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regulator of G-protein signaling 16

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2806

Nomenclature: regulator of G-protein signaling 16

Abbreviated Name: RGS16

Family: R4 family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 202 1q25.3 RGS16 regulator of G protein signaling 16 43,45
Mouse - 201 1 65.43 cM Rgs16 regulator of G-protein signaling 16 6,43
Rat - 199 13q21 Rgs16 regulator of G-protein signaling 16 6
Previous and Unofficial Names Click here for help
A28-RGS14 | RGS-R | A24-RGS14p
Database Links Click here for help
Alphafold O15492 (Hs), P97428 (Mm), P56700 (Rn)
CATH/Gene3D 1.10.196.10
ChEMBL Target CHEMBL3707469 (Hs)
Ensembl Gene ENSG00000143333 (Hs), ENSMUSG00000026475 (Mm), ENSRNOG00000027024 (Rn)
Entrez Gene 6004 (Hs), 19734 (Mm), 360857 (Rn)
Human Protein Atlas ENSG00000143333 (Hs)
KEGG Gene hsa:6004 (Hs), mmu:19734 (Mm), rno:360857 (Rn)
OMIM 602514 (Hs)
Pharos O15492 (Hs)
RefSeq Nucleotide NM_002928 (Hs), NM_011267 (Mm), NM_001077589 (Rn)
RefSeq Protein NP_002919 (Hs), NP_035397 (Mm), NP_001071057 (Rn)
UniProtKB O15492 (Hs), P97428 (Mm), P56700 (Rn)
Wikipedia RGS16 (Hs)
Associated Proteins Click here for help
G Proteins
Name References
Gαi/o, Gαq/11, Gα12/13 1,3,5,17,25,30,34,41,44,52
Interacting Proteins
Name Effect References
TP53 TP53 induces RGS16 transcription 3,54
Membrane interacting protein of RGS16 (MIR16: gene symbol GDE1)) 57-58
Transducin Accelerates GTPase activity and enhances recycling of transducin. 6,12
Calmodulin Ca2+ dependent binding of calmodulin can activate Rgs proteins by displaceing an inhibitor of GAP activity. 40
Spinophilin 53
PAR2 Inhibits PAR2/Gαi/o -mediated signalling 30
δEF1 family proteins [indirect] Expression levels of RGS16 are negatively correlated with those of the δEF1 family proteins. δEF1 family proteins (δEF1/ZEB1 and SIP1/ZEB2) are key regulators of EMT, positively correlated with EMT phenotypes and aggressiveness of breast cancer. 19
Immunopharmacology Comments
RGS proteins, including RGS16, modulate Gαi2 signaling to facilitate thymocyte egress and T cell trafficking [24,32]. RGS protein/Gαi2 interactions are essential for normal thymocyte egress, T cell trafficking, and homeostasis. Mature thymocytes with a Gαi2 mutation that disables RGS protein binding accumulated in the perivascular channels of thymic corticomedullary venules.
Tissue Distribution Click here for help
Breast tissue
Species:  Human
Technique: 
References:  50,54
Dendritic cells
Species:  Human
Technique: 
References:  7
Megakaryocytes, platelets
Species:  Human
Technique:  RT-PCR, Western blot
References:  2
Retinally abundant but not specific
Species:  Human
Technique:  Northern blot
References:  45
Liver, endocrine pancreas, pancreatic ductal adenocarcinoma
Species:  Mouse
Technique:  Northern blot, in situ hybridization, qRT-PCR, GFP transgene reporter
References:  5,18,22,35-36,51
Suprachiasmatic nucleus and thalamus
Species:  Mouse
Technique:  Microarray analysis, In situ hybridization, Northern blot
References:  10,13,16,22,49
Retina
Species:  Mouse
Technique:  RT-PCR
References:  6,18,45
Pituitary
Species:  Mouse
Technique:  Northern blot
References:  5,18
Several regions in the brain
Species:  Rat
Technique:  In situ hybridization
References:  15
Cardiac myocytes
Species:  Rat
Technique:  Northern blot, Western blot
References:  27,37-38,47
Functional Assays Click here for help
Mediates cAMP signaling and expression of clock gene Per1
Species:  Mouse
Tissue:  Suprachiasmatic nucleus
Response measured:  Increased levels of cAMP and acclerated expression of Per1
References:  10
Inhibits Gα13 signaling via a GAP-independent mechanism. Rgs16 binds Gα13 and translocates it to detergent-resistant membranes and prevents effector interaction and thus inhibits Gα13 signaling.
Species:  None
Tissue: 
Response measured: 
References:  25
EGFR-mediated phosphorylation
Species:  Human
Tissue:  HEK 293T or COS-7 cells
Response measured:  EGFR-mediated phosphorylation depends on residue Y168 and phosphorylation enhances GAP activity. Y177 is important for regulated Gi-coupled M2 muscarinic receptor signaling.
References:  9
Physiological Functions Click here for help
Determines the period of circadian rhytms in behavior.
Species:  Mouse
Tissue:  Dorsomedial cells of suprachiasmatic nucleus
References:  10
Negative regulation of SDF-1-CXCR4 signalling.
Species:  Human
Tissue:  Megakaryocytes
References:  2
Rgs16 regulates T lymphocyte migration induced by CXCR4, CCR3 and CCR5.
Species:  Mouse
Tissue:  T lymphocytes
References:  32
Inhibits fatty acid oxidation in the liver of fasted mice, suppresses Fgf21 expression in liver of fasted mice.
