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regulator of G-protein signaling 3

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Target not currently curated in GtoImmuPdb

Target id: 2810

Nomenclature: regulator of G-protein signaling 3

Abbreviated Name: RGS3

Family: R4 family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1198 9q32 RGS3 regulator of G protein signaling 3 2
Mouse - 966 4 33.19 cM Rgs3 regulator of G-protein signaling 3
Rat - 967 5q24 Rgs3 regulator of G-protein signaling 3
Previous and Unofficial Names Click here for help
C2PA | PDZ-RGS3  | RGP3
Database Links Click here for help
Alphafold P49796 (Hs), Q9DC04 (Mm), P49797 (Rn)
CATH/Gene3D 1.10.196.10, 2.30.29.30, 2.60.40.150
Ensembl Gene ENSG00000138835 (Hs), ENSMUSG00000059810 (Mm), ENSRNOG00000024501 (Rn)
Entrez Gene 5998 (Hs), 50780 (Mm), 54293 (Rn)
Human Protein Atlas ENSG00000138835 (Hs)
KEGG Gene hsa:5998 (Hs), mmu:50780 (Mm), rno:54293 (Rn)
OMIM 602189 (Hs)
Pharos P49796 (Hs)
RefSeq Nucleotide NM_144488 (Hs), NM_001282922 (Hs), NM_001282923 (Hs), NM_144489 (Hs), NM_017790 (Hs), NM_130795 (Hs), NM_134257 (Mm), NM_019340 (Rn)
RefSeq Protein NP_652759 (Hs), NP_570613 (Hs), NP_001269851 (Hs), NP_001106852 (Hs), NP_652760 (Hs), NP_599018 (Mm), NP_062213 (Rn)
UniProtKB P49796 (Hs), Q9DC04 (Mm), P49797 (Rn)
Wikipedia RGS3 (Hs)
Associated Proteins Click here for help
G Proteins
Name References
Gαi/0
Gαq/11
Gαs
Interacting Proteins
Name Effect References
14-3-3 protein Inhibits GAP activity of RGS3. 31,38
GluA2 Regulates glutamatergic synapses. 25
EPH receptor B2 Inhibits heterotremeric G protein signal. 22,45
Phospholipid scramblase 1 (PLSCR1) 1,39
Guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 3 9
Polyubiquitin-C 18
Amyloid beta (A4) precursor protein 32
Arrestin, beta 1 49
Interferon, alpha-inducible protein 46
Tissue Distribution Click here for help
Brain, heart, kindey, liver and pancreas, digestive tract, urinary bladder, male reproductive system, breast and female reproductive system, skin, blood and immune system, respiratory system.
Species:  Human
Technique:  Immunohistochemistry.
References:  6,14,20,26
Heart, brain, kindey, blood and immune system.
Species:  Mouse
Technique:  Immunohistochemistry.
References:  14,21,30,37,48
Heart, spleen, brain, testis, intestine, uterus, ovary, lung.
Species:  Rat
Technique:  Western blot and immunohistochemistry.
References:  16,19,53
Functional Assays Click here for help
Positive regulation of GTPase activity.
Species:  Human
Tissue:  HEK293 cells and mouse NIH 3T3 fibroblasts.
Response measured:  Increase in GTPase activation.
References:  10
Translocation to the membrane.
Species:  Human
Tissue:  HEK293 cells and mouse NIH 3T3 fibroblasts.
Response measured:  Regulation of G-protein coupled receptor protein signaling pathway.
References:  10
Inactivation of MAPK activity.
Species:  Human
Tissue:  Mammalian cells.
Response measured:  Inactivation of MAPK activity.
References:  8
Impairs signal transduction through the muscarinic M1 receptor and beta-adrenergic receptor.
Species:  Human
Tissue:  HEK 293T cells.
Response measured:  Inhibition of IP3 production.
References:  40
Attenuation of Gqαα protein activation of phospholipase C.
Species:  Unknown
