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regulator of G-protein signaling 12

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Target id: 2819

Nomenclature: regulator of G-protein signaling 12

Abbreviated Name: RGS12

Family: R12 family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1447 4p16.3 RGS12 regulator of G protein signaling 12
Mouse - 1381 5 17.96 cM Rgs12 regulator of G-protein signaling 12
Rat - 1387 14q21 Rgs12 regulator of G-protein signaling 12
Database Links Click here for help
Alphafold O14924 (Hs), Q8CGE9 (Mm), O08774 (Rn)
CATH/Gene3D 1.10.196.10, 2.30.29.30
ChEMBL Target CHEMBL1293276 (Hs)
Ensembl Gene ENSG00000159788 (Hs), ENSMUSG00000029101 (Mm), ENSRNOG00000030568 (Rn)
Entrez Gene 6002 (Hs), 71729 (Mm), 54292 (Rn)
Human Protein Atlas ENSG00000159788 (Hs)
KEGG Gene hsa:6002 (Hs), mmu:71729 (Mm), rno:54292 (Rn)
OMIM 602512 (Hs)
Pharos O14924 (Hs)
RefSeq Nucleotide NM_198227 (Hs), AF030109 (Hs), AF030111 (Hs), NM_173402 (Mm), AK014569 (Mm), NM_019339 (Rn)
RefSeq Protein NP_937870 (Hs), NP_937870 (Hs), NP_937872 (Hs), NP_775578 (Mm), NP_001156984 (Mm), NP_062212 (Rn)
UniProtKB O14924 (Hs), Q8CGE9 (Mm), O08774 (Rn)
Wikipedia RGS12 (Hs)
Associated Proteins Click here for help
G Proteins
Name References
Gαi/0 21
Interacting Proteins
Name Effect References
TrkA, H-Ras-GTP, B-Raf, MEK2 Prolongs ERK signaling 26
CXCR2 21
platelet derived growth factor receptor beta Inhibition of downstream signaling 17
Cav2.2 Voltage-independent inhibition 15-16,18
Tyrosine phosphorylated calcium channel RGS12 accelerates the rate of reversal of the voltage-independent pathway mediated by tyrosine kinase. 18
NF-κB(p65), COX-2 RGS12 binds to NF-κBB(p65) through its PTB domain, promoting NF-κBB(p65) phosphorylation and nuclear translocation. RGS12 and NF-κB(p65) associate with COX2. Overexpression of COX2 leads to an increase in nuclear translocation of RGS12 and NF-κBB(p65). 32
κ receptor RGS12 attenuates G protein signaling and augments β-arrestin signaling downstream of KOR via independent signaling mechanisms. 4
ATP5A RGS12 regulates tyrosine phosphorylation of ATP5A 31
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 Click here for help
Osteoclasts
Species:  Human
Technique:  Western blot
References:  29
Myometrium
Species:  Human
Technique:  RT-PCR
References:  13
Spleen, testis, ovary, cerebellum, caudate nucleus, kidney, thymus, prostate
Species:  Human
Technique:  Northern blot
References:  21
Prostate tissue and prostate epithelial cell line
Species:  Human
Technique:  qRT-PCR
References:  22
Brain, heart, lung, liver, kidney, skeletal muscle, intestine, lymphocytes, placenta, testis
Species:  Human
Technique:  RT-PCR, PCR
References:  1,9
Rheumatoid arthritis synovial tissue and synovial fluid macrophages
Species:  Human
Technique:  Immunofluorescence, RNA seq
References:  32
2.Tibialis anterior (TA) muscle
Species:  Mouse
Technique:  RNA-seq, immunoblotting
References:  19
Cartilage cells (mitochondria, cytoplasm and nucleus)
Species:  Mouse
Technique:  Immunostaining
References:  31
Cortex, hippocampus, striatum, midbrain, VTA and substantia nigra pars compacta
Species:  Mouse
Technique:  In situ hybridization, immunoblotting
References:  5
Osteoclasts, osteoclast-like cells
Species:  Mouse
Technique:  qPCR, Western blot
References:  33
Atrium
Species:  Rat
Technique:  RT-PCR
References:  3
Brain and lung (high); testis, heart, and spleen (low)
Species:  Rat
Technique:  Northern blot
References:  20
Cortex, hippocampus, striatum, thalamus, substantia nigra
Species:  Rat
Technique:  Immunohistochemistry
References:  11
Functional Assays Click here for help
Inhibits Gi-GDP dissociation (GDI)
Species:  Rat
Tissue:  Purified protein
Response measured:  Stabilization of GDP-bound Gi proteins
References:  8
Positive regulation of Gi/o GTPase activity
Species:  Rat
Tissue:  Purified protein
Response measured:  Increase in GTPase activation
References:  21
Negative regulation of MAPK
Species:  Rat
Tissue:  HEK293 cells
Response measured:  Reduced PDGF-stimulated phosphoERK
References:  17
Scaffold for TrkA/Ras/Raf/MEK
Species:  Rat
Tissue:  PC12 cells
Response measured:  Prolongs ERK activation and mediates NGF-stimulated neurite outgrowth
References:  26
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:  15-16,18