Species:  Mouse
Tissue:  Hepatocytes
References:  36
RGS16 plays an important role in platelet function by modulating CXCL12-dependent platelet activation.
Species:  Mouse
Tissue:  Platelets
References:  28
In pancreatic acinar cells, Rgs proteins inhibit secretion of digestive enzymes evoked by G-protein-coupled-receptor (GPCR) agonists. In an aggressive model of pancreatitis and pancreatic ductal adenocarcinoma (PDA), KCR8-16 mice (global exon 5 deletion of the Rgs domain in both Rgs8 and Rgs16 genes, oncogenic KrasG12D expressed in all pancreatic cells) rapidly progressed to starvation after mild metabolic challenges. The starvation phenotype is caused by a combination of pancreatic insufficiency and hyperactive utilization of fats in liver of malnourished KCR8-16 mice. Dietary pancreatic enzyme supplements reversed malnutrition in KC and KCR8-16 animals, and extended survival slightly, but also increased PDA tumor burden
Species:  Mouse
Tissue:  Pancreas
References:  59
RGS16 is a regulator of β-cell function that co-ordinately controls insulin secretion and proliferation by limiting the tonic inhibitory signal exerted by δ-cell-derived somatostatin in islets.
Species:  Human
Tissue:  Pancreas islet
References:  52
Rgs16 is one of the ChREBP-controlled genes that potentiate accumulation of lipid droplets in β-cells. ChREBP was sufficient and necessary for regulation of Eno1, Pklr, Mdh1, Me1, Pdha1, Acly, Acaca, Fasn, Elovl6, Gpd1, Cpt1a, Rgs16, Mid1ip1, Txnip, and Chrebpββ
Species:  Rat
Tissue:  Pancreas
References:  42
Intracellular Ca2+ responses to angiotensin II were markedly attenuated by transiently expressed RGS2, RGS3 and RGS8, compared to weak inhibition by RGS1, RGS4, RGS5 and RGS16
Species:  None
Tissue: 
References:  46
RGS16 is indispensable for the circadian regulation of cAMP in the suprachiasmatic nucleus (SCN). Described in a review of circadian pharmacology. GPCRs in the SCN tune the body clock.
Species:  None
Tissue:  Suprachiasmatic nucleus
References:  10,14
Prominent roles in the trafficking of B and T lymphocytes and macrophages have been described for RGS1, RGS13, and RGS16.
Species:  None
Tissue:  Platelets
References:  56
Physiological Consequences of Altering Gene Expression Click here for help
Overexpression of RGS16 promotes glioma progression
Species:  Human
Tissue:  Glioma cell lines
Technique: 
References:  23
RGS16 is strongly associated with early morning activity in humans.
Species:  Human
Tissue:  SCN, retina
Technique:  Genome-wide association (GWAS)
References:  21
Lenghtening of the circadian period of behavior.
Species:  Mouse
Tissue:  Brain
Technique:  Gene knockout
References:  10
Elevated fatty acid oxidation rate and elevated beta-ketone level. During caloric restriction, before feeding, increased abulatory activity. After feeding, increased rate of food consumption.
Species:  Mouse
Tissue:  Liver, hepatocytes
Technique:  Gene knockout
References:  36
Develops fatty liver during prolonged fast.
Species:  Mouse
Tissue:  Liver, Hepatocytes
Technique:  Gene over-expression
References:  36
Rgs16 inhibits migration and invasion of pancreatic cancer cells
Species:  Human
Tissue:  BxBP3, AsPC-1
Technique:  Gene over-expression
References:  4
RGS16 knockdown by RNAi upregulates IL-1b, IL-6 and TNFα. RGS16 enhances Pam3-mediated induction of the anti inflammatory cytokine IL-10.
Species:  Human
Tissue:  Monocytes (THP-1 cell line)
Technique:  RNA intererence (RNAi)
References:  48
RGS16 overexpression in THP-1 cells restricts the induction of pro-inflammatory response by TLR2 agonist Pam3.
Species:  Human
Tissue:  Monocytes (THP-1 cell line)
Technique:  Gene over-expression
References:  48
RGS16 Knockdown enhances breast cancer cell growth and cell cycle progression. It also negatively regulates growth of MCF7 cells induced by specific factors including EGF. It impairs EGF-induced growth of breast cancer cells specifically by binding p85 and suppressing activation of the PI3K-Akt signaling pathway.
Species:  Human
Tissue:  MCF7 cells
Technique:  RNA intererence (RNAi)
References:  31
Restriction of the pro-Inflammatory response of monocytes.
Species:  Human
Tissue:  Promonocytic cell line THP-1
Technique:  RNA intererence (RNAi), Gene knockouts were also used, with cells obtained from Rgs16-/- mice
References:  48
Elevated Rgs16 in B-cells reduces B-cell chemotaxis responses to chemokines, and promotes retention of B cells within germinal centers, thus provides optimal microenvironment for the production of pathogenic autoantibodies.
Species:  Mouse
Tissue:  B Cells
Technique: 
References:  20,55
