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Gene Review

GPA1  -  guanine nucleotide-binding protein subunit...

Saccharomyces cerevisiae S288c

Synonyms: CDC70, DAC1, GP1-alpha, Guanine nucleotide-binding protein alpha-1 subunit, SCG1, ...
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Disease relevance of GPA1


High impact information on GPA1

  • We demonstrate that Gpa1 is present at endosomes, where it interacts directly with both Vps34 and Vps15 and stimulates increased production of phosphatidylinositol 3-phosphate [5].
  • To identify candidate Gpa1 effectors, we expressed the constitutively active Gpa1(Q323L) mutant in each of nearly 5000 gene-deletion strains and measured mating-specific responses [5].
  • Positional cloning and functional assays showed that polymorphisms in GPA1 and AMN1 affect expression of genes involved in pheromone response and daughter cell separation, respectively [6].
  • The GPA1 gene of S. cerevisiae encodes a G alpha subunit that plays a positive role in the transduction of signals stimulating recovery from pheromone-induced cell cycle arrest [7].
  • The suppression of a gpa1 null (G alpha subunit) by a fus3 null also suggests FUS3 is in the signal transduction pathway [8].

Biological context of GPA1

  • GPA1 hyperexpression suppressed the phenotype of STE4 overexpression [9].
  • These results suggest that the dac1 mutation is an allele of the GPA1 gene and thus provide genetic evidence that the yeast G protein homolog is directly involved in the mating pheromone signal transduction pathway [10].
  • The Saccharomyces cerevisiae GPA1 gene encodes a protein highly homologous to the alpha subunit of mammalian G proteins and is essential for haploid cell growth [1].
  • These observations suggest that GPA1 (SGP1) and SGP2 are involved in mating factor-mediated signal transduction, which causes both cell cycle arrest in the late G1 phase and induction of genes necessary for mating such as FUS1 [1].
  • On GTP hydrolysis, G(alpha) (GDP) then reassociates with G(betagamma) [Gilman, A. G. (1987) Annu. Rev. Biochem. 56, 615-649] [11].

Anatomical context of GPA1

  • Electrophysiological measurements indicated that the membrane conductance of oocytes injected with STE2 mRNA, or with both STE2 and GPA1 (encoding a yeast G protein alpha-subunit) mRNAs, did not change and was not affected by pheromone binding [12].
  • Unlike the mammalian G alpha i proteins alpha i and alpha o, nonmyristoylated Gpa1 is able to associate with membranes [13].
  • In contrast, wild-type Gpa1p reaches the plasma membrane in cells that do not express Gbetagamma or cell surface receptors [14].
  • In this case, Gpa1 accumulates in both the cytoplasm and vacuole [15].

Associations of GPA1 with chemical compounds

  • Introduction of the GPA1 gene encoding an S. cerevisiae homolog of the alpha subunit of mammalian guanine nucleotide-binding regulatory proteins (G proteins) into sterile dac1 mutants resulted in restoration of pheromone responsiveness and mating competence to both a and alpha cells [10].
  • A mutation of the GPA1 protein, GPA1Val-50, in which Gly-50 was replaced by valine, could complement the growth defect of a GPA1 disruption, gpal::HIS3 [16].
  • Upon regulation of expression of GPA1 by the galactose-inducible GAL1 promoter, the loss of GPA1 function was found to lead to cell-cycle arrest at the late G1 phase [17].
  • We have isolated seven mutant alleles of GPA1 that confer pheromone resistance: G50D (a glycine-to-aspartate change at position 50), G322E, G322R, E355K, E364K, G470D, and an E364K-G470D double mutant [18].
  • A number of genes have been implicated in the regulation of laccase and melanization, including IPC1, GPA1, MET3, and STE12 [19].

Physical interactions of GPA1

  • Growth arrest in G1 phase is activated by the Ste4p/Ste18p complex via a downstream pathway and it is negatively controlled by the Scg1p subunit [20].
  • Golf complements a GPA1 null mutation in Saccharomyces cerevisiae and functionally couples to the STE2 pheromone receptor [21].
  • We also show that signaling by activated Gpa1 requires direct coupling to an RNA binding protein Scp160 [22].
  • Mutation of the Q323 residue of Gpa1p resulted in constitutive activation of the pheromone response pathway and eliminated the ability to interact with Ste4p, consistent with a defect in GTPase activity [23].