Tissue:  COS1 cels.
Response measured:  Inhibition of IP3 production.
References:  27
RGS3T (a truncated variant comprising amino acids 314–519) is localized to the nucleus and induces apoptosis.
Species:  Human
Tissue:  Chinese hamster ovary (CHO) cells.
Response measured:  Apoptosis assay.
References:  9
Physiological Functions Click here for help
Inhibition of MEK-ERK1/2 signaling.
Species:  Mouse
Tissue:  Heart.
References:  21
Modulating the LH secretory responsiveness of the pituitary gonadotrope to GnRH.
Species:  Human
Tissue:  Gonadotropic alpha T3-1 cells.
References:  27
Shaping the magnitude and kinetics of physiological events.
Species:  Human
Tissue:  HEK293 cells.
References:  24
Promotes epithelial mesenchymal transition.
Species:  Human
Tissue:  HEK 293 cells.
References:  43
Cortical development: KIF20A is essential for maintaining progenitor cell state and acts by facilitating the localization of RGS3 to the ICB/midbody of dividing NPCs where KIF20A, RGS3, and Gα subunit may work together to control the outcome of cell division in mice.
Species:  Mouse
Tissue: 
References:  13
RGS3 might be an essential factor in follicular growth and have a potential inhibitory effect on follicle number; RGS3 can regulate follicle development and growth via activation of the NFκB signaling pathway.
Species:  Chicken
Tissue: 
References:  42
RGS3 may provide protection against pathological changes of adventitial fibroblasts and the development of atherosclerosis by inhibiting TGF-β1/Smad signaling.
Species:  None
Tissue: 
References:  50
Potent inhibition of angiotensin AT1 receptor signaling
Species:  None
Tissue: 
References:  44
Involved in shortening neutrophil lifespan in response to the endogenous ribosomal protein S19 ploymer (which is a C5a mimic).
Species:  Human
Tissue:  HL-60 neutrophils
References:  29
MicroRNA‑126‑3p inhibits the proliferation, migration, invasion, and angiogenesis of triple‑negative breast cancer cells by targeting RGS3
Species:  Human
Tissue: 
References:  15
The RGS3-KIF20A axis regulates the balance between proliferation and differentiation in the mammalian cortex via a mechanism that is independent of spindle/cleavage plane orientation.
Species:  None
Tissue: 
References:  34
Physiological Consequences of Altering Gene Expression Click here for help
Overexpression of RGS3 protects against cardiac hypertrophy.
Species:  Mouse
Tissue:  Heart.
Technique:  Gene over-expression.
References:  21
Transformation of HL-60 cells to overexpress RGS3 promotes apoptosis in association with the downregulation of the extracellular signal-regulated kinase signal, and vice versa in the RGS3 knocked-down cells.
Species:  Mouse
Tissue:  HL-60 cells, fate of Q137N-HL-60 cells.
Technique:  RNA interference (RNAi).
References:  28
RGS3 deficiency causes early cell cycle exit and precocious differentiation in neural progenitor cells of the developing cerebral cortex, leading to a loss of cortical neural progenitor cells.
Species:  Mouse
Tissue:  Embryonic brain cells.
Technique:  Gene knock-out.
References:  35
RGS3 is significantly upregulated in gastric cancer tumours (regulated by microRNA-126), and is associated with a poor prognosis.
Species:  Human
Tissue: 
