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Gene Review

RGS2  -  regulator of G-protein signaling 2

Homo sapiens

Synonyms: Cell growth-inhibiting gene 31 protein, G0/G1 switch regulatory protein 8, G0S8, GIG31, Regulator of G-protein signaling 2
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Disease relevance of RGS2


High impact information on RGS2

  • Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice [4].
  • When reconstituted with phospholipid vesicles, RGS2 is 10-fold more potent than RGS4 in blocking Gqalpha-directed activation of phospholipase Cbeta1 [5].
  • RGS2 selectively binds Gqalpha, but not other Galpha proteins (Gi, Go, Gs, G12/13) in brain membranes; RGS4 binds Gqalpha and Gialpha family members [5].
  • We identified RGS2, a regulator of G-protein signaling, as a gene specifically repressed by Flt3-ITD [6].
  • Expression analyses in myeloid cell lines revealed induction of RGS2 during granulocytic but not during monocytic differentiation [6].

Chemical compound and disease context of RGS2

  • In human neuroblastoma SH-SY5Y cells stimulation of muscarinic receptors by carbachol activates phosphoinositide signaling and also caused a rapid, large, and long lasting increase in RGS2 mRNA levels [7].
  • In human astrocytoma 1321N1 cells RGS2 expression was increased by activation of muscarinic receptors coupled to phosphoinositide signaling with carbachol, or by increased cyclic AMP production, demonstrating that both signaling systems can increase the expression of a RGS family member in a single cell type [8].
  • We next investigated the effects of RGS2 overexpression produced by infecting cells with an adenovirus encoding RGS2-cDNA on cardiomyocyte responses to PE [9].

Biological context of RGS2

  • Although purified RGS2 blocks PLC-beta activation by the nonhydrolyzable GTP analog guanosine 5'-O-thiophosphate (GTPgammaS), its capacity to regulate inositol lipid signaling under conditions where GTPase-promoted hydrolysis of GTP is operative has not been fully explored [10].
  • In vitro phosphorylation of RGS2 by PKC decreased its capacity to attenuate both GTP and GTPgammaS-stimulated PLC-betat activation, with the extent of attenuation correlating with the level of RGS2 phosphorylation [10].
  • Although RGS2 possesses a nuclear targeting motif, it lacks a nuclear import signal and enters the nucleus by passive diffusion [11].
  • In these cells, RGS2 or -3 reduced receptor-mediated inositol phosphate generation in cell populations and reduced both the magnitude and kinetics (rise-time) of single cell Ca2+ signals [12].
  • In this study, we determined genetic variation in the human RGS2 gene by sequencing DNA in normotensive and hypertensive populations of whites (n=128) and blacks (n=122) [13].

Anatomical context of RGS2

  • In contrast, RGS2 and RGS4 completely inhibit Gq-directed activation of phospholipase C in cell membranes [5].
  • RGS2 and RGS10 accumulated in the nucleus of COS-7 cells transfected with GFP constructs of these proteins [14].
  • Because the mitogen and cytokine receptors that trigger expression of RGS2 and RGS16 in T cells do not activate heterotrimeric G proteins, these RGS proteins and the G proteins that they regulate may play a heretofore unrecognized role in T cell functional responses to Ag and cytokine activation [15].
  • Utilizing the turkey erythrocyte membrane model of inositol lipid signaling, we investigated regulation by RGS2 of both GTP and GTPgammaS-stimulated Galpha(11) signaling [10].
  • These data provide functional evidence that RGS2 modulates purinergic signaling in human and ovine ciliated airway epithelial cells [16].

Associations of RGS2 with chemical compounds

  • RGS2 has been shown to regulate Galpha(q)-mediated inositol lipid signaling [10].
  • Alanine scanning of the N-terminal amino acids of RGS2 identified three residues responsible for the inhibitory function of RGS2 [17].
  • Different inhibitory potencies of RGS2 were observed under conditions assessing its activity as a GAP versus as an effector antagonist; i.e. RGS2 was a 10-20-fold more potent inhibitor of aluminum fluoride and GTP-stimulated PLC-betat activity than of GTPgammaS-promoted PLC-betat activity [10].
  • In human embryonic kidney (HEK) 293 cells expressing recombinant Galpha(q/11)-coupled muscarinic M3 receptors, transient coexpression of RGS proteins with fluorescently-tagged biosensors for either Ins(1,4,5)P3 or diacylglycerol demonstrated that RGS2 and 3 inhibited receptor-mediated events [12].
  • Using single cell, real-time imaging, this study compared the impact of members of the B/R4 subfamily of the regulators of G-protein signaling (RGS) (RGS2, -3, and -4) on receptor-mediated inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], diacylglycerol, and Ca2+ signaling [12].

