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

Identity

Other namesG0S8
HGNC (Hugo) RGS2
LocusID (NCBI) 5997
Location 1q31.2
Location_base_pair Starts at 192778169 and ends at 192781407 bp from pter ( according to hg19-Feb_2009)  [Mapping]
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.
Transcription 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.

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).
Expression 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).
Localisation RGS2 is localized to the nucleus and the plasma membrane (Roy et al., 2003; Gu et al., 2007).
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 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).
Homology 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 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.
  
Entity Breast cancer
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.
  
Entity 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.
  
Entity Acute myeloid leukemia
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 alterations in proliferation and differentiation in these cells.
  
Entity 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).
  

External links

Nomenclature
HGNC (Hugo)RGS2   9998
Entrez_Gene (NCBI)RGS2  5997  regulator of G-protein signaling 2, 24kDa
Cards
AtlasRGS2ID42102ch1q31
GeneCards (Weizmann)RGS2
Ensembl (Hinxton)ENSG00000116741 [Gene_View]  chr1:192778169-192781407 [Contig_View]  RGS2 [Vega]
AceView (NCBI)RGS2
Genatlas (Paris)RGS2
SOURCE (Stanford)NM_002923
Genomic and cartography
GoldenPath (UCSC)RGS2  -  1q31.2   chr1:192778169-192781407 +  1q31   [Description]    (hg19-Feb_2009)
EnsemblRGS2 - 1q31 [CytoView]
Mapping of homologs : NCBIRGS2 [Mapview]
OMIM600861   
Gene and transcription
Genbank (Entrez)AF493926 AK313668 AY971351 BC007049 BC042755
RefSeq transcript (SRS)NM_002923
RefSeq transcript (Entrez)NM_002923
RefSeq genomic (SRS)AC_000133 NC_000001 NC_018912 NG_012800 NT_004487 NW_001838533 NW_004077999
RefSeq genomic (Entrez)AC_000133 NC_000001 NC_018912 NG_012800 NT_004487 NW_001838533 NW_004077999
Consensus coding sequences : CCDS (NCBI)RGS2
Cluster EST : UnigeneHs.78944 [ SRS ] Hs.78944 [ NCBI ]
CGAP (NCI)Hs.78944
Alternative Splicing : Fast-db (Paris)GSHG0001292
Alternative Splicing GalleryENSG00000116741
Gene ExpressionRGS2 [ NCBI-GEO ]   RGS2 [ EBI - ARRAY_EXPRESS ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP41220 (SRS) P41220 (Uniprot)
NextProtP41220
With graphics : InterProP41220
Splice isoforms : SwissVarP41220(Swissvar)
Domaine pattern : Prosite (SRS)RGS (PS50132)   
Domaine pattern : Prosite (Expaxy)RGS (PS50132)   
Domains : Interpro (SRS)Regulat_G_prot_signal    Regulat_G_prot_signal_dom1    Regulat_G_prot_signal_superfam   
Domains : Interpro (EBI)Regulat_G_prot_signal    Regulat_G_prot_signal_dom1    Regulat_G_prot_signal_superfam   
Related proteins : CluSTrP41220
Domain families : Pfam (SRS)RGS (PF00615)   
Domain families : Pfam (Sanger)RGS (PF00615)   
Domain families : Pfam (NCBI)pfam00615   
Domain families : Smart (EMBL)RGS (SM00315)  
DMDM5997
Blocks (Seattle)P41220
PDB (SRS)2AF0    2V4Z   
PDB (PDBSum)2AF0    2V4Z   
PDB (IMB)2AF0    2V4Z   
PDB (RSDB)2AF0    2V4Z   
Human Protein AtlasENSG00000116741
HPRD02917
IPIIPI00013177   IPI01017975   IPI01017891   IPI01018248   
Protein Interaction databases
DIP (DOE-UCLA)P41220
IntAct (EBI)P41220
FunCoupENSG00000116741
REACTOMERGS2
Protein Interaction Database5997
BioGRIDRGS2
InParanoidP41220
Interologous Interaction database P41220
IntegromeDBRGS2
Polymorphism : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)RGS2
SNP (GeneSNP Utah)RGS2
SNP : HGBaseRGS2
Genetic variants : HAPMAPRGS2
Somatic Mutations in Cancer : COSMICRGS2 
CONAN: Copy Number AnalysisRGS2 
Mutations and Diseases : HGMDRGS2
OMIM600861   
GENETests600861   
Disease Genetic AssociationRGS2
Huge Navigator RGS2 [HugePedia]  RGS2 [HugeCancerGEM]
Genomic VariantsRGS2  RGS2 [DGVbeta]
snp3D : Map Gene to Disease5997
General knowledge
Homologs : HomoloGeneRGS2
Homology/Alignments : Family Browser (UCSC)RGS2
Phylogenetic Trees/Animal Genes : TreeFamRGS2
Chemical/Protein Interactions : CTD5997
Chemical/Pharm GKB GenePA34372
Clinical trialRGS2
Cancer Resource (Charite)ENSG00000116741
Ontology : AmiGOGTPase activator activity  protein binding  calmodulin binding  nucleolus  cytoplasm  mitochondrion  cytosol  plasma membrane  regulation of translation  cell cycle  spermatogenesis  regulation of G-protein coupled receptor protein signaling pathway  internal side of plasma membrane  negative regulation of phospholipase activity  negative regulation of cardiac muscle hypertrophy  termination of G-protein coupled receptor signaling pathway  negative regulation of MAP kinase activity  positive regulation of GTPase activity  positive regulation of GTPase activity  negative regulation of G-protein coupled receptor protein signaling pathway  brown fat cell differentiation  relaxation of cardiac muscle  relaxation of vascular smooth muscle  positive regulation of cardiac muscle contraction  regulation of adrenergic receptor signaling pathway  
Ontology : EGO-EBIGTPase activator activity  protein binding  calmodulin binding  nucleolus  cytoplasm  mitochondrion  cytosol  plasma membrane  regulation of translation  cell cycle  spermatogenesis  regulation of G-protein coupled receptor protein signaling pathway  internal side of plasma membrane  negative regulation of phospholipase activity  negative regulation of cardiac muscle hypertrophy  termination of G-protein coupled receptor signaling pathway  negative regulation of MAP kinase activity  positive regulation of GTPase activity  positive regulation of GTPase activity  negative regulation of G-protein coupled receptor protein signaling pathway  brown fat cell differentiation  relaxation of cardiac muscle  relaxation of vascular smooth muscle  positive regulation of cardiac muscle contraction  regulation of adrenergic receptor signaling pathway  
Other databases
Probes
Litterature
PubMed102 Pubmed reference(s) in Entrez
PubGeneRGS2
iHOPRGS2

