regulator of G-protein signaling 14 | R12 family | IUPHAR Guide to IMMUNOPHARMACOLOGY

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regulator of G-protein signaling 14

Target not currently curated in GtoImmuPdb

Target id: 2820

Nomenclature: regulator of G-protein signaling 14

Abbreviated Name: RGS14

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 - 566 5q35.3 RGS14 regulator of G protein signaling 14
Mouse - 547 13 B1 Rgs14 regulator of G-protein signaling 14
Rat - 544 17p14 Rgs14 regulator of G-protein signaling 14
Previous and Unofficial Names
A28-RGS14 | RGS-r | RPIP1
Database Links
CATH/Gene3D
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Associated Proteins
G Proteins
Name References
Gαi0 5,8,10-11,16,23
Interacting Proteins
Name Effect References
Gai1-GDP; Gai3-GDP High affinity binding to the GPR motif resulting in RGS14 localization to the plasma membrane 10-11,23
α2A-adrenoceptor A preformed Gai1-GDP:RGS14 complex interacts with the receptor and is uncoupled by agonist activation of receptor 24-25
Gai/o-GTP Binding to the RGS domain resulting in accelerated Ga-GTP hydrolysis 5,10-11,22
Rap2A-GTP; Rap1-GTP Binding to the R1 Ras/Rap-binding domain (RBD) 22
H-Ras-GTP Binding to the R1 Ras/Rap-binding domain (RBD) 20,24,27
regulator of G-protein signaling 4 RGS4 and RGS5: Binding of RGS4 within the tandem R1-R2 RBD region enhances RGS activity of RGS4 towards Gai2-GTP 8,28
Raf kinases (Raf-1, B-Raf, A-Raf) Specific binding site uncertain, with unknown consequences 20,27
Resistance to cholinesterase 8A (Ric-8A) The non-receptor guanine nucleotide exchange factor (GEF) Ric-8A stimulates dissociation of a RGS14:Gαi1-GDP complex to form a stable Ric-8A-Gαi complex in the absence of GTP 24,26
Associated Protein Comments
RGS14 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 Gα-i/o subfamily of G proteins including Gai1, Gai2, Gai3 and Gao. The GPR motif selectively binds inactive (GDP bound) Gai1 and Gai3.
Tissue Distribution
Brain, temporal lobe, spleen, lymphocytes, kidney
Species:  Human
Technique:  In situ hybridization, Western blot
References:  6
Brain, CA2 hippocampus, caudate
Species:  Human
Technique:  In situ hybridization
References:  1
Brain (area CA2 hippocampus)
Species:  Mouse
Technique:  Immunocytochemistry, in situ hybridisation, Western blot
References:  7,12,22
Brain (hippocampus), lung, spleen, heart
Species:  Rat
Technique:  Immunocytochemistry, Western blot
References:  10,21-22
Tissue Distribution Comments
Levels of messenger RNA that encode for this protein are detectable in most tissues by RT-PCR. However, detectable protein expression is very limited.
Functional Assays
GTPase activating protein (GAP)
Species:  Rat
Tissue:  Pure protein
Response measured:  Marked enhancement of Gai/o GTPase activity in single-turnover assays; enhancement of receptor-stimulated steady state GTPase activity of Gai2.
References:  5,8,10,17
Guanine nucleotide dissociation inhibition (GDI)
Species:  Rat
Tissue:  Pure protein
Response measured:  RGS14 inhibits GDP release for Gai1.
References:  10-11,17
Bioluminesence Resonance Energy Transfer (BRET)
Species:  Rat
Tissue:  HEK293 cells (human)
Response measured:  RGS14 interactions with active and inactive Gai1, active Gao, and H-Ras-GTP in live cells.
References:  2-3,24
Intracellular translocation assay using immunocytochemistry-ICC
Species:  Rat
Tissue:  RGS14 translocation from cytosol to the plasma membrane or to nucleus.
Response measured:  HeLa cells
References:  4,19
Activity-induced long-term potentation (LTP)
Species:  Mouse
Tissue:  CA2 hippocampal neurons of hippocampal slices
Response measured:  Loss of RGS14 (RGS14-KO) results in nascent robust LTP in proximal dendrites of CA2 neurons.
References:  12
Co-expression of RGS14 with the Cav1.2 calcium channel in HEK cells