Regulatory relationships of RGS2

  • In contrast, RGS2 expression inhibited the GIP-induced cAMP response by 50%, a response similar to that of cells desensitized by preincubation with 10(-7) M GIP [18].
  • The bombesin-elicited translocation of vesicular ARF6 was mimicked by activated Galphaq and was partially inhibited by expression of RGS2, which down regulates Gq function [19].

Other interactions of RGS2

  • Expression of both genes increases in response to ConA, with RGS2 mRNA levels increasing briskly to a maximum between 0.5 and 1 hr and decreasing to baseline by 6 hr, whereas the RGS1 mRNA increase is delayed reaching a maximum between 1 and 2 hr [20].
  • These results suggest a potential role for RGS2 in modulating GIP-mediated insulin secretion in pancreatic islet cells [18].
  • METHODS AND RESULTS: Using RNase protection assays (RPAs) RGS2, 3L, 3S, 4, 5 and 6 were identified in the myocardium from terminally failing human hearts with dilated (DCM, n=22) or ischemic (ICM, n=18) cardiomyopathy and from nonfailing donor hearts (NF, n=9) [21].
  • The inhibition was not observed with RGS2, RGS5, and a functionally defective form of RGS16, RGS16(R169S/F170C) [22].
  • Channel stimulation is blocked by regulator of G-protein signaling 2 (RGS2) or the C-terminal region of phospholipase C-beta1 (PLCbeta1ct), which have been previously shown to function as GTPase-activating proteins for Galphaq [23].