Technique: 
References:  47
RGS3, a potential inhibitor of the MEK-ERK1/2 signaling axis, was found to be downregulated by ectopic noncoding RNA HOXD-AS1 overexpression, leading to a reduced apoptotic effect.
Species:  Human
Tissue:  Human hepatocellular carcinoma cells
Technique: 
References:  23
RGS3 appears to be upregulated by inflammatory processes that are associated with neuropathic pain,
Species:  Rat
Tissue: 
Technique:  Rat model of neuropathic pain
References:  7
RGS3 inhibition by miR-25 which is upregulated in NSCLC, is associated with inhibition of apoptosis.
Species:  Human
Tissue:  Human lung cancer cells
Technique: 
References:  5
Expression of RGS3 was inhibited by adenosine agonists in both human astrocytoma cells and rat astrocytes.
Species:  Human
Tissue:  Astrocytes and astrocytoma cells
Technique: 
References:  11
Physiological Consequences of Altering Gene Expression Comments
RGS3 is upregulated in p53-mutated breast tumors, and may be a useful predictor of response to docetaxel [33].
RGS3 deficient C. elegans fail to respond to intense sensory stimuli [12].
Xenobiotics Influencing Gene Expression Click here for help
Rgs3 gene expression is repressed by high-fat feeding.
Species:  Mouse
Tissue:  Hepatic cells.
Technique:  Misroarray.
References:  36
Gene Expression and Pathophysiology Comments
Experiments in rats suggests that modulation of Rgs3 gene expression (and/or other genes involved in the control of G-protein signalling) may play a role the pathology of hypertension-associated bladder dysfunction [52].
Biologically Significant Variants Click here for help
Type:  mRNA transcript variant.
Species:  Human
Description:  This RGS3 variant enhances canonical Wnt signaling and promotes epithelial mesenchymal transition via inhibition of G-protein-mediated MAP kinase activation
Amino acids:  93
Nucleotide accession:  NM_001282923
Protein accession:  NP_001106852
References:  8,43
Type:  mRNA transcript variant.
Species:  Human
Description:  This RGS3 variant enhances canonical Wnt signaling and promotes epithelial mesenchymal transition.
Amino acids:  311
Nucleotide accession:  NM_144489
Protein accession:  NP_652760
References:  3-4,17
Type:  mRNA transcript variant.
Species:  Human
Description:  This RGS3 variant leads to inhibition of G-protein-mediated MAP kinase activation.
Amino acids:  519
Nucleotide accession:  NM_017790
Protein accession:  NP_001269851
References:  2,4,8
Type:  mRNA transcript variant.
Species:  Human
Description:  This variant localizes RGS3 to the nucleus and induces apoptosis.
Amino acids:  519
Nucleotide accession:  NM_001282922
Protein accession:  NP_001269851
References:  2
Type:  mRNA transcript variant.
Species:  Human
Description:  This RGS3 variant inhibits G-protein-mediated signal transduction.
Amino acids:  1198
Nucleotide accession:  NM_144488
Protein accession:  NP_652759
References:  4,41
Type:  mRNA transcript variant.
Species:  Human
Amino acids:  917
Nucleotide accession:  NM_130795
Protein accession:  NP_570613
References:  4,17,43
Biologically Significant Variant Comments
A multi-trait approach identified rs144636307 as a rare mutation in RGS3 that is associated with abnormalities of cardiac structure and function [51].