Bibliography

A human gene encoding a putative basic helix-loop-helix phosphoprotein whose mRNA increases rapidly in cycloheximide-treated blood mononuclear cells.
Siderovski DP, Heximer SP, Forsdyke DR.
DNA Cell Biol. 1994 Feb;13(2):125-47.
PMID 8179820
 
RGS2/G0S8 is a selective inhibitor of Gqalpha function.
Heximer SP, Watson N, Linder ME, Blumer KJ, Hepler JR.
Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14389-93.
PMID 9405622
 
Dynamic regulation of RGS2 suggests a novel mechanism in G-protein signaling and neuronal plasticity.
Ingi T, Krumins AM, Chidiac P, Brothers GM, Chung S, Snow BE, Barnes CA, Lanahan AA, Siderovski DP, Ross EM, Gilman AG, Worley PF.
J Neurosci. 1998 Sep 15;18(18):7178-88.
PMID 9736641
 
G protein selectivity is a determinant of RGS2 function.
Heximer SP, Srinivasa SP, Bernstein LS, Bernard JL, Linder ME, Hepler JR, Blumer KJ.
J Biol Chem. 1999 Nov 26;274(48):34253-9.
PMID 10567399
 
Expression of RGS2 alters the coupling of metabotropic glutamate receptor 1a to M-type K+ and N-type Ca2+ channels.
Kammermeier PJ, Ikeda SR.
Neuron. 1999 Apr;22(4):819-29.
PMID 10230801
 
Muscarinic receptor stimulation increases regulators of G-protein signaling 2 mRNA levels through a protein kinase C-dependent mechanism.
Song L, De Sarno P, Jope RS.
J Biol Chem. 1999 Oct 15;274(42):29689-93.
PMID 10514440
 
Dynamic regulation of RGS2 in bone: potential new insights into parathyroid hormone signaling mechanisms.
Miles RR, Sluka JP, Santerre RF, Hale LV, Bloem L, Boguslawski G, Thirunavukkarasu K, Hock JM, Onyia JE.
Endocrinology. 2000 Jan;141(1):28-36.
PMID 10614620
 