Analytical, diagnostic and therapeutic context of RGS2


  1. 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, M.F., Tu, Y. Oncogene (2006) [Pubmed]
  2. Differential expression of a basic helix-loop-helix phosphoprotein gene, G0S8, in acute leukemia and localization to human chromosome 1q31. Wu, H.K., Heng, H.H., Shi, X.M., Forsdyke, D.R., Tsui, L.C., Mak, T.W., Minden, M.D., Siderovski, D.P. Leukemia (1995) [Pubmed]
  3. A human gene encoding a putative basic helix-loop-helix phosphoprotein whose mRNA increases rapidly in cycloheximide-treated blood mononuclear cells. Siderovski, D.P., Heximer, S.P., Forsdyke, D.R. DNA Cell Biol. (1994) [Pubmed]
  4. Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice. Heximer, S.P., Knutsen, R.H., Sun, X., Kaltenbronn, K.M., Rhee, M.H., Peng, N., Oliveira-dos-Santos, A., Penninger, J.M., Muslin, A.J., Steinberg, T.H., Wyss, J.M., Mecham, R.P., Blumer, K.J. J. Clin. Invest. (2003) [Pubmed]
  5. RGS2/G0S8 is a selective inhibitor of Gqalpha function. Heximer, S.P., Watson, N., Linder, M.E., Blumer, K.J., Hepler, J.R. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  6. RGS2 is an important target gene of Flt3-ITD mutations in AML and functions in myeloid differentiation and leukemic transformation. Schwäble, J., Choudhary, C., Thiede, C., Tickenbrock, L., Sargin, B., Steur, C., Rehage, M., Rudat, A., Brandts, C., Berdel, W.E., Müller-Tidow, C., Serve, H. Blood (2005) [Pubmed]
  7. 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, R.S. J. Biol. Chem. (1999) [Pubmed]
  8. Second messengers regulate RGS2 expression which is targeted to the nucleus. Zmijewski, J.W., Song, L., Harkins, L., Cobbs, C.S., Jope, R.S. Biochim. Biophys. Acta (2001) [Pubmed]
  9. RGS2 is upregulated by and attenuates the hypertrophic effect of alpha(1)-adrenergic activation in cultured ventricular myocytes. Zou, M.X., Roy, A.A., Zhao, Q., Kirshenbaum, L.A., Karmazyn, M., Chidiac, P. Cell. Signal. (2006) [Pubmed]
  10. Protein kinase C phosphorylates RGS2 and modulates its capacity for negative regulation of Galpha 11 signaling. Cunningham, M.L., Waldo, G.L., Hollinger, S., Hepler, J.R., Harden, T.K. J. Biol. Chem. (2001) [Pubmed]
  11. Mechanisms governing subcellular localization and function of human RGS2. Heximer, S.P., Lim, H., Bernard, J.L., Blumer, K.J. J. Biol. Chem. (2001) [Pubmed]
  12. Single-cell imaging of intracellular Ca2+ and phospholipase C activity reveals that RGS 2, 3, and 4 differentially regulate signaling via the Galphaq/11-linked muscarinic M3 receptor. Tovey, S.C., Willars, G.B. Mol. Pharmacol. (2004) [Pubmed]
  13. Polymorphisms and haplotypes of the regulator of G protein signaling-2 gene in normotensives and hypertensives. Riddle, E.L., Rana, B.K., Murthy, K.K., Rao, F., Eskin, E., O'Connor, D.T., Insel, P.A. Hypertension (2006) [Pubmed]
  14. Cytoplasmic, nuclear, and golgi localization of RGS proteins. Evidence for N-terminal and RGS domain sequences as intracellular targeting motifs. Chatterjee, T.K., Fisher, R.A. J. Biol. Chem. (2000) [Pubmed]
  15. Regulators of G protein signaling exhibit distinct patterns of gene expression and target G protein specificity in human lymphocytes. Beadling, C., Druey, K.M., Richter, G., Kehrl, J.H., Smith, K.A. J. Immunol. (1999) [Pubmed]
  16. Regulator of G-protein signaling protein 2 modulates purinergic calcium and ciliary beat frequency responses in airway epithelia. Nlend, M.C., Bookman, R.J., Conner, G.E., Salathe, M. Am. J. Respir. Cell Mol. Biol. (2002) [Pubmed]
  17. Identification of RGS2 and type V adenylyl cyclase interaction sites. Salim, S., Sinnarajah, S., Kehrl, J.H., Dessauer, C.W. J. Biol. Chem. (2003) [Pubmed]
  18. Role of regulator of G protein signaling in desensitization of the glucose-dependent insulinotropic peptide receptor. Tseng, C.C., Zhang, X.Y. Endocrinology (1998) [Pubmed]
  19. ADP-ribosylation factor 6 regulates actin cytoskeleton remodeling in coordination with Rac1 and RhoA. Boshans, R.L., Szanto, S., van Aelst, L., D'Souza-Schorey, C. Mol. Cell. Biol. (2000) [Pubmed]
  20. Comparison of mRNA expression of two regulators of G-protein signaling, RGS1/BL34/1R20 and RGS2/G0S8, in cultured human blood mononuclear cells. Heximer, S.P., Cristillo, A.D., Forsdyke, D.R. DNA Cell Biol. (1997) [Pubmed]
  21. Expression of ten RGS proteins in human myocardium: functional characterization of an upregulation of RGS4 in heart failure. Mittmann, C., Chung, C.H., Höppner, G., Michalek, C., Nose, M., Schüler, C., Schuh, A., Eschenhagen, T., Weil, J., Pieske, B., Hirt, S., Wieland, T. Cardiovasc. Res. (2002) [Pubmed]
  22. RGS16 attenuates galphaq-dependent p38 mitogen-activated protein kinase activation by platelet-activating factor. Zhang, Y., Neo, S.Y., Han, J., Yaw, L.P., Lin, S.C. J. Biol. Chem. (1999) [Pubmed]
  23. Muscarinic stimulation of alpha1E Ca channels is selectively blocked by the effector antagonist function of RGS2 and phospholipase C-beta1. Melliti, K., Meza, U., Adams, B. J. Neurosci. (2000) [Pubmed]
  24. RGS4 and RGS2 bind coatomer and inhibit COPI association with Golgi membranes and intracellular transport. Sullivan, B.M., Harrison-Lavoie, K.J., Marshansky, V., Lin, H.Y., Kehrl, J.H., Ausiello, D.A., Brown, D., Druey, K.M. Mol. Biol. Cell (2000) [Pubmed]
  25. A functional polymorphism in RGS6 modulates the risk of bladder cancer. Berman, D.M., Wang, Y., Liu, Z., Dong, Q., Burke, L.A., Liotta, L.A., Fisher, R., Wu, X. Cancer Res. (2004) [Pubmed]
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