Species:  None
Tissue:  HEK293 cells (human)
Response measured:  Partial inhibition of Cav1.2 calcium currents
References:  15
RGS14 Inhibition of ERK activation
Species:  Rat
Tissue:  HeLa cells
Response measured:  RGS14 inhibits PDGF-stimulated ERK phosphorylation.
References:  20
Physiological Functions
Natural suppressor of hippocampal (CA2)-based learning and memory
Species:  Mouse
Tissue:  Freely moving whole animal
References:  12
Suppression of long-term potentiation in CA2 neurons
Species:  Mouse
Tissue:  CA2 neurons
References:  12
Physiological Consequences of Altering Gene Expression
RGS14 is not naturally expressed in visual cortex. However, ectopic over-expression of recombinant RGS14 in neurons of layer 6 of V2 visual secondary visual cortex promoted the conversion of a normal short-term object-recognition memory (45 minutes) into long-term memory detectable even after many months.
Species:  Rat
Tissue:  Visual cortex
Technique:  Viral gene transfer
References:  13
Mice engineered to lack RGS14 perform significantly better than paired wild-type litter mates in tests of hippocampal-mediated spatial learning (Morris Water maze) and memory (novel object recognition) with no changes in non-hippocampal behaviors.
Species:  Mouse
Tissue:  Freely moving whole animal
Technique:  Gene knockout
References:  12
Physiological Consequences of Altering Gene Expression Comments
One study [14] reports that knock-out of RGS14 is embryonic lethal. However, other studies [18] suggests this is an artifact of the method (PGK-neo) used to generate the aforementioned KO mouse. This study shows that use of PGK-neo results in unexpected phenotypes including embryonic lethality that reflect more than just the loss of function of the targeted gene.
Biologically Significant Variants
Type:  Point mutation
Species:  Rat
Description:  Point mutation within the R1 domain of Rgs14 significantly reduces interactions with active H-Ras-GTP and Rap2-GTP.
Amino acid change:  Arg333Leu (R333L)
References:  20,23
Type:  Point mutation
Species:  Rat
Description:  Double point mutations within the RGS domain of Rgs14 blocks interactions with Gai/o-GTP and prevents RGS activity.
Amino acid change:  Glu92Ala (E92A) plus Asn93>Ala (N93A)
References:  5,19,23,25
Type:  Point mutation
Species:  Rat
Description:  Thr494Ala (T494A) substitution mutation adjacent to the GPR/GoLoco motif prevents phosphoylation of this residue of Rgs14 by protein kinase A (PKA), whereas a Thr494Glu substitution mutation mimics phosphorylation at this site and increases Rgs14 affinity for Gai1 binding 3-fold.
Amino acid change:  Thr494Ala (T494A)
References:  9
Type:  Point mutation
Species:  Mouse
Description:  Mutating Leu506>Ala plus Leu507>Ala (LL/AA) within a defined nucelar export signal (NES) on Rgs14 causes Rgs14 to accumulate in the nucleus.
Amino acid change:  Leu506Ala (L506A) plus Leu507Ala (L507A)
References:  4,19
Type:  Point mutation
Species:  Rat
Description:  Double point mutation within the GPR/GoLoco motif blocks interactions with Gai/o-GDP.
Amino acid change:  Gln515Ala (Q515A) plus Glu516Ala (E516A)
References:  19,23,25
General Comments
To date, there is no reported protein crystal structure for full-length RGS14. However, structural data has been reported for isolated domains of RGS14 (X-ray and NMR) or full-length protein (hydrogen-deuterium exchange, HDX). This includes:
1) X-ray protein crystal data for human Gai1-GDP bound to a peptide corresponding to the GPR/GoLoco motif of rat Rgs14 (PDB 1KJY)
2) NMR data for the isolated RGS domain of human RGS14 (PDB 2JNU)
3) NMR data for the isolated RBD2 domain of mouse Rgs14 (PDB 1WFY)
4) HDX data for full-length RGS14 alone (apo RGS14) and RGS14 bound to either Gao-AlF4-, Gai1-GDP, or both has been reported [3].