Regulation of T cell activation, anxiety, and male aggression by RGS2.
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.
Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):12272-7.
PMID 11027316
 
GTPase-activating proteins for heterotrimeric G proteins: regulators of G protein signaling (RGS) and RGS-like proteins.
Ross EM, Wilkie TM.
Annu Rev Biochem. 2000;69:795-827.
PMID 10966476
 
Protein kinase C phosphorylates RGS2 and modulates its capacity for negative regulation of Galpha 11 signaling.
Cunningham ML, Waldo GL, Hollinger S, Hepler JR, Harden TK.
J Biol Chem. 2001 Feb 23;276(8):5438-44. Epub 2000 Nov 3.
PMID 11063746
 
Oxidative stress and heat shock stimulate RGS2 expression in 1321N1 astrocytoma cells.
Zmijewski JW, Song L, Harkins L, Cobbs CS, Jope RS.
Arch Biochem Biophys. 2001 Aug 15;392(2):192-6.
PMID 11488592
 
Characterization and comparison of RGS2 and RGS4 as GTPase-activating proteins for m2 muscarinic receptor-stimulated G(i).
Cladman W, Chidiac P.
Mol Pharmacol. 2002 Sep;62(3):654-9.
PMID 12181442
 
Evolution of the regulators of G-protein signaling multigene family in mouse and human.
Sierra DA, Gilbert DJ, Householder D, Grishin NV, Yu K, Ukidwe P, Barker SA, He W, Wensel TG, Otero G, Brown G, Copeland NG, Jenkins NA, Wilkie TM.
Genomics. 2002 Feb;79(2):177-85.
PMID 11829488
 
Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice.
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.
J Clin Invest. 2003 Feb;111(4):445-52.
PMID 12588882
 
Recruitment of RGS2 and RGS4 to the plasma membrane by G proteins and receptors reflects functional interactions.
Roy AA, Lemberg KE, Chidiac P.
Mol Pharmacol. 2003 Sep;64(3):587-93.
PMID 12920194
 
Identification of RGS2 and type V adenylyl cyclase interaction sites.
Salim S, Sinnarajah S, Kehrl JH, Dessauer CW.
J Biol Chem. 2003 May 2;278(18):15842-9. Epub 2003 Feb 25.
PMID 12604604
 
Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure.
Tang KM, Wang GR, Lu P, Karas RH, Aronovitz M, Heximer SP, Kaltenbronn KM, Blumer KJ, Siderovski DP, Zhu Y, Mendelsohn ME.
Nat Med. 2003 Dec;9(12):1506-12. Epub 2003 Nov 9.
PMID 14608379
 
RGS2 binds directly and selectively to the M1 muscarinic acetylcholine receptor third intracellular loop to modulate Gq/11alpha signaling.
Bernstein LS, Ramineni S, Hague C, Cladman W, Chidiac P, Levey AI, Hepler JR.
J Biol Chem. 2004 May 14;279(20):21248-56. Epub 2004 Feb 19.
PMID 14976183
 
Selective expression of regulators of G-protein signaling (RGS) in the human central nervous system.
Larminie C, Murdock P, Walhin JP, Duckworth M, Blumer KJ, Scheideler MA, Garnier M.
Brain Res Mol Brain Res. 2004 Mar 17;122(1):24-34.
PMID 14992813
 
A specific gene expression program triggered by Gram-positive bacteria in the cytosol.
McCaffrey RL, Fawcett P, O'Riordan M, Lee KD, Havell EA, Brown PO, Portnoy DA.
Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11386-91. Epub 2004 Jul 21.
PMID 15269347
 
Selective inhibition of alpha1A-adrenergic receptor signaling by RGS2 association with the receptor third intracellular loop.
Hague C, Bernstein LS, Ramineni S, Chen Z, Minneman KP, Hepler JR.
J Biol Chem. 2005 Jul 22;280(29):27289-95. Epub 2005 May 24.
PMID 15917235
 
RGS2 is an important target gene of Flt3-ITD mutations in AML and functions in myeloid differentiation and leukemic transformation.
Schwable J, Choudhary C, Thiede C, Tickenbrock L, Sargin B, Steur C, Rehage M, Rudat A, Brandts C, Berdel WE, Muller-Tidow C, Serve H.
Blood. 2005 Mar 1;105(5):2107-14. Epub 2004 Nov 9.
PMID 15536149
 
