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Gene Review

RGS19  -  regulator of G-protein signaling 19

Homo sapiens

Synonyms: G-alpha-interacting protein, GAIP, GNAI3IP, RGSGAIP, Regulator of G-protein signaling 19
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Disease relevance of RGS19

  • In the present study we show that the GAIP mRNA content declines during the enterocytic differentiation of two cell lines derived from human colon adenocarcinomas: HT-29 and Caco-2 [1].
  • In undifferentiated HT-29 cells, when the GDP/GTP cycle on the trimeric Gi3 protein is interrupted by either pertussis toxin treatment or by the transfection of a mutant of the Galphai3 protein with no GTPase activity (Q204L), we observed a decrease in the GAIP mRNA content [1].
  • Activation of ERK1/2 stimulates macroautophagy in the human colon cancer cell line HT-29 by favoring the phosphorylation of the Galpha-interacting protein (GAIP) in an amino acid-dependent manner (Ogier-Denis, E., Pattingre, S., El Benna, J., and Codogno, P. (2000) J. Biol. Chem. 275, 39090-39095) [2].
  • Here we report the cloning and functional characterization of a unique cDNA isoform of GAIP, derived from embryonic chicken dorsal root ganglion neurons [3].

High impact information on RGS19

  • GAIP and RGS4 are GTPase-activating proteins for the Gi subfamily of G protein alpha subunits [4].
  • The extent of inhibition of Gz GAP, GAIP, RGS4, and RGS10 correlated roughly with their intrinsic GAP activities for the Galpha target used in the assay [5].
  • GIPN (GAIP interacting protein N terminus) is a 38-kDa protein with an N-terminal leucine-rich region, a central RING finger-like domain, and a putative C-terminal transmembrane domain [6].
  • Phosphoamino acid analysis revealed that phosphorylation of GAIP occurred largely on serine residues [7].
  • Membrane-associated GAIP is a phosphoprotein and can be phosphorylated by clathrin-coated vesicles [7].

Chemical compound and disease context of RGS19

  • We have explored the selectivity of chick GAIP in electrophysiological assays of two G(o)-mediated forms of Ca(2+) channel inhibition produced by gamma-aminobutyric acid in chick dorsal root ganglion neurons, voltage-independent inhibition (mediated by G(o)alpha) and voltage-dependent inhibition (mediated by G(o)betagamma) [3].

Biological context of RGS19

  • GAIP/RGS19 alternative splicing patterns are differentially expressed in various tissues [8].
  • In both human and mouse, the GAIP/RGS19 gene is composed of seven exons [8].
  • Purified, recombinant RGSZ1, RET-RGS1, and GAIP each accelerated the hydrolysis of Galphaz-GTP over 400-fold with Km values of approximately 2 nM [9].
  • We report the genomic structure and functional activities of the promoter regions of the human opioid-receptor-like gene ORL1 and its 5'-adjacent gene GAIP (G alpha interacting protein) [10].
  • We demonstrate herein that either of two such RGS proteins, RGS4 or GAIP, attenuated signal transduction mediated by endogenous receptors, G proteins, and effectors when stably expressed as tagged proteins in transfected mammalian cells [11].

Anatomical context of RGS19

  • Dynamic translocation of GAIP to the plasma membrane and coassembly in a protein complex in which GIPC was a required component was dictated by D2R activation and physical interactions [12].
  • RGSZ1, RET-RGS1, and GAIP share a cysteine string sequence, perhaps targeting them to secretory vesicles and allowing them to participate in the proposed control of secretion by Gz [9].
  • Previously, we demonstrated that GAIP is localized on clathrin-coated vesicles (CCVs) [13].
  • The reconstitution of the interaction between a heterotrimeric G protein and GAIP on CCVs provides biochemical evidence for a model whereby the G protein and its GAP are compartmentalized on different membranes and come into contact at the time of vesicle fusion [13].
  • When Cos cells were transiently transfected with GAIP and metabolically labeled with [35S]methionine, two pools of GAIP--a soluble and a membrane-anchored pool--were found [14].

