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regulator of G-protein signaling 18

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Target not currently curated in GtoImmuPdb

Target id: 2807

Nomenclature: regulator of G-protein signaling 18

Abbreviated Name: RGS18

Family: R4 family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 235 1q31.2 RGS18 regulator of G protein signaling 18 26
Mouse - 235 1 62.99 cM Rgs18 regulator of G-protein signaling 18 26
Rat - 235 13q21 Rgs18 regulator of G-protein signaling 18
Previous and Unofficial Names Click here for help
RGS13
Database Links Click here for help
Alphafold Q9NS28 (Hs), Q99PG4 (Mm), Q4L0E8 (Rn)
CATH/Gene3D 1.10.196.10
Ensembl Gene ENSG00000150681 (Hs), ENSMUSG00000026357 (Mm), ENSRNOG00000003959 (Rn)
Entrez Gene 64407 (Hs), 64214 (Mm), 289076 (Rn)
Human Protein Atlas ENSG00000150681 (Hs)
KEGG Gene hsa:64407 (Hs), mmu:64214 (Mm), rno:289076 (Rn)
OMIM 607192 (Hs)
Pharos Q9NS28 (Hs)
RefSeq Nucleotide NM_130782 (Hs), NM_022881 (Mm), NM_001047084 (Rn)
RefSeq Protein NP_570138 (Hs), NP_075019 (Mm), NP_001040549 (Rn)
UniProtKB Q9NS28 (Hs), Q99PG4 (Mm), Q4L0E8 (Rn)
Wikipedia RGS18 (Hs)
Associated Proteins Click here for help
G Proteins
Name References
Gαi/0 10
Gαq/11 5
Interacting Proteins
Name Effect References
Gi, Gq alpha subunits GTP hydrolysis 21
Gnai-3 GTP hydrolysis 30
Gnai-1, i-2, i-3, Gnaq 4
Gnai, Gnaq GTP hydrolysis 19
14-3-3γ 14-3-3γ protein binds to phosphorylated serines 49 and 218 of RGS18, which blocks activity. 5
PAR2 Inhibits PAR2/Gαi/o -mediated signalling 10
14-3-3γ-phosphoSer216 Prevents Rgs18 binding to 14-3-3γ-phosphoSer49, thus releasing Rgs18 for Gq-GAP activity 5
14-3-3γ-phosphoSer49 Inhibits Rgs18 Gq-GAP activity 5
spinophilin (SPL), SPLtyrosine phosphorylation; the tyrosine phosphatase, SHP-1 bind Rgs18 Sequesters Rgs18; inhibits Rgs18 GAP activity 15-17
Associated Protein Comments
Phosphorylation of SPL at Ser94 inhibits Rgs18- SPL binding and releases Rgs18 GAP activity [17].
Tissue Distribution Click here for help
RGS18 protein is upregulated in the plasma of patients with amyotrophic lateral sclerosis (ALS).
Species:  Human
Technique:  Western blot.
References:  8
Hematopoietic stem cells, fetal liver, spleen, and lung.
Species:  Human
Technique:  Northern blot and RT-PCR.
References:  21
Platelets, monocytes, lymphocytes, megakaryocytes, fetal liver.
Species:  Human
Technique:  RT-PCR, northern and western blots.
References:  4,12,25,30
Platelets
Species:  Mouse
Technique:  Western blot
References:  17
Hematopoietic stem cells, fetal liver, spleen, and lung. Megakaryocytes, platelets, fetal liver (qRT-PCR).
Species:  Mouse
Technique:  Western blot and quantitative RT-PCR.
References:  21,30
Megakaryocytes, spleen, hematopoietic cells and monocytes.
Species:  Mouse
Technique:  Northern blot and RT-PCR.
References:  19,25
Natural killer (NK) cells.
Species:  Rat
Technique:  RT-PCR and western blot.
References:  11
Cancer.
Species:  None
Technique:  Microarray analysis.
References:  23
Functional Assays Click here for help
GTP hydrolysis by Gαi-GTP and Gαq-GTP
Species:  None
Tissue:  Megakaryocytes, platelets, granulocytes/monocytes.
Response measured:  RGS18 GTPase-activating protein (GAP) activity for Gαi and Gαq.
References:  19,21,30
RGS18 inhibited mitogen-activated-protein kinase activation in HEK-293/chemokine receptor 2 cells treated with monocyte chemotactic protein-1.
Species:  None
Tissue:  HEK-293 cells.
Response measured:  Inhibition of MAPK activation.
References:  30
Physiological Functions Click here for help
Activity dependent inhibition of TXA2 and thrombin.
Species:  Human
Tissue:  Platelets.
References:  16
Rgs18 can reduce cell migration evoked by CXC chemokine ligand (CXCL)12, CC chemokine ligand (CCL)19, or CCL21.
Species:  Mouse
Tissue:  Hematopoietic dendritic cells.
References:  25
Rgs18 inhibited osteoclastogenesis evoked by RANKL in RAW264.7, and primary osteoclast precursor monocytes derived from mouse bone marrow cultured with macrophage-colony stimulating factor (M-CSF).
Species:  Mouse
Tissue:  RAW264.7 cells and primary osteoclast precursor monocytes from mouse bone marrow.
References:  9
The transcriptional repressor Gfi1b stringently represses Rgs18 expression in erythroid cells. Rgs18 regulates downstream signalling and gene expression programs to orchestrate erythro-megakaryocytic lineage choices by effecting on Gfi1b. Rgs18 regulates activity of the p38 MAPK family proteins, and ERK1 and ERK2 in the two lineages, which in turn alter the balance between the mutually antagonistic transcription factors Fli1 and Klf1; (human and mouse)
