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Gene Review

GPA2  -  guanine nucleotide-binding protein subunit...

Saccharomyces cerevisiae S288c

Synonyms: GP2-alpha, Guanine nucleotide-binding protein alpha-2 subunit, SSP101, YER020W
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Disease relevance of GPA2

  • These findings suggest that Gpr1 and Gpa2 are involved in the glucose-sensing machinery that regulates morphogenesis and hypha formation in solid media via a cAMP-dependent mechanism, but they are not required for hypha formation in liquid medium or during invasive candidiasis [1].

High impact information on GPA2

  • The G protein-coupled receptor Gpr1 and associated Galpha subunit Gpa2 govern dimorphic transitions in response to extracellular nutrients by signaling coordinately with Ras to activate adenylyl cyclase in the yeast Saccharomyces cerevisiae [2].
  • Our genetic and biochemical studies identify Gpa2 interaction partners (Gpb1/2, Gpg1) and provide evidence that these proteins function as G protein subunit mimics and signaling effectors [3].
  • A GPA2 null allele conferred a severe growth defect on cells containing a null allele of RAS2, although either mutation alone had little effect on growth rate [4].
  • Constitutive GPA2 conferred heat shock sensitivity on both wild-type cells and cells lacking RAS function, but had no effect in a strain containing a null allele of SCH9, which encodes a kinase related to protein kinase A. The GPR1 gene was isolated and was found to encode a protein with the characteristics of a G protein-coupled receptor [4].
  • A constitutive allele of GPA2 could stimulate growth of a strain lacking both RAS genes [4].

Biological context of GPA2

  • Here we report the isolation of another G-protein-homologous gene, GPA2, which encodes an amino acid sequence of 449 amino acid residues with a Mr of 50,516 [5].
  • Haploid cells carrying a disrupted GPA2 gene are viable [5].
  • Cells carrying a high copy number of plasmid GPA2 (YEpGPA2) had markedly elevated levels of cAMP and could suppress a temperature-sensitive mutation of RAS2 [5].
  • In support of this notion, addition of exogenous cAMP to the growth media was also sufficient to rescue the phenotype of a GPA2 deletion strain [6].
  • In addition, an increased ORD1 gene expression was observed in the Deltagpa2 mutant cells, meaning that GPA2 maintains a low basal level of ORD1 transcripts [7].

Anatomical context of GPA2

  • Using polyribosome fractionation and RT-PCR analysis, we identified STE12, GPA2, and CLN1 as translation regulation target genes during filamentous growth [8].
  • In this work, we show that glucose-induced activation of plasma membrane H(+)-ATPase from Saccharomyces cerevisiae is strongly dependent on calcium metabolism and that the glucose sensor Snf3p works in a parallel way with the G protein Gpa2p in the control of the pathway [9].

Associations of GPA2 with chemical compounds

  • Isolation of a second yeast Saccharomyces cerevisiae gene (GPA2) coding for guanine nucleotide-binding regulatory protein: studies on its structure and possible functions [5].
  • Because deletion of GPR1 or GPA2 reduces the glucose-induced cAMP increase the observed enhancement of Ras2 GTP loading is not sufficient for full stimulation of cAMP synthesis [10].
  • Yeast cells (Saccharomyces cerevisiae) contain a glucose/sucrose-sensitive seven-transmembrane domain receptor, Gpr1, that was proposed to activate adenylate cyclase through the G(alpha) protein Gpa2 [11].
  • When aligned with the alpha subunit of Gi (Gi alpha) to obtain maximal homology, GP2 alpha was found to contain a stretch of 83 additional amino acid residues near the NH2 terminus [5].
  • Deletion of Gpr1 and/or Gpa2 affected cAPK-controlled features (levels of trehalose, glycogen, heat resistance, expression of STRE-controlled genes and ribosomal protein genes) specifically during the transition to growth on glucose [12].
  • Residues Gln-419 and Asn-425 are located in the beta6-alpha5 loop and alpha5 helix of Gpa2p, which is the region that couples receptor binding to guanine nucleotide exchange [13].

Physical interactions of GPA2

  • Recent studies have established a physical and functional link between the Galpha protein Gpa2 and the G protein-coupled receptor homolog Gpr1 [14].
  • A two-hybrid screen using a constitutively active allele of GPA2 identified the KRH1 gene as encoding a potential binding partner of Gpa2p [15].
  • In contrast to conventional Galpha subunits, Gpa2 forms an atypical G protein complex with the kelch repeat Gbeta mimic proteins Gpb1 and Gpb2 [16].

Regulatory relationships of GPA2

  • These results suggest that the Cdc25 factor might also control Gpa2p [17].
  • The negative control of Ime2p kinase activity is exerted at least in part through the activated form of Gpa2p and is released as soon as nutrients are exhausted [18].
  • Gpb1/2 negatively regulate cAMP signaling by inhibiting Gpa2 and an as yet unidentified target [16].

Other interactions of GPA2

  • GPR1 encodes a putative G protein-coupled receptor that associates with the Gpa2p Galpha subunit and functions in a Ras-independent pathway [4].
  • The activity of adenylate cyclase in the yeast Saccharomyces cerevisiae is controlled by two G-protein systems, the Ras proteins and the Galpha protein Gpa2 [10].
  • Of the two yeast G-protein alpha-subunits (GPA1 and GPA2), only GPA1 has been well studied and shown to negatively regulate the mitogen-activated protein kinase pathway upon pheromone stimulation [6].
  • However, we find that although Krh1 associates with both GDP and GTP-bound Gpa2, it displays a preference for GTP-Gpa2 [11].
  • The hormone receptor-like protein Gpr1p physically interacts with phosphatidylinositol-specific phospholipase C (Plc1p) and with the Galpha protein Gpa2p, as shown by two-hybrid assays and co-immune precipitation of epitope-tagged proteins [19].