Associations of RGS19 with chemical compounds

  • Furthermore, the only Galphai2 variant that interacted strongly with GAIP contained a replacement of the corresponding Galphai2 Switch 3 residue (Ala230) with aspartate [15].
  • GAIP is a GAP or guanosine triphosphatase-activating protein that was initially discovered by virtue of its ability to bind to the heterotrimeric G protein Galphai3, which is found on both the plasma membrane (PM) and Golgi membranes [16].
  • By screening a rat brain cDNA library using the yeast two-hybrid system with the C-terminus domain of the dopamine D(3) receptor (D(3)R) as bait, we characterized a new interaction with the PDZ domain-containing protein, GIPC (GAIP interacting protein, C terminus) [17].
  • Accordingly, ATA challenge increased the rate of macroautophagy, whereas epidermal growth factor did not significantly affect macroautophagy and GAIP phosphorylation status [2].

Physical interactions of RGS19

  • Some of RGS4 residues involved in the Galpha-RGS binding interface have similar orientations in GAIP (free form), indicating that upon binding these residues do not suffer conformational rearrangements, and therefore, their role does not seem to be restricted to Galpha interaction but also to RGS folding and stability [18].
  • A chimeric G protein composed of a Galphai2 N terminus and a Galphai1 C terminus interacted as strongly with GAIP as native Galphai1, whereas a chimeric N-terminal Galphai1 with a Galphai2 C terminus did not interact [15].

Regulatory relationships of RGS19


Other interactions of RGS19

  • A core-promoter region functions bi-directionally for human opioid-receptor-like gene ORL1 and its 5'-adjacent gene GAIP [10].
  • GAIP, a protein that specifically interacts with the trimeric G protein G alpha i3, is a member of a protein family with a highly conserved core domain [21].
  • GAIP appears to interact exclusively with G alpha i3, as it did not interact with G alpha i2 and G alpha q [21].
  • Using the yeast two-hybrid system we have identified a human protein, GAIP (G Alpha Interacting Protein), that specifically interacts with the heterotrimeric GTP-binding protein G alpha i3 [21].
  • RGS4 was more effective than GAIP in blocking Gq-mediated activation of phospholipase Cbeta [11].

