie Y, Khan O, Dowd F, Scofield M, Lin MF, Tu
Y. Regulator of G-protein signaling 2 (RGS2) inhibits
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11)
1038