References

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1. BioGRID3.4. PLSCR1. Accessed on 14/09/2015. Modified on 14/09/2015. BioGRID3.4, http://thebiogrid.org/111373/summary/homo-sapiens/plscr1.html

2. Chatterjee TK, Eapen A, Kanis AB, Fisher RA. (1997) Genomic organization, 5'-flanking region, and chromosomal localization of the human RGS3 gene. Genomics, 45 (2): 429-33. [PMID:9344672]

3. Chatterjee TK, Eapen AK, Fisher RA. (1997) A truncated form of RGS3 negatively regulates G protein-coupled receptor stimulation of adenylyl cyclase and phosphoinositide phospholipase C. J Biol Chem, 272 (24): 15481-7. [PMID:9182581]

4. Chen B, Siderovski DP, Neubig RR, Lawson MA, Trejo J. (2014) Regulation of protease-activated receptor 1 signaling by the adaptor protein complex 2 and R4 subfamily of regulator of G protein signaling proteins. J Biol Chem, 289 (3): 1580-91. [PMID:24297163]

5. Chen Z, Wu Y, Meng Q, Xia Z. (2016) Elevated microRNA-25 inhibits cell apoptosis in lung cancer by targeting RGS3. In Vitro Cell Dev Biol Anim, 52 (1): 62-7. [PMID:26416661]

6. Cho H, Harrison K, Schwartz O, Kehrl JH. (2003) The aorta and heart differentially express RGS (regulators of G-protein signalling) proteins that selectively regulate sphingosine 1-phosphate, angiotensin II and endothelin-1 signalling. Biochem J, 371 (Pt 3): 973-80. [PMID:12564955]

7. Doyen PJ, Vergouts M, Pochet A, Desmet N, van Neerven S, Brook G, Hermans E. (2017) Inflammation-associated regulation of RGS in astrocytes and putative implication in neuropathic pain. J Neuroinflammation, 14 (1): 209. [PMID:29078779]

8. Druey KM, Blumer KJ, Kang VH, Kehrl JH. (1996) Inhibition of G-protein-mediated MAP kinase activation by a new mammalian gene family. Nature, 379 (6567): 742-6. [PMID:8602223]

9. Dulin NO, Pratt P, Tiruppathi C, Niu J, Voyno-Yasenetskaya T, Dunn MJ. (2000) Regulator of G protein signaling RGS3T is localized to the nucleus and induces apoptosis. J Biol Chem, 275 (28): 21317-23. [PMID:10749886]

10. Dulin NO, Sorokin A, Reed E, Elliott S, Kehrl JH, Dunn MJ. (1999) RGS3 inhibits G protein-mediated signaling via translocation to the membrane and binding to Galpha11. Mol Cell Biol, 19 (1): 714-23. [PMID:9858594]

11. Eusemann TN, Willmroth F, Fiebich B, Biber K, van Calker D. (2015) Adenosine Receptors Differentially Regulate the Expression of Regulators of G-Protein Signalling (RGS) 2, 3 and 4 in Astrocyte-Like Cells. PLoS One, 10 (8): e0134934. [PMID:26263491]

12. Ferkey DM, Hyde R, Haspel G, Dionne HM, Hess HA, Suzuki H, Schafer WR, Koelle MR, Hart AC. (2007) C. elegans G protein regulator RGS-3 controls sensitivity to sensory stimuli. Neuron, 53 (1): 39-52. [PMID:17196529]

13. Geng A, Qiu R, Murai K, Liu J, Wu X, Zhang H, Farhoodi H, Duong N, Jiang M, Yee JK et al.. (2018) KIF20A/MKLP2 regulates the division modes of neural progenitor cells during cortical development. Nat Commun, 9 (1): 2707. [PMID:30006548]

14. Grüning W, Arnould T, Jochimsen F, Sellin L, Ananth S, Kim E, Walz G. (1999) Modulation of renal tubular cell function by RGS3. Am J Physiol, 276 (4 Pt 2): F535-43. [PMID:10198412]

15. Hong Z, Hong C, Ma B, Wang Q, Zhang X, Li L, Wang C, Chen D. (2019) MicroRNA‑126‑3p inhibits the proliferation, migration, invasion, and angiogenesis of triple‑negative breast cancer cells by targeting RGS3. Oncol Rep, 42 (4): 1569-1579. [PMID:31364749]

16. Ikeda M, Hirokawa M, Satani N, Kinoshita T, Watanabe Y, Inoue H, Tone S, Ishikawa T, Minatogawa Y. (2001) Molecular cloning and characterization of a steroid receptor-binding regulator of G-protein signaling protein cDNA. Gene, 273 (2): 207-14. [PMID:11595167]

17. Kehrl JH, Srikumar D, Harrison K, Wilson GL, Shi CS. (2002) Additional 5' exons in the RGS3 locus generate multiple mRNA transcripts, one of which accounts for the origin of human PDZ-RGS3. Genomics, 79 (6): 860-8. [PMID:12036301]

18. Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ et al.. (2011) Systematic and quantitative assessment of the ubiquitin-modified proteome. Mol Cell, 44 (2): 325-40. [PMID:21906983]

19. Koelle MR, Horvitz HR. (1996) EGL-10 regulates G protein signaling in the C. elegans nervous system and shares a conserved domain with many mammalian proteins. Cell, 84 (1): 115-25. [PMID:8548815]

20. Larminie C, Murdock P, Walhin JP, Duckworth M, Blumer KJ, Scheideler MA, Garnier M. (2004) Selective expression of regulators of G-protein signaling (RGS) in the human central nervous system. Brain Res Mol Brain Res, 122 (1): 24-34. [PMID:14992813]

21. Liu Y, Huang H, Zhang Y, Zhu XY, Zhang R, Guan LH, Tang Q, Jiang H, Huang C. (2014) Regulator of G protein signaling 3 protects against cardiac hypertrophy in mice. J Cell Biochem, 115 (5): 977-86. [PMID:24375609]

22. Lu Q, Sun EE, Flanagan JG. (2004) Analysis of PDZ-RGS3 function in ephrin-B reverse signaling. Meth Enzymol, 390: 120-8. [PMID:15488174]

23. Lu S, Zhou J, Sun Y, Li N, Miao M, Jiao B, Chen H. (2017) The noncoding RNA HOXD-AS1 is a critical regulator of the metastasis and apoptosis phenotype in human hepatocellular carcinoma. Mol Cancer, 16 (1): 125. [PMID:28724429]

24. Melliti K, Meza U, Fisher R, Adams B. (1999) Regulators of G protein signaling attenuate the G protein-mediated inhibition of N-type Ca channels. J Gen Physiol, 113 (1): 97-110. [PMID:9874691]

25. Meyer G, Varoqueaux F, Neeb A, Oschlies M, Brose N. (2004) The complexity of PDZ domain-mediated interactions at glutamatergic synapses: a case study on neuroligin. Neuropharmacology, 47 (5): 724-33. [PMID:15458844]

26. Mittmann C, Schüler C, Chung CH, Höppner G, Nose M, Kehrl JH, Wieland T. (2001) Evidence for a short form of RGS3 preferentially expressed in the human heart. Naunyn Schmiedebergs Arch Pharmacol, 363 (4): 456-63. [PMID:11330340]

27. Neill JD, Duck LW, Sellers JC, Musgrove LC, Scheschonka A, Druey KM, Kehrl JH. (1997) Potential role for a regulator of G protein signaling (RGS3) in gonadotropin-releasing hormone (GnRH) stimulated desensitization. Endocrinology, 138 (2): 843-6. [PMID:9003025]

28. Nishiura H, Nonaka H, Revollo IS, Semba U, Li Y, Ota Y, Irie A, Harada K, Kehrl JH, Yamamoto T. (2009) Pro- and anti-apoptotic dual functions of the C5a receptor: involvement of regulator of G protein signaling 3 and extracellular signal-regulated kinase. Lab Invest, 89 (6): 676-94. [PMID:19333232]

29. Nishiura H, Yamanegi K, Kawabe M, Kato-Kogoe N, Yamada N, Nakasho K. (2015) The roles of ribosomal protein S19 C-terminus in a shortened neutrophil lifespan through delta lactoferrin. Immunobiology, 220 (9): 1085-92. [PMID:26003841]

30. Norlin EM, Berghard A. (2001) Spatially restricted expression of regulators of G-protein signaling in primary olfactory neurons. Mol Cell Neurosci, 17 (5): 872-82. [PMID:11358484]