Species:  Human
Tissue: 
References:  22
RGS18 appears to control platelet and osteoclast functions.
Species:  Human
Tissue:  Osteoclasts
References:  28
Platelet activation by thrombin, thromboxane A2, or ADP stimulates the association of RGS18 and 14-3-3γ-phosphoSer49 – this sequesters Rgs18 and inhibits its Gq-GAP activity. By contrast, cAMP or cGMP signalling evoked by prostacyclin and nitric oxide induces 14-3-3γ-phosphoSer216, thus releasing RGS18 from 14-3-3γ-phosphoSer49, and stimulating Rgs18 Gq-GAP activity. Therefore, PKA- and PKGI-mediated detachment of 14-3-3 activates RGS18 to block Gq-dependent calcium signalling.
Species:  Mouse
Tissue:  Platelets
References:  5,17
Physiological Consequences of Altering Gene Expression Click here for help
Lentiviral RGS18 overexpression during differentiation of mouse Sca1 hematopoietic stem cells induces increase of megakaryocyte proliferation. RGS18 depletion in zebrafish results in thrombocytopenia (embryos lack thrombocytes after injection of an ATG or splice-blocking morpholino); all RGS18 depleted embryos have curly tails and an almost absent response to acoustic stimuli. In situ hybridization in zebrafish, Xenopus, and mouse embryos shows RGS18 expression in thrombocytes and/or hematological tissues but also in brain and otic vesicles. RGS18 interferes with development of cilia in hair cells of the inner ear and neuromast cells.
Species:  Mouse
Tissue:  Hematopoietic stem cells.
Technique:  Viral gene transfer. Immunoblot and RT-PCR were also used. Zebrafish and Xenopus were also investigated.
References:  13
RGS18-/- mice present a mild thrombocytopenia, accompanied with a marked deficit in megakaryocyte (MK) number in the bone marrow; defective megakaryopoiesis; lower bone marrow content of only the most committed MK precursors and defect of platelet recovery in vivo under acute conditions of thrombocytopenia.
Species:  Mouse
Tissue:  Bone marrow.
Technique:  Gene knockout.
References:  2-3,16
Xenobiotics Influencing Gene Expression Click here for help
Thrombin, thromboxane A2, or ADP stimulate the interaction of RGS18 and 14-3-3γ protein by increasing the phosphorylation of serine residue S49 of RGS18. This is believed to integrate activating and inhibitory signaling in platelets.
Species:  Human
Tissue:  Platelets.
Technique:  Western blot.
References:  5-6
Long-acting β2-adrenoreceptor agonists (formoterol) and glucocorticoids (dexamethasone, budesonide) synergistically enhance RGS2 expression.
Species:  Human
Tissue:  Bronchial epithelial BEAS-2B cells
Technique:  RT-PCR, Western blot
References:  20
Pirfenidone enhances RGS2 mRNA and protein expression which contributes to its anti-fibrotic effect.
Species:  Human
Tissue:  HLF1 human lung fibroblasts
Technique:  Genechip microarray, RT-PCR, Western blot
References:  27
Chronic intermittent ethanol exposure increased RGS2 mRNA and protein levels in rats.
Species:  Rat
Tissue:  Brain (prefrontal cortex)
Technique:  RT-PCR, Western blot
References:  14
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Cancer
Disease Ontology: DOID:162
Role:  RGS18 is induced in solid tumors of the kidney and stomach and is down regulated in solid tumors of the colon and lung. RGS18 is also induced in diffuse large B, unspecified peripheral T-cell and follicular lymphomas and is down regulated in acute lymphoblastic leukemina (B-cell) and chronic lymphocytic leukemia.
References:  7,23
Disease:  Metabolic syndrome
Synonyms: Metabolic syndrome X [Disease Ontology: DOID:14221]
Disease Ontology: DOID:14221
Role:  RGS18 transcript is up-regulated in aspirin-resistant platelets from patients with metabolic syndrome.
References:  18
Gene Expression and Pathophysiology Click here for help
RGS18 is associated with the RYR3 gene in cardiovascular disease (CVD)
Tissue or cell type: 
Pathophysiology: 
Species:  Human
Technique: 
References:  24
Gene Expression and Pathophysiology Comments
Rgs18 was one of several genes whose expression was found to be dysregulated in rats fed with a high-salt diet [29]. These rats exhibited abnormal cardiovascular development and organ injury.
General Comments
RGS18 and other R4 class RGS proteins lack the putative disruptor elements of the R12 subfamily. Introducing R12 disruptor elements attenuates R4 class activity (inactivates GAP) for specific Gαi proteins [1].