Spinophilin regulates Ca2+ signalling by binding the N-terminal domain of RGS2 and the third intracellular loop of G-protein-coupled receptors.
Wang X, Zeng W, Soyombo AA, Tang W, Ross EM, Barnes AP, Milgram SL, Penninger JM, Allen PB, Greengard P, Muallem S.
Nat Cell Biol. 2005 Apr;7(4):405-11. Epub 2005 Mar 27.
PMID 15793568
 
Regulator of G-protein signaling 2 (RGS2) inhibits androgen-independent activation of androgen receptor in prostate cancer cells.
Cao X, Qin J, Xie Y, Khan O, Dowd F, Scofield M, Lin MF, Tu Y.
Oncogene. 2006 Jun 22;25(26):3719-34. Epub 2006 Jan 30.
PMID 16449965
 
RGS2 promotes formation of neurites by stimulating microtubule polymerization.
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.
Cell Signal. 2006 Dec;18(12):2182-92. Epub 2006 May 23.
PMID 16820281
 
RGS2 interacts with Gs and adenylyl cyclase in living cells.
Roy AA, Baragli A, Bernstein LS, Hepler JR, Hebert TE, Chidiac P.
Cell Signal. 2006a Mar;18(3):336-48. Epub 2005 Aug 10.
PMID 16095880
 
Up-regulation of endogenous RGS2 mediates cross-desensitization between Gs and Gq signaling in osteoblasts.
Roy AA, Nunn C, Ming H, Zou MX, Penninger J, Kirshenbaum LA, Dixon SJ, Chidiac P.
J Biol Chem. 2006b Oct 27;281(43):32684-93. Epub 2006 Sep 1.
PMID 16950788
 
RGS2 inhibits the epithelial Ca2+ channel TRPV6.
Schoeber JP, Topala CN, Wang X, Diepens RJ, Lambers TT, Hoenderop JG, Bindels RJ.
J Biol Chem. 2006 Oct 6;281(40):29669-74. Epub 2006 Aug 8.
PMID 16895908
 
Cellular stress increases RGS2 mRNA and decreases RGS4 mRNA levels in SH-SY5Y cells.
Song L, Jope RS.
Neurosci Lett. 2006 Jul 24;402(3):205-9. Epub 2006 Jun 2.
PMID 16733081
 
RGS2 is upregulated by and attenuates the hypertrophic effect of alpha1-adrenergic activation in cultured ventricular myocytes.
Zou MX, Roy AA, Zhao Q, Kirshenbaum LA, Karmazyn M, Chidiac P.
Cell Signal. 2006 Oct;18(10):1655-63. Epub 2006 Mar 6.
PMID 16517124
 
Unique 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, He J, Ho WT, Ramineni S, Thal DM, Natesh R, Tesmer JJ, Hepler JR, Heximer SP.
J Biol Chem. 2007 Nov 9;282(45):33064-75. Epub 2007 Sep 11.
PMID 17848575
 
Regulator of G-protein signalling 2 mRNA is differentially expressed in mammary epithelial subpopulations and over-expressed in the majority of breast cancers.
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.
Breast Cancer Res. 2007;9(6):R85.
PMID 18067675
 
Alternative translation initiation of human regulators of G-protein signaling-2 yields a set of functionally distinct proteins.
Gu S, Anton A, Salim S, Blumer KJ, Dessauer CW, Heximer SP.
Mol Pharmacol. 2008 Jan;73(1):1-11. Epub 2007 Sep 27.
PMID 17901199
 
Translational control by RGS2.
Nguyen CH, Ming H, Zhao P, Hugendubler L, Gros R, Kimball SR, Chidiac P.
J Cell Biol. 2009 Sep 7;186(5):755-65.
PMID 19736320
 
Analysis of RGS2 expression and prognostic significance in stage II and III colorectal cancer.
Jiang Z, Wang Z, Xu Y, Wang B, Huang W, Cai S.
Biosci Rep.. [Epub ahead of print]
PMID 20001967
 
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Contributor(s)

Written01-2010Chau H Nguyen
Department of Physiology and Pharmacology, University of Western Ontario, London, ON, N6A 5C1, Canada

Citation

This paper should be referenced as such :
Nguyen CH . RGS2 (regulator of G-protein signaling 2, 24kDa). Atlas Genet Cytogenet Oncol Haematol. January 2010 .
URL : http://AtlasGeneticsOncology.org/Genes/RGS2ID42102ch1q31.html

This paper is referenced by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/44889/1/01-2010-RGS2ID42102ch1q31.pdf   [ Bibliographic record ]

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