Aging, with or without melatonin, as well as repeated 6 h advance/delay phase shifts in the light/dark cycle, which increased inactivity as a correlate of sleep during the dark phase of the light/dark cycle (i.e. during the active phase for nocturnal animals), had a minor effect on immune state in the colonic mucosa; all these conditions caused down regulation of Rgs16 gene, which is involved in attenuation of the inflammatory response in the colon, but did not affect expression of the other immune markers.
Species:  Rat
Tissue:  Colon
Technique:  qRT-PCR
References:  39
Rgs16 overexpression lead to dramatically increased amounts of lipids in 832/13 cells.
Species:  Rat
Tissue:  832/13 rat insulinoma cells
Technique: 
References:  42
RGS16 mRNA levels are strongly up-regulated in islets of Langerhans under hyperglycemic conditions in vivo and ex vivo. RGS16 overexpression stimulated glucose-induced insulin secretion. RGS16 overexpression increased intracellular cAMP levels, and its effects were blocked by an adenylyl cyclase inhibitor. RGS16 overexpression prevented the inhibitory effect of somatostatin on insulin secretion and β-cell proliferation
Species:  Human
Tissue: 
Technique: 
References:  52
RGS16-deficient platelets had increased protease activated receptor 4 (PAR4) and collagen-induced aggregation, as well as increased CXCL12-dependent agonist-induced aggregation, dense and alpha granule secretion, integrin αIIbβ3 activation and phosphatidylserine exposure compared to those from WT littermates. Platelets from Rgs16-/- mice displayed enhanced phosphorylation of ERK and Akt following CXCL12 stimulation relative to controls. PKCδ is involved in regulating CXCL12-dependent activation of ERK and Akt, in the Rgs16-deficient platelets.
Species:  Mouse
Tissue: 
Technique: 
References:  28
Xenobiotics Influencing Gene Expression Click here for help
Upregulation of Rgs16 gene expression by combined application of LSD1 inhibitor, pargyline and HDAC inhibitor, SAHA.
Species:  Human
Tissue:  Breast cancer cell lines
Technique:  Microarray analysis of gene expression, qRT-PCR
References:  50
Anti-cancer and DNA damaging agent doxorubicin leads to induction of RGS16 transcript.
Species:  Human
Tissue:  RKO colon carcinoma cells
Technique:  Northern blot
References:  3
Bacterial endotoxin (LPS) causes upregulation of Rgs16 expression by a IL-1b, TNFα mediated pathway.
Species:  Rat
Tissue:  Cardiac myocytes
Technique:  Western blot
References:  37-38
300-fold induction of Rgs16 mRNA in Zone 1, 2, 3 hepatocytes of sucrose fed mice provided 5% sucrose-water > 3 days, and no chow for the final 18 hours.
Species:  Mouse
Tissue:  Liver, hepatocytes
Technique:  qPCR, in situ hybridization
References:  36
The TNF-κB p65 (Ser276) inhibitory peptide inhibits interleukin 17 mediated expression of Rgs16.
Species:  Mouse
Tissue:  B-cells
Technique:  qRT-PCR
References:  55
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Alpha-1 antitrypsin deficiency (A1ATD)
Description: A1ATD is an autosomal recessive disorder, characterised by defective production of alpha 1-antitrypsin (protein product of the SERPINA1 gene). This leads to decreased A1AT activity in the blood and lungs, and deposition of excessive abnormal A1AT protein in liver cells. The form and severity of disease depends on whether the sufferer is homozygous or heterozygous for a deffective SERPINA1 allele. Vertex Pharmaceuticals had a small molecule (VX-814) in development as a protein expression 'corrector', that was proposed to boost levels of correctly folded A1AT protein. However, in October 2020, Vertex terminated development at phase 2 (NCT04167345) due to issues of liver toxicity.
OMIM: 613490
Orphanet: ORPHA60
Disease:  Breast cancer
Disease Ontology: DOID:1612
OMIM: 114480
References:  31,54
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Deletion Human none A 104bp-1.4kb deletion of th 5'-regulatory site of RGS16 54
Disease:  Colorectal cancer
Disease Ontology: DOID:9256
OMIM: 114500
References:  33
Disease:  Fatty liver disease, nonalcoholic, susceptibility to, 1; NAFLD1
OMIM: 613282
References:  36
Disease:  Hematological malignancies
Description: Tumours of the hematopoietic and lymphoid tissues. Examples of hematologic cancer are acute and chronic leukemias, lymphomas, multiple myeloma and myelodysplastic syndromes.
References:  8
Disease:  Pancreatic cancer
Disease Ontology: DOID:1793
OMIM: 260350
Role:  Pancreatic cancer with lymph node metastasis.
References:  29,35
Clinically-Relevant Mutations and Pathophysiology Comments
Cancer mutation overview, a summary of information held by the cBioPortal for Cancer Genomics and The Cancer Genome Atlas (TGCA database) for RGS16:

