regulator of G-protein signaling 12 | R12 family | IUPHAR/BPS Guide to PHARMACOLOGY

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regulator of G-protein signaling 12

Target not currently curated in GtoImmuPdb

Target id: 2819

Nomenclature: regulator of G-protein signaling 12

Abbreviated Name: RGS12

Family: R12 family

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 799 4p16.3 RGS12 regulator of G protein signaling 12
Mouse - 1381 5 B2 Rgs12 regulator of G-protein signaling 12
Rat - 1387 14q21 Rgs12 regulator of G-protein signaling 12
Database Links
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
RefSeq Nucleotide
RefSeq Protein
Associated Proteins
G Proteins
Name References
Gαi/0 16
Interacting Proteins
Name Effect References
TrkA, H-Ras-GTP, B-Raf, MEK2 Prolongs ERK signaling 17
Cav2.2 Voltage-independent inhibition 14
CXCR2 16
platelet derived growth factor receptor beta Inhibition of downstream signaling 13
Associated Protein Comments
RGS12 has two distinct G protein binding sites, the RGS domain and the GPR motif (also known as GoLoco). The RGS domain can bind and serve as a GTPase activating protein (GAP) for activated (GTP bound) members of the Gαi/o subfamily of G proteins including Gai1, Gai2, Gai3 and Gao. The GPR motif selectively binds inactive (GDP bound) Gai1 and Gai3.
Tissue Distribution
Species:  Human
Technique:  Western blot
References:  20
Species:  Human
Technique:  RT-PCR
References:  9
Spleen, testis, ovary, cerebellum, caudate nucleus, kidney, thymus, prostate
Species:  Human
Technique:  Northern blot
References:  16
Species:  Rat
Technique:  RT-PCR
References:  3
Brain and lung (high); testis, heart, and spleen (low)
Species:  Rat
Technique:  Northern blot
References:  15
Cortex, hippocampus, striatum, thalamus, substantia nigra
Species:  Rat
Technique:  Immunohistochemistry
References:  7
Functional Assays
Negative regulation of MAPK
Species:  Rat
Tissue:  HEK293 cells
Response measured:  Reduced PDGF-stimulated phosphoERK
References:  13
Recruitment to Gi2
Species:  Rabbit
Tissue:  Smooth muscle cells
Response measured:  Gi2 tyrosine phosphorylation by Gbetagamma-PI3K-Src recruits RGS12 to Gi2, enhancing GTPase activity
References:  5
Positive regulation of Gi/o GTPase activity
Species:  Rat
Tissue:  Purified protein
Response measured:  Increase in GTPase activation
References:  16
Inhibits Gi-GDP dissociation (GDI)
Species:  Rat
Tissue:  Purified protein
Response measured:  Stabilization of GDP-bound Gi proteins
References:  6
Scaffold for TrkA/Ras/Raf/MEK
Species:  Rat
Tissue:  PC12 cells
Response measured:  Prolongs ERK activation and mediates NGF-stimulated neurite outgrowth
References:  17
Negative regulation on GABAB-CaV2.2 coupling
Species:  Human
Tissue:  Dorsal root ganglia
Response measured:  GABAB inhibits CaV2.2, and RGS12 accelerates rate of reversal
References:  11-12,14
Physiological Functions
Mediates osteoclastogenesis
Species:  Mouse
Tissue:  Osteoclasts
References:  22
Regulates GABAB-CaV2.2 coupling
Species:  Human
Tissue:  Dorsal root gangiia
References:  11-12,14
Physiological Consequences of Altering Gene Expression
Knockdown of Rgs12 inhibits NGF-induced axonal growth in primary dorsal root ganglia neurons.
Species:  Mouse
Tissue:  PC12 and primary dorsal root ganglia neurons
Technique:  RNA intererence (RNAi)
References:  17
Knockdown of Rgs12 inhibits phosphorylation of PLC, Ca2+ oscillations, NFAT2 expression, osteoclast differentiation
Species:  Human
Tissue:  Osteoclasts
Technique:  RNA intererence (RNAi)
References:  20
RGS12 knockout mice have increased bone mass: reduced osteoclasts, growth retardation and increased bone mass
Species:  Mouse
Tissue:  Monocytes/macrophages
Technique:  Gene knockout
References:  21
Clinically-Relevant Mutations and Pathophysiology
Disease:  Colorectal cancer
Disease Ontology: DOID:9256
OMIM: 114500
References:  10,18
Disease:  Lung cancer
Disease Ontology: DOID:1324
OMIM: 211980
References:  2
Biologically Significant Variants
Type:  Frameshift mutation
Species:  Human
Description:  Coding mononucleotide repeat (C8): Colorectal cancer
References:  10
Type:  Missense mutation
Species:  Human
Description:  Heterozygous missense variants linked with familial goiter
Amino acid change:  V56M
References:  19
Type:  Missense mutation
Species:  Human
Description:  A missense mutation G161T changes R702L: Sporadic schizophrenia
Amino acid change:  R702L
References:  4
Type:  Single nucleotide polymorphism
Species:  Human
Description:  A/G SNP associated with enhaced survival in non-small cell lung cancer
References:  2
Type:  Splice variant
Species:  Human
Description:  Lacks the PDZ domain and localizes to the nucleus in COS-7 cells.
Amino acids:  799
Nucleotide accession: 
Protein accession: 
References:  1,16
Type:  Splice variant
Species:  Human
Description:  Nuclear localization is controlled by the cell cycle. Induces formation of abnormally shaped and multiple nuclei in COS-7 cells when overexpressed.
Amino acids:  1447
Nucleotide accession: 
Protein accession: 
References:  1
Type:  Splice variant
Species:  Mouse
Description:  Lacks the PDZ domain and is differentially expressed compared to the PDZ-containing isoform.
Amino acids:  723
Nucleotide accession: 
Protein accession: 
References:  8


