HGNC Approved Gene Symbol: RGS14
Cytogenetic location: 5q35.3 Genomic coordinates (GRCh38): 5:177,357,924-177,372,596 (from NCBI)
Members of the 'regulator of G protein signaling' (RGS) gene family encode proteins that downregulate signaling by heterotrimeric G proteins. See 602189 for background. By PCR on rat glioma cell cDNA using primers based on the conserved RGS domain, Snow et al. (1997) identified 2 novel cDNAs, Rgs12 (602512) and Rgs14. The Rgs14 cDNA encodes a predicted 544-amino acid protein. Northern blot analysis showed 2.5- and 3-kb Rgs14 transcripts at high levels in brain, spleen, and lung and at very low levels in other tissues. Snow et al. (1997) identified human ESTs that are highly homologous to Rgs14 and that map to chromosome 5, between marker D52006 and 5qter.
Using the yeast 2-hybrid system, Traver et al. (2000) isolated a mouse brain cDNA encoding a protein that interacts with both Rap1a (179520) and Rap2 (179540) but not with Ras (190020). Sequence analysis revealed that the protein is 96% identical to rat Rgs14. Mutation analysis defined the Rap-interacting domain between residues 300 to 427. Binding analysis demonstrated that Rgs14 interacts preferentially with the G-alpha-o (139311) subunits of heterotrimeric G proteins to stimulate GTPase activity. Northern blot and Western blot analysis detected strong expression restricted to brain and spleen of a 65-kD, primarily cytosolic protein. In situ hybridization analysis showed coexpression of G-alpha-o and Rgs14, as well as Rgs14 and Rap2 but not Rap1, in various brain regions, particularly the hippocampus, late in embryonic development. Traver et al. (2000) suggested that Rgs14 may constitute a bridging molecule that allows cross-regulation of signaling pathways downstream from G protein-coupled receptors.
Heterotrimeric G proteins bind to cell surface receptors and are integral in transmission of signals from outside the cell. Upon activation of the G-alpha subunit by binding of GTP, the G-alpha and G-beta-gamma subunits dissociate and interact with effector proteins for signal transduction. Regulatory proteins with the 19-amino acid GoLoco motif, described by Takesono et al. (1999), can bind to G-alpha subunits and maintain G protein subunit dissociation in the absence of G-alpha activation. Kimple et al. (2002) described the structural determinants of GoLoco activity as revealed by the crystal structure of G-alpha-i1 (139310)-GDP bound to the GoLoco region of RGS14. They described key contacts between the GoLoco motif and G-alpha protein, including the extension of GoLoco's highly conserved Asp/Glu-Gln-Arg triad into the nucleotide-binding pocket of G-alpha to make direct contact with the GDP alpha- and beta-phosphates. The structural organization of the GoLoco-G-alpha-i1 complex suggests that the G-alpha all-helical domain and GoLoco region carboxy-terminal residues control the specificity of GoLoco-G-alpha interactions.
Sierra et al. (2002) determined that RGS14 contains 15 exons and spans more than 16 kb.
By genomic sequence analysis, Sierra et al. (2002) mapped the RGS14 gene to chromosome 5q35.3. They mapped the mouse Rgs14 gene to chromosome 13 by interspecific backcross mapping.
Kimple, R. J., Kimple, M. E., Betts, L., Sondek, J., Siderovski, D. P. Structural determinants for GoLoco-induced inhibition of nucleotide release by G-alpha subunits. Nature 416: 878-881, 2002. [PubMed: 11976690] [Full Text: https://doi.org/10.1038/416878a]
Sierra, D. A., Gilbert, D. J., Householder, D., Grishin, N. V., Yu, K., Ukidwe, P., Barker, S. A., He, W., Wensel, T. G., Otero, G., Brown, G., Copeland, N. G., Jenkins, N. A., Wilkie, T. M. Evolution of the regulators of G-protein signaling multigene family in mouse and human. Genomics 79: 177-185, 2002. [PubMed: 11829488] [Full Text: https://doi.org/10.1006/geno.2002.6693]
Snow, B. E., Antonio, L., Suggs, S., Gutstein, H. B., Siderovski, D. P. Molecular cloning and expression analysis of rat Rgs12 and Rgs14. Biochem. Biophys. Res. Commun. 233: 770-777, 1997. [PubMed: 9168931] [Full Text: https://doi.org/10.1006/bbrc.1997.6537]
Takesono, A., Cisnowski, M. J., Ribas, C., Bernard, M., Chung, P., Hazard, S., III, Duzic, E., Lanier, S. M. Receptor-independent activators of heterotrimeric G-protein signaling pathways. J. Biol. Chem. 274: 33202-33205, 1999. [PubMed: 10559191] [Full Text: https://doi.org/10.1074/jbc.274.47.33202]
Traver, S., Bidot, C., Spassky, N., Baltauss, T., de Tand, M.-F., Thomas, J.-L., Zalc, B., Janoueix-Lerosey, I., de Gunzburg, J. RGS14 is a novel Rap effector that preferentially regulates the GTPase activity of G-alpha-0. Biochem. J. 350: 19-29, 2000. [PubMed: 10926822]