A total of 58 mutations have been recorded (3 nonsense), distributed from amino acids 11-178,
there are 47 single occurrences,
missense mutation S174L has 3 independent occurrences in uterine cancer and melanoma,
4 residues appear with 2 independent occurrences (including S174L).

RGS16 mutaions are reported in these cancers:
Uterine carcinosarcoma/uterine malignant mixed müllerian tumor (>4%)
Cutaneious melanoma (>4%)
Lung
Bladder
Colorectal
Pancreas
Breast
Bladder
Stomach
Prostate
Liver
Head and neck
Breast (<0.5%)
Gene Expression and Pathophysiology Click here for help
Human cytomegalovirus (HCMV) infection in neonates leads to a highly plastic and functional robust programming of dendritic cells in vivo and in vitro.
Tissue or cell type: 
Pathophysiology: 
Species:  Human
Technique: 
References:  7
Biologically Significant Variant Comments
Genome-wide association studies (GWAS) of self-reported chronotype (morning/evening person) and self-reported sleep duration in 128, 266 white British individuals showed that sixteen variants were associated with chronotype, including variants near the known circadian rhythm gene RGS16 [26]. 6 out of the 41 alleles previously identified by GWAS to be chronotype loci in European participants (in the genes RGS16, PER2 and AK5 and between the genes APH1A and CA14) are absent from some non-European population groups [11].

