Disease relevance of RGS2

• Here, we identified RGS2 as a gene specifically downregulated in androgen-independent prostate cancer cells [1].
• G0S8 mRNA was also detected in all cases tested of chronic myelogenous leukemia (CML) in blast crisis [2].
• G0S8 expression was observed in most fresh samples of acute myelogenous leukemia (AML) (28/30) and most cases of adult acute lymphoblastic leukemia (ALL) (9/11) regardless of clinical classification [2].
• G0S8 has been mapped using fluorescence in situ hybridization (FISH) to human chromosome 1q31, the same site reported for the B cell homolog BL34/1R20 and within a region implicated in the development of hematological malignancies [2].
• Sequence similarities are noted between G0S8 and a variety of genes involved in the immune system, in the regulation of retroviruses, and in the cell cycle [3].

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

• Endogenous cytosolic RGS4 from NG108 cells and RGS2 from HEK293T cells cofractionated with the COPI complex by gel filtration [24].
• RT-PCR of both human and ovine epithelial cell RNA yielded fragments of expected size ( approximately 491 bp) and sequence, confirming RGS2 message [16].
• RGS2 messenger RNA was identified by Northern blot analysis to be expressed endogenously in betaTC3 and L293 cells, and its level was significantly induced by GIP treatment in betaTC3 cells [18].
• Immunofluorescence demonstrated RGS2 protein expression in cultured airway epithelial cells of both species [16].
• In an epidemiologic study of 477 bladder cancer patients and 446 matched controls, three noncoding single-nucleotide polymorphisms (SNPs) in RGS2 and RGS6 were each associated with a statistically significant reduction in bladder cancer risk [25].

References