Analytical, diagnostic and therapeutic context of RGS19


  1. Control of the expression and activity of the Galpha-interacting protein (GAIP) in human intestinal cells. Ogier-Denis, E., Petiot, A., Bauvy, C., Codogno, P. J. Biol. Chem. (1997) [Pubmed]
  2. Amino acids interfere with the ERK1/2-dependent control of macroautophagy by controlling the activation of Raf-1 in human colon cancer HT-29 cells. Pattingre, S., Bauvy, C., Codogno, P. J. Biol. Chem. (2003) [Pubmed]
  3. Unique isoform of Galpha -interacting protein (RGS-GAIP) selectively discriminates between two Go-mediated pathways that inhibit Ca2+ channels. Tosetti, P., Turner, T., Lu, Q., Dunlap, K. J. Biol. Chem. (2002) [Pubmed]
  4. GAIP and RGS4 are GTPase-activating proteins for the Gi subfamily of G protein alpha subunits. Berman, D.M., Wilkie, T.M., Gilman, A.G. Cell (1996) [Pubmed]
  5. Inhibition of brain Gz GAP and other RGS proteins by palmitoylation of G protein alpha subunits. Tu, Y., Wang, J., Ross, E.M. Science (1997) [Pubmed]
  6. Promotion of G alpha i3 subunit down-regulation by GIPN, a putative E3 ubiquitin ligase that interacts with RGS-GAIP. Fischer, T., De Vries, L., Meerloo, T., Farquhar, M.G. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  7. Membrane-associated GAIP is a phosphoprotein and can be phosphorylated by clathrin-coated vesicles. Fischer, T., Elenko, E., Wan, L., Thomas, G., Farquhar, M.G. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  8. Gene structure, dual-promoters and mRNA alternative splicing of the human and mouse regulator of G protein signaling GAIP/RGS19. Xie, G.X., Han, X., Ito, E., Yanagisawa, Y., Maruyama, K., Sugano, S., Suzuki, Y., Wang, Y., Gabriel, A., Stevens, S.K., Mitchell, J., Sharma, M., Palmer, P.P. J. Mol. Biol. (2003) [Pubmed]
  9. RGSZ1, a Gz-selective RGS protein in brain. Structure, membrane association, regulation by Galphaz phosphorylation, and relationship to a Gz gtpase-activating protein subfamily. Wang, J., Ducret, A., Tu, Y., Kozasa, T., Aebersold, R., Ross, E.M. J. Biol. Chem. (1998) [Pubmed]
  10. A core-promoter region functions bi-directionally for human opioid-receptor-like gene ORL1 and its 5'-adjacent gene GAIP. Ito, E., Xie, G., Maruyama, K., Palmer, P.P. J. Mol. Biol. (2000) [Pubmed]
  11. Attenuation of Gi- and Gq-mediated signaling by expression of RGS4 or GAIP in mammalian cells. Huang, C., Hepler, J.R., Gilman, A.G., Mumby, S.M. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  12. GIPC recruits GAIP (RGS19) to attenuate dopamine D2 receptor signaling. Jeanneteau, F., Guillin, O., Diaz, J., Griffon, N., Sokoloff, P. Mol. Biol. Cell (2004) [Pubmed]
  13. Clathrin-coated vesicles bearing GAIP possess GTPase-activating protein activity in vitro. Fischer, T., Elenko, E., McCaffery, J.M., DeVries, L., Farquhar, M.G. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  14. GAIP is membrane-anchored by palmitoylation and interacts with the activated (GTP-bound) form of G alpha i subunits. De Vries, L., Elenko, E., Hubler, L., Jones, T.L., Farquhar, M.G. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  15. Structural basis for the selectivity of the RGS protein, GAIP, for Galphai family members. Identification of a single amino acid determinant for selective interaction of Galphai subunits with GAIP. Woulfe, D.S., Stadel, J.M. J. Biol. Chem. (1999) [Pubmed]
  16. RGS-GAIP, a GTPase-activating protein for Galphai heterotrimeric G proteins, is located on clathrin-coated vesicles. De Vries, L., Elenko, E., McCaffery, J.M., Fischer, T., Hubler, L., McQuistan, T., Watson, N., Farquhar, M.G. Mol. Biol. Cell (1998) [Pubmed]
  17. Interactions of GIPC with dopamine D2, D3 but not D4 receptors define a novel mode of regulation of G protein-coupled receptors. Jeanneteau, F., Diaz, J., Sokoloff, P., Griffon, N. Mol. Biol. Cell (2004) [Pubmed]
  18. Solution structure of human GAIP (Galpha interacting protein): a regulator of G protein signaling. de Alba, E., De Vries, L., Farquhar, M.G., Tjandra, N. J. Mol. Biol. (1999) [Pubmed]
  19. RGS4 and GAIP are GTPase-activating proteins for Gq alpha and block activation of phospholipase C beta by gamma-thio-GTP-Gq alpha. Hepler, J.R., Berman, D.M., Gilman, A.G., Kozasa, T. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  20. Erk1/2-dependent phosphorylation of Galpha-interacting protein stimulates its GTPase accelerating activity and autophagy in human colon cancer cells. Ogier-Denis, E., Pattingre, S., El Benna, J., Codogno, P. J. Biol. Chem. (2000) [Pubmed]
  21. GAIP, a protein that specifically interacts with the trimeric G protein G alpha i3, is a member of a protein family with a highly conserved core domain. De Vries, L., Mousli, M., Wurmser, A., Farquhar, M.G. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  22. Spatial regulation of Galphai protein signaling in clathrin-coated membrane microdomains containing GAIP. Elenko, E., Fischer, T., Niesman, I., Harding, T., McQuistan, T., Von Zastrow, M., Farquhar, M.G. Mol. Pharmacol. (2003) [Pubmed]
  23. Subcellular localization of the Galphai3 protein and G alpha interacting protein, two proteins involved in the control of macroautophagy in human colon cancer HT-29 cells. Petiot, A., Ogier-Denis, E., Bauvy, C., Cluzeaud, F., Vandewalle, A., Codogno, P. Biochem. J. (1999) [Pubmed]
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