References

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1. Allen Brain Atlas. RGS14. Accessed on 21/06/2016. Modified on 21/06/2016. Allen Brain Atlas, http://human.brain-map.org/microarray/search/show?exact_match=false&search_term=RGS14&search_type=gene

2. Brown NE, Blumer JB, Hepler JR. (2015) Bioluminescence resonance energy transfer to detect protein-protein interactions in live cells. Methods Mol. Biol., 1278: 457-65. [PMID:25859969]

3. Brown NE, Goswami D, Branch MR, Ramineni S, Ortlund EA, Griffin PR, Hepler JR. (2015) Integration of G protein α (Gα) signaling by the regulator of G protein signaling 14 (RGS14). J. Biol. Chem., 290 (14): 9037-49. [PMID:25666614]

4. Cho H, Kim DU, Kehrl JH. (2005) RGS14 is a centrosomal and nuclear cytoplasmic shuttling protein that traffics to promyelocytic leukemia nuclear bodies following heat shock. J. Biol. Chem., 280 (1): 805-14. [PMID:15520006]

5. Cho H, Kozasa T, Takekoshi K, De Gunzburg J, Kehrl JH. (2000) RGS14, a GTPase-activating protein for Gialpha, attenuates Gialpha- and G13alpha-mediated signaling pathways. Mol. Pharmacol., 58 (3): 569-76. [PMID:10953050]

6. EMBL-EBI Expression Atlas. RGS14 regulator of G-protein signaling 14. Accessed on 21/06/2016. Modified on 21/06/2016. EMBL-EBI Expression Atlas, http://www.ebi.ac.uk/gxa/genes/ENSG00000169220

7. Evans PR, Lee SE, Smith Y, Hepler JR. (2014) Postnatal developmental expression of regulator of G protein signaling 14 (RGS14) in the mouse brain. J. Comp. Neurol., 522 (1): 186-203. [PMID:23817783]

8. Hepler JR, Cladman W, Ramineni S, Hollinger S, Chidiac P. (2005) Novel activity of RGS14 on Goalpha and Gialpha nucleotide binding and hydrolysis distinct from its RGS domain and GDI activity. Biochemistry, 44 (14): 5495-502. [PMID:15807543]

9. Hollinger S, Ramineni S, Hepler JR. (2003) Phosphorylation of RGS14 by protein kinase A potentiates its activity toward G alpha i. Biochemistry, 42 (3): 811-9. [PMID:12534294]

10. Hollinger S, Taylor JB, Goldman EH, Hepler JR. (2001) RGS14 is a bifunctional regulator of Galphai/o activity that exists in multiple populations in brain. J. Neurochem., 79 (5): 941-9. [PMID:11739605]

11. 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]

12. Lee SE, Simons SB, Heldt SA, Zhao M, Schroeder JP, Vellano CP, Cowan DP, Ramineni S, Yates CK, Feng Y et al.. (2010) RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory. Proc. Natl. Acad. Sci. U.S.A., 107 (39): 16994-8. [PMID:20837545]

13. López-Aranda MF, López-Téllez JF, Navarro-Lobato I, Masmudi-Martín M, Gutiérrez A, Khan ZU. (2009) Role of layer 6 of V2 visual cortex in object-recognition memory. Science, 325 (5936): 87-9. [PMID:19574389]

14. Martin-McCaffrey L, Willard FS, Oliveira-dos-Santos AJ, Natale DR, Snow BE, Kimple RJ, Pajak A, Watson AJ, Dagnino L, Penninger JM et al.. (2004) RGS14 is a mitotic spindle protein essential from the first division of the mammalian zygote. Dev. Cell, 7 (5): 763-9. [PMID:15525537]