31. Obsilova V, Kopecka M, Kosek D, Kacirova M, Kylarova S, Rezabkova L, Obsil T. (2014) Mechanisms of the 14-3-3 protein function: regulation of protein function through conformational modulation. Physiol Res, 63 Suppl 1: S155-64. [PMID:24564655]

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33. Ooe A, Kato K, Noguchi S. (2007) Possible involvement of CCT5, RGS3, and YKT6 genes up-regulated in p53-mutated tumors in resistance to docetaxel in human breast cancers. Breast Cancer Res Treat, 101 (3): 305-15. [PMID:16821082]

34. Qiu R, Murai K, Lu Q. (2020) Spindle Orientation-Independent Control of Cell Fate Determination by RGS3 and KIF20A. Cereb Cortex Commun, 1 (1): tgaa003. [PMID:32864611]

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39. Rolland T, Taşan M, Charloteaux B, Pevzner SJ, Zhong Q, Sahni N, Yi S, Lemmens I, Fontanillo C, Mosca R et al.. (2014) A proteome-scale map of the human interactome network. Cell, 159 (5): 1212-26. [PMID:25416956]

40. Scheschonka A, Dessauer CW, Sinnarajah S, Chidiac P, Shi CS, Kehrl JH. (2000) RGS3 is a GTPase-activating protein for g(ialpha) and g(qalpha) and a potent inhibitor of signaling by GTPase-deficient forms of g(qalpha) and g(11alpha). Mol Pharmacol, 58 (4): 719-28. [PMID:10999941]

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44. Song D, Nishiyama M, Kimura S. (2016) Potent inhibition of angiotensin AT1 receptor signaling by RGS8: importance of the C-terminal third exon part of its RGS domain. J Recept Signal Transduct Res, 36 (5): 478-87. [PMID:26754208]

45. Su Z, Xu P, Ni F. (2004) Single phosphorylation of Tyr304 in the cytoplasmic tail of ephrin B2 confers high-affinity and bifunctional binding to both the SH2 domain of Grb4 and the PDZ domain of the PDZ-RGS3 protein. Eur J Biochem, 271 (9): 1725-36. [PMID:15096211]

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48. Williams JW, Yau D, Sethakorn N, Kach J, Reed EB, Moore TV, Cannon J, Jin X, Xing H, Muslin AJ et al.. (2013) RGS3 controls T lymphocyte migration in a model of Th2-mediated airway inflammation. Am J Physiol Lung Cell Mol Physiol, 305 (10): L693-701. [PMID:24077945]

49. Xiao K, McClatchy DB, Shukla AK, Zhao Y, Chen M, Shenoy SK, Yates 3rd JR, Lefkowitz RJ. (2007) Functional specialization of beta-arrestin interactions revealed by proteomic analysis. Proc Natl Acad Sci USA, 104 (29): 12011-6. [PMID:17620599]

50. Xu F, Liu Y, Shi L, Cai H, Liu W, Hu Y, Li Y, Yuan W. (2017) RGS3 inhibits TGF-β1/Smad signalling in adventitial fibroblasts. Cell Biochem Funct, 35 (6): 334-338. [PMID:28845525]

51. Yazdani A, Yazdani A, Méndez Giráldez R, Aguilar D, Sartore L. (2019) A Multi-Trait Approach Identified Genetic Variants Including a Rare Mutation in RGS3 with Impact on Abnormalities of Cardiac Structure/Function. Sci Rep, 9 (1): 5845. [PMID:30971721]

52. Yono M, Yoshida M, Yamamoto Y, Imanishi A, Fukagawa A, Latifpour J, Eto M. (2010) Identification of potential therapeutic targets in hypertension-associated bladder dysfunction. BJU Int, 105 (6): 877-83. [PMID:19689474]

53. Zhang S, Watson N, Zahner J, Rottman JN, Blumer KJ, Muslin AJ. (1998) RGS3 and RGS4 are GTPase activating proteins in the heart. J Mol Cell Cardiol, 30 (2): 269-76. [PMID:9515003]

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