References

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1. Beadling C, Druey KM, Richter G, Kehrl JH, Smith KA. (1999) Regulators of G protein signaling exhibit distinct patterns of gene expression and target G protein specificity in human lymphocytes. J Immunol, 162 (5): 2677-82. [PMID:10072511]

2. Berthebaud M, Rivière C, Jarrier P, Foudi A, Zhang Y, Compagno D, Galy A, Vainchenker W, Louache F. (2005) RGS16 is a negative regulator of SDF-1-CXCR4 signaling in megakaryocytes. Blood, 106 (9): 2962-8. [PMID:15998835]

3. Buckbinder L, Velasco-Miguel S, Chen Y, Xu N, Talbott R, Gelbert L, Gao J, Seizinger BR, Gutkind JS, Kley N. (1997) The p53 tumor suppressor targets a novel regulator of G protein signaling. Proc Natl Acad Sci USA, 94 (15): 7868-72. [PMID:9223279]

4. Carper MB, Denvir J, Boskovic G, Primerano DA, Claudio PP. (2014) RGS16, a novel p53 and pRb cross-talk candidate inhibits migration and invasion of pancreatic cancer cells. Genes Cancer, 5 (11-12): 420-35. [PMID:25568667]

5. Chen C, Zheng B, Han J, Lin SC. (1997) Characterization of a novel mammalian RGS protein that binds to Galpha proteins and inhibits pheromone signaling in yeast. J Biol Chem, 272 (13): 8679-85. [PMID:9079700]

6. Chen CK, Wieland T, Simon MI. (1996) RGS-r, a retinal specific RGS protein, binds an intermediate conformation of transducin and enhances recycling. Proc Natl Acad Sci USA, 93 (23): 12885-9. [PMID:8917514]

7. Dantoft W, Martínez-Vicente P, Jafali J, Pérez-Martínez L, Martin K, Kotzamanis K, Craigon M, Auer M, Young NT, Walsh P et al.. (2017) Genomic Programming of Human Neonatal Dendritic Cells in Congenital Systemic and In Vitro Cytomegalovirus Infection Reveal Plastic and Robust Immune Pathway Biology Responses. Front Immunol, 8: 1146. [PMID:28993767]

8. Davidsson J, Andersson A, Paulsson K, Heidenblad M, Isaksson M, Borg A, Heldrup J, Behrendtz M, Panagopoulos I, Fioretos T et al.. (2007) Tiling resolution array comparative genomic hybridization, expression and methylation analyses of dup(1q) in Burkitt lymphomas and pediatric high hyperdiploid acute lymphoblastic leukemias reveal clustered near-centromeric breakpoints and overexpression of genes in 1q22-32.3. Hum Mol Genet, 16 (18): 2215-25. [PMID:17613536]

9. Derrien A, Druey KM. (2001) RGS16 function is regulated by epidermal growth factor receptor-mediated tyrosine phosphorylation. J Biol Chem, 276 (51): 48532-8. [PMID:11602604]

10. Doi M, Ishida A, Miyake A, Sato M, Komatsu R, Yamazaki F, Kimura I, Tsuchiya S, Kori H, Seo K et al.. (2011) Circadian regulation of intracellular G-protein signalling mediates intercellular synchrony and rhythmicity in the suprachiasmatic nucleus. Nat Commun, 2: 327. [PMID:21610730]

11. Emmanuel P, von Schantz M. (2018) Absence of morningness alleles in non-European populations. Chronobiol Int, 35 (12): 1758-1761. [PMID:30084654]

12. Faurobert E, Hurley JB. (1997) The core domain of a new retina specific RGS protein stimulates the GTPase activity of transducin in vitro. Proc Natl Acad Sci USA, 94 (7): 2945-50. [PMID:9096326]