References

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1. Asli A, Sadiya I, Avital-Shacham M, Kosloff M. (2018) "Disruptor" residues in the regulator of G protein signaling (RGS) R12 subfamily attenuate the inactivation of Gα subunits. Sci Signal, 11 (534). [PMID:29895615]

2. DeHelian D, Gupta S, Wu J, Thorsheim C, Estevez B, Cooper M, Litts K, Lee-Sundlov MM, Hoffmeister KM, Poncz M et al.. (2020) RGS10 and RGS18 differentially limit platelet activation, promote platelet production, and prolong platelet survival. Blood, 136 (15): 1773-1782. [PMID:32542378]

3. Delesque-Touchard N, Pendaries C, Volle-Challier C, Millet L, Salel V, Hervé C, Pflieger AM, Berthou-Soulie L, Prades C, Sorg T et al.. (2014) Regulator of G-protein signaling 18 controls both platelet generation and function. PLoS ONE, 9 (11): e113215. [PMID:25405900]

4. Gagnon AW, Murray DL, Leadley RJ. (2002) Cloning and characterization of a novel regulator of G protein signalling in human platelets. Cell Signal, 14 (7): 595-606. [PMID:11955952]

5. Gegenbauer K, Elia G, Blanco-Fernandez A, Smolenski A. (2012) Regulator of G-protein signaling 18 integrates activating and inhibitory signaling in platelets. Blood, 119 (16): 3799-807. [PMID:22234696]

6. Gegenbauer K, Nagy Z, Smolenski A. (2013) Cyclic nucleotide dependent dephosphorylation of regulator of G-protein signaling 18 in human platelets. PLoS ONE, 8 (11): e80251. [PMID:24244663]

7. Hurst JH, Hooks SB. (2009) Regulator of G-protein signaling (RGS) proteins in cancer biology. Biochem Pharmacol, 78 (10): 1289-97. [PMID:19559677]

8. Häggmark A, Mikus M, Mohsenchian A, Hong MG, Forsström B, Gajewska B, Barańczyk-Kuźma A, Uhlén M, Schwenk JM, Kuźma-Kozakiewicz M et al.. (2014) Plasma profiling reveals three proteins associated to amyotrophic lateral sclerosis. Ann Clin Transl Neurol, 1 (8): 544-53. [PMID:25356426]

9. Iwai K, Koike M, Ohshima S, Miyatake K, Uchiyama Y, Saeki Y, Ishii M. (2007) RGS18 acts as a negative regulator of osteoclastogenesis by modulating the acid-sensing OGR1/NFAT signaling pathway. J Bone Miner Res, 22 (10): 1612-20. [PMID:17576169]

10. Kim K, Lee J, Ghil S. (2018) The regulators of G protein signaling RGS16 and RGS18 inhibit protease-activated receptor 2/Gi/o signaling through distinct interactions with Gα in live cells. FEBS Lett, 592 (18): 3126-3138. [PMID:30117167]

11. Kveberg L, Ryan JC, Rolstad B, Inngjerdingen M. (2005) Expression of regulator of G protein signalling proteins in natural killer cells, and their modulation by Ly49A and Ly49D. Immunology, 115 (3): 358-65. [PMID:15946253]

12. 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]

13. Louwette S, Labarque V, Wittevrongel C, Thys C, Metz J, Gijsbers R, Debyser Z, Arnout J, Van Geet C, Freson K. (2012) Regulator of G-protein signaling 18 controls megakaryopoiesis and the cilia-mediated vertebrate mechanosensory system. FASEB J, 26 (5): 2125-36. [PMID:22308195]

14. Luessen DJ, Sun H, McGinnis MM, McCool BA, Chen R. (2017) Chronic intermittent ethanol exposure selectively alters the expression of Gα subunit isoforms and RGS subtypes in rat prefrontal cortex. Brain Res, 1672: 106-112. [PMID:28736108]