15. Martín-Montañez E, Acevedo MJ, López-Téllez JF, Duncan RS, Mateos AG, Pavía J, Koulen P, Khan ZU. (2010) Regulator of G-protein signaling 14 protein modulates Ca²+ influx through Cav1 channels. Neuroreport, 21 (16): 1034-9. [PMID:20842066]

16. Mittal V, Linder ME. (2004) The RGS14 GoLoco domain discriminates among Galphai isoforms. J. Biol. Chem., 279 (45): 46772-8. [PMID:15337739]

17. Mittal V, Linder ME. (2006) Biochemical characterization of RGS14: RGS14 activity towards G-protein alpha subunits is independent of its binding to Rap2A. Biochem. J., 394 (Pt 1): 309-15. [PMID:16246175]

18. Scacheri PC, Crabtree JS, Novotny EA, Garrett-Beal L, Chen A, Edgemon KA, Marx SJ, Spiegel AM, Chandrasekharappa SC, Collins FS. (2001) Bidirectional transcriptional activity of PGK-neomycin and unexpected embryonic lethality in heterozygote chimeric knockout mice. Genesis, 30 (4): 259-63. [PMID:11536432]

19. Shu FJ, Ramineni S, Amyot W, Hepler JR. (2007) Selective interactions between Gi alpha1 and Gi alpha3 and the GoLoco/GPR domain of RGS14 influence its dynamic subcellular localization. Cell. Signal., 19 (1): 163-76. [PMID:16870394]

20. Shu FJ, Ramineni S, Hepler JR. (2010) RGS14 is a multifunctional scaffold that integrates G protein and Ras/Raf MAPkinase signalling pathways. Cell. Signal., 22 (3): 366-76. [PMID:19878719]

21. 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]

22. Traver S, Bidot C, Spassky N, Baltauss T, De Tand MF, Thomas JL, Zalc B, Janoueix-Lerosey I, Gunzburg JD. (2000) RGS14 is a novel Rap effector that preferentially regulates the GTPase activity of galphao. Biochem. J., 350 Pt 1: 19-29. [PMID:10926822]

23. Traver S, Splingard A, Gaudriault G, De Gunzburg J. (2004) The RGS (regulator of G-protein signalling) and GoLoco domains of RGS14 co-operate to regulate Gi-mediated signalling. Biochem. J., 379 (Pt 3): 627-32. [PMID:15112653]

24. Vellano CP, Brown NE, Blumer JB, Hepler JR. (2013) Assembly and function of the regulator of G protein signaling 14 (RGS14)·H-Ras signaling complex in live cells are regulated by Gαi1 and Gαi-linked G protein-coupled receptors. J. Biol. Chem., 288 (5): 3620-31. [PMID:23250758]

25. Vellano CP, Maher EM, Hepler JR, Blumer JB. (2011) G protein-coupled receptors and resistance to inhibitors of cholinesterase-8A (Ric-8A) both regulate the regulator of g protein signaling 14 RGS14·Gαi1 complex in live cells. J. Biol. Chem., 286 (44): 38659-69. [PMID:21880739]

26. Vellano CP, Shu FJ, Ramineni S, Yates CK, Tall GG, Hepler JR. (2011) Activation of the regulator of G protein signaling 14-Gαi1-GDP signaling complex is regulated by resistance to inhibitors of cholinesterase-8A. Biochemistry, 50 (5): 752-62. [PMID:21158412]

27. Willard FS, Willard MD, Kimple AJ, Soundararajan M, Oestreich EA, Li X, Sowa NA, Kimple RJ, Doyle DA, Der CJ et al.. (2009) Regulator of G-protein signaling 14 (RGS14) is a selective H-Ras effector. PLoS ONE, 4 (3): e4884. [PMID:19319189]

28. Zhao P, Nunn C, Ramineni S, Hepler JR, Chidiac P. (2013) The Ras-binding domain region of RGS14 regulates its functional interactions with heterotrimeric G proteins. J. Cell. Biochem., 114 (6): 1414-23. [PMID:23255434]

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