  1. Gpr1, a putative G-protein-coupled receptor, regulates morphogenesis and hypha formation in the pathogenic fungus Candida albicans. Miwa, T., Takagi, Y., Shinozaki, M., Yun, C.W., Schell, W.A., Perfect, J.R., Kumagai, H., Tamaki, H. Eukaryotic Cell (2004) [Pubmed]
  2. The kelch proteins Gpb1 and Gpb2 inhibit Ras activity via association with the yeast RasGAP neurofibromin homologs Ira1 and Ira2. Harashima, T., Anderson, S., Yates, J.R., Heitman, J. Mol. Cell (2006) [Pubmed]
  3. The Galpha protein Gpa2 controls yeast differentiation by interacting with kelch repeat proteins that mimic Gbeta subunits. Harashima, T., Heitman, J. Mol. Cell (2002) [Pubmed]
  4. GPR1 encodes a putative G protein-coupled receptor that associates with the Gpa2p Galpha subunit and functions in a Ras-independent pathway. Xue, Y., Batlle, M., Hirsch, J.P. EMBO J. (1998) [Pubmed]
  5. Isolation of a second yeast Saccharomyces cerevisiae gene (GPA2) coding for guanine nucleotide-binding regulatory protein: studies on its structure and possible functions. Nakafuku, M., Obara, T., Kaibuchi, K., Miyajima, I., Miyajima, A., Itoh, H., Nakamura, S., Arai, K., Matsumoto, K., Kaziro, Y. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  6. Gpa2p, a G-protein alpha-subunit, regulates growth and pseudohyphal development in Saccharomyces cerevisiae via a cAMP-dependent mechanism. Kübler, E., Mösch, H.U., Rupp, S., Lisanti, M.P. J. Biol. Chem. (1997) [Pubmed]
  7. At acidic pH, the GPA2-cAMP pathway is necessary to counteract the ORD1-mediated repression of the hypoxic SRP1/TIR1 yeast gene. Bourdineaud, J.P. Yeast (2001) [Pubmed]
  8. Identification of Translational Regulation Target Genes during Filamentous Growth in Saccharomyces cerevisiae: Regulatory Role of Caf20 and Dhh1. Park, Y.U., Hur, H., Ka, M., Kim, J. Eukaryotic Cell (2006) [Pubmed]
  9. Calcium signaling and sugar-induced activation of plasma membrane H(+)-ATPase in Saccharomyces cerevisiae cells. Trópia, M.J., Cardoso, A.S., Tisi, R., Fietto, L.G., Fietto, J.L., Martegani, E., Castro, I.M., Brandão, R.L. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  10. Activation state of the Ras2 protein and glucose-induced signaling in Saccharomyces cerevisiae. Colombo, S., Ronchetti, D., Thevelein, J.M., Winderickx, J., Martegani, E. J. Biol. Chem. (2004) [Pubmed]
  11. Kelch-repeat proteins interacting with the Galpha protein Gpa2 bypass adenylate cyclase for direct regulation of protein kinase A in yeast. Peeters, T., Louwet, W., Geladé, R., Nauwelaers, D., Thevelein, J.M., Versele, M. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  12. A Saccharomyces cerevisiae G-protein coupled receptor, Gpr1, is specifically required for glucose activation of the cAMP pathway during the transition to growth on glucose. Kraakman, L., Lemaire, K., Ma, P., Teunissen, A.W., Donaton, M.C., Van Dijck, P., Winderickx, J., de Winde, J.H., Thevelein, J.M. Mol. Microbiol. (1999) [Pubmed]
  13. Kelch repeat protein interacts with the yeast Galpha subunit Gpa2p at a site that couples receptor binding to guanine nucleotide exchange. Niranjan, T., Guo, X., Victor, J., Lu, A., Hirsch, J.P. J. Biol. Chem. (2007) [Pubmed]
  14. The G protein-coupled receptor gpr1 is a nutrient sensor that regulates pseudohyphal differentiation in Saccharomyces cerevisiae. Lorenz, M.C., Pan, X., Harashima, T., Cardenas, M.E., Xue, Y., Hirsch, J.P., Heitman, J. Genetics (2000) [Pubmed]
  15. Krh1p and Krh2p act downstream of the Gpa2p G(alpha) subunit to negatively regulate haploid invasive growth. Batlle, M., Lu, A., Green, D.A., Xue, Y., Hirsch, J.P. J. Cell. Sci. (2003) [Pubmed]
  16. Galpha subunit Gpa2 recruits kelch repeat subunits that inhibit receptor-G protein coupling during cAMP-induced dimorphic transitions in Saccharomyces cerevisiae. Harashima, T., Heitman, J. Mol. Biol. Cell (2005) [Pubmed]
  17. At acidic pH, the diminished hypoxic expression of the SRP1/TIR1 yeast gene depends on the GPA2-cAMP and HOG pathways. Bourdineaud, J.P. Res. Microbiol. (2000) [Pubmed]
  18. The yeast trimeric guanine nucleotide-binding protein alpha subunit, Gpa2p, controls the meiosis-specific kinase Ime2p activity in response to nutrients. Donzeau, M., Bandlow, W. Mol. Cell. Biol. (1999) [Pubmed]
  19. Phospholipase C binds to the receptor-like GPR1 protein and controls pseudohyphal differentiation in Saccharomyces cerevisiae. Ansari, K., Martin, S., Farkasovsky, M., Ehbrecht, I.M., Küntzel, H. J. Biol. Chem. (1999) [Pubmed]
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