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:  7
RGS12 accelerates GTP hydrolysis
Species:  None
Tissue:  Purified protein
Response measured:  Nucleotide binding and hydrolysis
References:  25
cAMP inhibition
Species:  Human
Tissue:  HEK293T cells
Response measured:  Receptor-mediated, Gαi/o-dependent inhibition of isoproterenol-induced cAMP increase.
References:  4
β-arrestin recruitment
Species:  None
Tissue:  HTLA cells
Response measured:  β-arrestin recruitment following receptor activation
References:  25
Physiological Functions Click here for help
Regulates GABAB-CaV2.2 coupling
Species:  Human
Tissue:  Dorsal root gangiia
References:  15-16,18
Mediates osteoclastogenesis
Species:  Mouse
Tissue:  Osteoclasts
References:  10,30,33
RGS12 plays a role in regulating rheumatoid arthritis (RA) inflammation
Species:  Human
Tissue:  Macrophages (human and mouse)
References:  32
RGS12 affects mitochondrial phospho-tyrosine (p-Tyr) expression
Species:  Mouse
Tissue:  Chondrocytes and cartilage tissue
References:  31
RGS12 reduces the potency of KOR agonist (U50,488) and increases agonist-stimulated recruitment of β-arrestin to KOR.
Species:  Human
Tissue:  HEK293T cells
References:  4
Physiological Consequences of Altering Gene Expression Click here for help
RGS12 knockout mice have increased bone mass: reduced osteoclasts, growth retardation and increased bone mass
Species:  Mouse
Tissue:  Monocytes/macrophages
Technique:  Gene knockout
References:  30
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:  26
Knockdown of Rgs12 inhibits phosphorylation of PLC, Ca2+ oscillations, NFAT2 expression, osteoclast differentiation
Species:  Human
Tissue:  Osteoclasts
Technique:  RNA intererence (RNAi)
References:  29
RGS12 loss diminishes locomotor responses of C57BL/6J mice to dopamine transporter (DAT)-targeting psychostimulants.
Species:  Mouse
Tissue:  In vivo.
Technique:  Gene knockout
References:  24
Loss of RGS12 in mice affects serotonin transporter expression and function.
Species:  Mouse
Tissue:  Cortex, hippocampus, midbrain, ventral striatum, and dorsal striatum
Technique:  Gene knockout
References:  24
RGS12 transcript levels are reduced in tissue from African American patients with prostate cancer, and in prostate cancer cell lines (relative to benign prostate epithelial cells).
Species:  Human
Tissue:  Prostate tissue, prostate cancer cell line, LNCaP cells with RGS12 knockdown
Technique:  Cluster analysis, expression array analysis, qRT-PCR, cell proliferation assay
References:  22
RGS12-null mice show increased dopamine transporter-mediated dopamine (DA) uptake in the ventral striatum, and reduced psychostimulant-induced hyperlocomotion.
Species:  Mouse
Tissue:  Synaptosome, in vivo.
Technique:  Gene knockout, synaptosomal uptake, locomotor activity
References:  4
GS12 null mice myoblasts have impaired ability to differentiate into myotubes.
Species:  Mouse
Tissue:  Skeletal muscle
Technique:  Gene knockout
References:  19
RGS12 expression is increased in the development of pathological cardiac hypertrophy and heart failure.
Species:  Human
Tissue:  Heart
Technique:  Western blot
References:  23
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Colorectal cancer
Disease Ontology: DOID:9256
OMIM: 114500
Comments:  Colorectal tumors with high microsatellite instability
References:  14,27
Disease:  Lung cancer
Disease Ontology: DOID:1324
OMIM: 211980
Comments:  Non-small cell lung cancer
References:  2
Biologically Significant Variants Click here for help
Type:  Frameshift mutation
Species:  Human
Description:  Coding mononucleotide repeat (C8): Colorectal cancer
References:  14
Type:  Missense mutation
Species:  Human
Description:  Heterozygous missense variants linked with familial goiter
Amino acid change:  V56M
References:  28
Type:  Missense mutation
Species:  Human
Description:  A missense mutation G161T changes R702L: Sporadic schizophrenia
Amino acid change:  R702L
References:  6
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:  AF030109
Protein accession:  NP_937870
References:  1,21
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:  AF030111
Protein accession:  NP_937872
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:  AK014569
Protein accession:  NP_001156984
References:  12