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1. Chatterjee TK, Fisher RA. (2000) Novel alternative splicing and nuclear localization of human RGS12 gene products. J. Biol. Chem., 275 (38): 29660-71. [PMID:10869340]

2. Dai J, Gu J, Lu C, Lin J, Stewart D, Chang D, Roth JA, Wu X. (2011) Genetic variations in the regulator of G-protein signaling genes are associated with survival in late-stage non-small cell lung cancer. PLoS ONE, 6 (6): e21120. [PMID:21698121]

3. Doupnik CA, Xu T, Shinaman JM. (2001) Profile of RGS expression in single rat atrial myocytes. Biochim. Biophys. Acta, 1522 (2): 97-107. [PMID:11750060]

4. Guipponi M, Santoni FA, Setola V, Gehrig C, Rotharmel M, Cuenca M, Guillin O, Dikeos D, Georgantopoulos G, Papadimitriou G et al.. (2014) Exome sequencing in 53 sporadic cases of schizophrenia identifies 18 putative candidate genes. PLoS ONE, 9 (11): e112745. [PMID:25420024]

5. Huang J, Nalli AD, Mahavadi S, Kumar DP, Murthy KS. (2014) Inhibition of Gαi activity by Gβγ is mediated by PI 3-kinase-γ- and cSrc-dependent tyrosine phosphorylation of Gαi and recruitment of RGS12. Am. J. Physiol. Gastrointest. Liver Physiol., 306 (9): G802-10. [PMID:24578342]

6. Kimple RJ, De Vries L, Tronchère H, Behe CI, Morris RA, Gist Farquhar M, Siderovski DP. (2001) RGS12 and RGS14 GoLoco motifs are G alpha(i) interaction sites with guanine nucleotide dissociation inhibitor Activity. J. Biol. Chem., 276 (31): 29275-81. [PMID:11387333]

7. López-Aranda MF, Acevedo MJ, Carballo FJ, Gutiérrez A, Khan ZU. (2006) Localization of the GoLoco motif carrier regulator of G-protein signalling 12 and 14 proteins in monkey and rat brain. Eur. J. Neurosci., 23 (11): 2971-82. [PMID:16819986]

8. Martin-McCaffrey L, Hains MD, Pritchard GA, Pajak A, Dagnino L, Siderovski DP, D'Souza SJ. (2005) Differential expression of regulator of G-protein signaling R12 subfamily members during mouse development. Dev. Dyn., 234 (2): 438-44. [PMID:16145674]