13. Gerstner JR, Vander Heyden WM, Lavaute TM, Landry CF. (2006) Profiles of novel diurnally regulated genes in mouse hypothalamus: expression analysis of the cysteine and histidine-rich domain-containing, zinc-binding protein 1, the fatty acid-binding protein 7 and the GTPase, ras-like family member 11b. Neuroscience, 139 (4): 1435-48. [PMID:16517089]

14. Goto K, Doi M, Wang T, Kunisue S, Murai I, Okamura H. (2017) G-protein-coupled receptor signaling through Gpr176, Gz, and RGS16 tunes time in the center of the circadian clock [Review]. Endocr J, 64 (6): 571-579. [PMID:28502923]

15. Grafstein-Dunn E, Young KH, Cockett MI, Khawaja XZ. (2001) Regional distribution of regulators of G-protein signaling (RGS) 1, 2, 13, 14, 16, and GAIP messenger ribonucleic acids by in situ hybridization in rat brain. Brain Res Mol Brain Res, 88 (1-2): 113-23. [PMID:11295237]

16. Hayasaka N, Aoki K, Kinoshita S, Yamaguchi S, Wakefield JK, Tsuji-Kawahara S, Horikawa K, Ikegami H, Wakana S, Murakami T et al.. (2011) Attenuated food anticipatory activity and abnormal circadian locomotor rhythms in Rgs16 knockdown mice. PLoS ONE, 6 (3): e17655. [PMID:21408016]

17. Hendriks-Balk MC, Hajji N, van Loenen PB, Michel MC, Peters SL, Alewijnse AE. (2009) Sphingosine-1-phosphate regulates RGS2 and RGS16 mRNA expression in vascular smooth muscle cells. Eur J Pharmacol, 606 (1-3): 25-31. [PMID:19374869]

18. Hepler JR. (1999) Emerging roles for RGS proteins in cell signalling. Trends Pharmacol Sci, 20 (9): 376-82. [PMID:10462761]

19. Hoshi Y, Endo K, Shirakihara T, Fukagawa A, Miyazawa K, Saitoh M. (2016) The potential role of regulator of G-protein signaling 16 in cell motility mediated by δEF1 family proteins. FEBS Lett, 590 (2): 270-8. [PMID:26823172]

20. Hsu HC, Yang P, Wang J, Wu Q, Myers R, Chen J, Yi J, Guentert T, Tousson A, Stanus AL et al.. (2008) Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat Immunol, 9 (2): 166-75. [PMID:18157131]

21. Hu Y, Shmygelska A, Tran D, Eriksson N, Tung JY, Hinds DA. (2016) GWAS of 89,283 individuals identifies genetic variants associated with self-reporting of being a morning person. Nat Commun, 7: 10448. [PMID:26835600]

22. Huang J, Pashkov V, Kurrasch DM, Yu K, Gold SJ, Wilkie TM. (2006) Feeding and fasting controls liver expression of a regulator of G protein signaling (Rgs16) in periportal hepatocytes. Comp Hepatol, 5: 8. [PMID:17123436]

23. Huang R, Li G, Zhao Z, Zeng F, Zhang K, Liu Y, Wang K, Hu H. (2020) RGS16 promotes glioma progression and serves as a prognostic factor. CNS Neurosci Ther, 26 (8): 791-803. [PMID:32319728]

24. Hwang IY, Park C, Harrison K, Kehrl JH. (2017) Normal Thymocyte Egress, T Cell Trafficking, and CD4+ T Cell Homeostasis Require Interactions between RGS Proteins and Gαi2. J Immunol, 198 (7): 2721-2734. [PMID:28235863]

25. Johnson EN, Seasholtz TM, Waheed AA, Kreutz B, Suzuki N, Kozasa T, Jones TL, Brown JH, Druey KM. (2003) RGS16 inhibits signalling through the G alpha 13-Rho axis. Nat Cell Biol, 5 (12): 1095-103. [PMID:14634662]

26. Jones SE, Tyrrell J, Wood AR, Beaumont RN, Ruth KS, Tuke MA, Yaghootkar H, Hu Y, Teder-Laving M, Hayward C et al.. (2016) Genome-Wide Association Analyses in 128,266 Individuals Identifies New Morningness and Sleep Duration Loci. PLoS Genet, 12 (8): e1006125. [PMID:27494321]

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