References

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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. Gross JD, Kaski SW, Schmidt KT, Cogan ES, Boyt KM, Wix K, Schroer AB, McElligott ZA, Siderovski DP, Setola V. (2019) Role of RGS12 in the differential regulation of kappa opioid receptor-dependent signaling and behavior. Neuropsychopharmacology, 44 (10): 1728-1741. [PMID:31141817]

5. Gross JD, Kaski SW, Schroer AB, Wix KA, Siderovski DP, Setola V. (2018) Regulator of G protein signaling-12 modulates the dopamine transporter in ventral striatum and locomotor responses to psychostimulants. J Psychopharmacol, 32 (2): 191-203. [PMID:29364035]

6. 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]

7. 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]

8. 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]

9. 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]

10. Li Z, Liu T, Gilmore A, Gómez NM, Fu C, Lim J, Yang S, Mitchell CH, Li YP, Oursler MJ et al.. (2019) Regulator of G Protein Signaling Protein 12 (Rgs12) Controls Mouse Osteoblast Differentiation via Calcium Channel/Oscillation and Gαi-ERK Signaling. J Bone Miner Res, 34 (4): 752-764. [PMID:30489658]

11. 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]

12. 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]

13. 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]

14. 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]

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

16. 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]

17. 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]

18. 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]

19. Schroer AB, Mohamed JS, Willard MD, Setola V, Oestreich E, Siderovski DP. (2019) A role for Regulator of G protein Signaling-12 (RGS12) in the balance between myoblast proliferation and differentiation. PLoS One, 14 (8): e0216167. [PMID:31408461]

20. 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]

21. 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]

22. Wang Y, Wang J, Zhang L, Karatas OF, Shao L, Zhang Y, Castro P, Creighton CJ, Ittmann M. (2017) RGS12 Is a Novel Tumor-Suppressor Gene in African American Prostate Cancer That Represses AKT and MNX1 Expression. Cancer Res, 77 (16): 4247-4257. [PMID:28611045]

23. Weinberger MH, Miller JZ, Grim CE, Luft FC, Christian JC, Fineberg NS. (1989) Genetic and environmental approaches to the prevention of hypertension. J Hypertens Suppl, 7 (1): S7-8. [PMID:2709189]

24. White AN, Gross JD, Kaski SW, Trexler KR, Wix KA, Wetsel WC, Kinsey SG, Siderovski DP, Setola V. (2020) Genetic deletion of Rgs12 in mice affects serotonin transporter expression and function in vivo and ex vivo. J Psychopharmacol, 34 (12): 1393-1407. [PMID:32842837]

25. Willard FS, Kimple AJ, Johnston CA, Siderovski DP. (2005) A direct fluorescence-based assay for RGS domain GTPase accelerating activity. Anal Biochem, 340 (2): 341-51. [PMID:15840508]

26. 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]

27. 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]

28. 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]

29. 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]

30. 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]

31. Yuan G, Yang S, Liu M, Yang S. (2020) RGS12 is required for the maintenance of mitochondrial function during skeletal development. Cell Discov, 6: 59. [PMID:32922858]

32. Yuan G, Yang S, Ng A, Fu C, Oursler MJ, Xing L, Yang S. (2020) RGS12 Is a Novel Critical NF-κB Activator in Inflammatory Arthritis. iScience, 23 (6): 101172. [PMID:32512384]

33. 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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