9. O'Brien M, Morrison JJ, Smith TJ. (2008) Upregulation of PSCDBP, TLR2, TWIST1, FLJ35382, EDNRB, and RGS12 gene expression in human myometrium at labor. Reprod Sci, 15 (4): 382-93. [PMID:18497345]

10. Potocnik U, Glavac D, Ravnik-Glavac M. (2003) Identification of novel genes with somatic frameshift mutations within coding mononucleotide repeats in colorectal tumors with high microsatellite instability. Genes Chromosomes Cancer, 36 (1): 48-56. [PMID:12461749]

11. Richman RW, Diversé-Pierluissi MA. (2004) Mapping of RGS12-Cav2.2 channel interaction. Meth. Enzymol., 390: 224-39. [PMID:15488181]

12. Richman RW, Strock J, Hains MD, Cabanilla NJ, Lau KK, Siderovski DP, Diversé-Pierluissi M. (2005) RGS12 interacts with the SNARE-binding region of the Cav2.2 calcium channel. J. Biol. Chem., 280 (2): 1521-8. [PMID:15536086]

13. Sambi BS, Hains MD, Waters CM, Connell MC, Willard FS, Kimple AJ, Pyne S, Siderovski DP, Pyne NJ. (2006) The effect of RGS12 on PDGFbeta receptor signalling to p42/p44 mitogen activated protein kinase in mammalian cells. Cell. Signal., 18 (7): 971-81. [PMID:16214305]

14. Schiff ML, Siderovski DP, Jordan JD, Brothers G, Snow B, De Vries L, Ortiz DF, Diversé-Pierluissi M. (2000) Tyrosine-kinase-dependent recruitment of RGS12 to the N-type calcium channel. Nature, 408 (6813): 723-7. [PMID:11130074]

15. Snow BE, Antonio L, Suggs S, Gutstein HB, Siderovski DP. (1997) Molecular cloning and expression analysis of rat Rgs12 and Rgs14. Biochem. Biophys. Res. Commun., 233 (3): 770-7. [PMID:9168931]

16. Snow BE, Hall RA, Krumins AM, Brothers GM, Bouchard D, Brothers CA, Chung S, Mangion J, Gilman AG, Lefkowitz RJ et al.. (1998) GTPase activating specificity of RGS12 and binding specificity of an alternatively spliced PDZ (PSD-95/Dlg/ZO-1) domain. J. Biol. Chem., 273 (28): 17749-55. [PMID:9651375]

17. Willard MD, Willard FS, Li X, Cappell SD, Snider WD, Siderovski DP. (2007) Selective role for RGS12 as a Ras/Raf/MEK scaffold in nerve growth factor-mediated differentiation. EMBO J., 26 (8): 2029-40. [PMID:17380122]

18. Williams DS, Bird MJ, Jorissen RN, Yu YL, Walker F, Walker F, Zhang HH, Nice EC, Burgess AW. (2010) Nonsense mediated decay resistant mutations are a source of expressed mutant proteins in colon cancer cell lines with microsatellite instability. PLoS ONE, 5 (12): e16012. [PMID:21209843]

19. Yan J, Takahashi T, Ohura T, Adachi H, Takahashi I, Ogawa E, Okuda H, Kobayashi H, Hitomi T, Liu W et al.. (2013) Combined linkage analysis and exome sequencing identifies novel genes for familial goiter. J. Hum. Genet., 58 (6): 366-77. [PMID:23535966]

20. Yang S, Li YP. (2007) RGS12 is essential for RANKL-evoked signaling for terminal differentiation of osteoclasts in vitro. J. Bone Miner. Res., 22 (1): 45-54. [PMID:17042716]

21. Yang S, Li YP, Liu T, He X, Yuan X, Li C, Cao J, Kim Y. (2013) Mx1-cre mediated Rgs12 conditional knockout mice exhibit increased bone mass phenotype. Genesis, 51 (3): 201-9. [PMID:23349096]

22. Yuan X, Cao J, Liu T, Li YP, Scannapieco F, He X, Oursler MJ, Zhang X, Vacher J, Li C et al.. (2015) Regulators of G protein signaling 12 promotes osteoclastogenesis in bone remodeling and pathological bone loss. Cell Death Differ., 22 (12): 2046-57. [PMID:25909889]


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