15. Ma P, Cierniewska A, Signarvic R, Cieslak M, Kong H, Sinnamon AJ, Neubig RR, Newman DK, Stalker TJ, Brass LF. (2012) A newly identified complex of spinophilin and the tyrosine phosphatase, SHP-1, modulates platelet activation by regulating G protein-dependent signaling. Blood, 119 (8): 1935-45. [PMID:22210881]

16. Ma P, Foote DC, Sinnamon AJ, Brass LF. (2015) Dissociation of SHP-1 from spinophilin during platelet activation exposes an inhibitory binding site for protein phosphatase-1 (PP1). PLoS ONE, 10 (3): e0119496. [PMID:25785436]

17. Ma P, Ou K, Sinnamon AJ, Jiang H, Siderovski DP, Brass LF. (2015) Modulating platelet reactivity through control of RGS18 availability. Blood, 126 (24): 2611-20. [PMID:26407691]

18. Mao Y, Lei L, Su J, Yu Y, Liu Z, Huo Y. (2014) Regulators of G protein signaling are up-regulated in aspirin-resistant platelets from patients with metabolic syndrome. Pharmazie, 69 (5): 371-3. [PMID:24855830]

19. Nagata Y, Oda M, Nakata H, Shozaki Y, Kozasa T, Todokoro K. (2001) A novel regulator of G-protein signaling bearing GAP activity for Galphai and Galphaq in megakaryocytes. Blood, 97 (10): 3051-60. [PMID:11342430]

20. Newton R, Giembycz MA. (2016) Understanding how long-acting β2 -adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids in asthma - an update. Br J Pharmacol, 173 (24): 3405-3430. [PMID:27646470]

21. Park IK, Klug CA, Li K, Jerabek L, Li L, Nanamori M, Neubig RR, Hood L, Weissman IL, Clarke MF. (2001) Molecular cloning and characterization of a novel regulator of G-protein signaling from mouse hematopoietic stem cells. J Biol Chem, 276 (2): 915-23. [PMID:11042171]

22. Sengupta A, Upadhyay G, Sen S, Saleque S. (2016) Reciprocal regulation of alternative lineages by Rgs18 and its transcriptional repressor Gfi1b. J Cell Sci, 129 (1): 145-54. [PMID:26567214]

23. Sethakorn N, Dulin NO. (2013) RGS expression in cancer: oncomining the cancer microarray data. J Recept Signal Transduct Res, 33 (3): 166-71. [PMID:23464602]

24. Shendre A, Wiener HW, Irvin MR, Aouizerat BE, Overton ET, Lazar J, Liu C, Hodis HN, Limdi NA, Weber KM et al.. (2017) Genome-wide admixture and association study of subclinical atherosclerosis in the Women's Interagency HIV Study (WIHS). PLoS One, 12 (12): e0188725. [PMID:29206233]

25. Shi GX, Harrison K, Han SB, Moratz C, Kehrl JH. (2004) Toll-like receptor signaling alters the expression of regulator of G protein signaling proteins in dendritic cells: implications for G protein-coupled receptor signaling. J Immunol, 172 (9): 5175-84. [PMID:15100254]

26. Sierra DA, Gilbert DJ, Householder D, Grishin NV, Yu K, Ukidwe P, Barker SA, He W, Wensel TG, Otero G et al.. (2002) Evolution of the regulators of G-protein signaling multigene family in mouse and human. Genomics, 79 (2): 177-85. [PMID:11829488]

27. Xie Y, Jiang H, Zhang Q, Mehrotra S, Abel PW, Toews ML, Wolff DW, Rennard S, Panettieri Jr RA, Casale TB et al.. (2016) Upregulation of RGS2: a new mechanism for pirfenidone amelioration of pulmonary fibrosis. Respir Res, 17 (1): 103. [PMID:27549302]

28. Xie Z, Chan EC, Druey KM. (2016) R4 Regulator of G Protein Signaling (RGS) Proteins in Inflammation and Immunity. AAPS J, 18 (2): 294-304. [PMID:26597290]

29. Xu H, Qing T, Shen Y, Huang J, Liu Y, Li J, Zhen T, Xing K, Zhu S, Luo M. (2018) RNA-seq analyses the effect of high-salt diet in hypertension. Gene, 677: 245-250. [PMID:30059752]

30. Yowe D, Weich N, Prabhudas M, Poisson L, Errada P, Kapeller R, Yu K, Faron L, Shen M, Cleary J et al.. (2001) RGS18 is a myeloerythroid lineage-specific regulator of G-protein-signalling molecule highly expressed in megakaryocytes. Biochem J, 359 (Pt 1): 109-18. [PMID:11563974]

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