Regulatory relationships of GPA1

  • CLN2 overexpression suppressed the constitutive signaling and division-arrest phenotypes of cells with a disrupted gpa1 gene, indicating that the site of action for repression is downstream of the alpha-subunit (Gpa1p) of the heterotrimeric G protein [24].
  • In addition, overexpression of these mutant versions of STE18 causes a dominant negative phenotype and inhibits the constitutive mating response generated by GPA1 deletion in cells which contain a functional STE18 gene [25].
  • The dac2 mutation could suppress the lethality caused by the disruption of the GPA1 gene (previously shown to encode a protein with similarity to the alpha subunit of mammalian G proteins) [26].
  • The Saccharomyces cerevisiae RGS protein Sst2p is involved in desensitization to pheromone and acts as a GTPase-activating protein for the Galpha subunit Gpa1p [27].
  • The stability of Galpha/Gpa1 is influenced by the ubiquitin-dependent N-end rule pathway, suggesting that the regulation of G alpha levels may be important for effective mating response and recovery [28].

Other interactions of GPA1

  • Wild-type STE4 and STE18 gene products were not essential for membrane localization of the GPA1 gene product, as indicated by cell fractionation and immunological analyses, suggesting that G beta and G gamma subunits interact with the receptor or make the G alpha subunit competent to associate correctly with the receptor, or both [29].
  • These results suggest that the GPA1 protein functions downstream of the STE2 receptor [30].
  • Furthermore, the steady-state level of the FUS1 transcript, which normally increases in response to mating factors, was also elevated when the GPA1 function was impaired [30].
  • Cells from which AKR1 had been deleted were alive but misshapen at 30 degrees C and inviable at 37 degrees C. During a screen for mutants that required one or more copies of wild-type AKR1 for survival at 30 degrees C, we isolated mutations in GPA1, which encodes the G alpha subunit of the pheromone receptor-coupled G protein [31].
  • 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 [32].

Analytical, diagnostic and therapeutic context of GPA1

  • After treatment of MATa cells with alpha factor, the myristoylated form of Gpa1p increases dramatically, and the unmyristoylated form decreases concomitantly [33].
  • We have isolated a gene, GPA1, from Cryptococcus neoformans by the PCR technique [34].
  • Our results provide genetic validation of DAC1 and DAC3 as potential chemotherapy targets and demonstrate that T. brucei expresses at least three probable histone deacetylases with distinct function [35].
  • In gene targeting experiments, DAC1 and DAC3 appear to be essential whereas DAC2 and DAC4 are not required for viability [35].
  • Sequence analysis of a 4-kb genomic clone containing NAG1 indicates that this gene is part of a cluster containing two other genes of the GlcNAc catabolic pathway, i.e., DAC1, GlcNAc-6-phosphate deacetylase, and HXK1, hexokinase [36].


  1. Suppressors of a gpa1 mutation cause sterility in Saccharomyces cerevisiae. Miyajima, I., Nakayama, N., Nakafuku, M., Kaziro, Y., Arai, K., Matsumoto, K. Genetics (1988) [Pubmed]
  2. Identification of a second-site suppressor mutation of the GTPase defect associated with McCune - Albright syndrome: A model using the yeast heterotrimeric G protein, GPA1. Ooms, L.S., Koster, M.J., Mitchell, J.R., Pals-Rylaarsdam, R. Arch. Physiol. Biochem. (2006) [Pubmed]
  3. Degradation of G alpha by the N-end rule pathway. Madura, K., Varshavsky, A. Science (1994) [Pubmed]
  4. Cryptococcus neoformans mating and virulence are regulated by the G-protein alpha subunit GPA1 and cAMP. Alspaugh, J.A., Perfect, J.R., Heitman, J. Genes Dev. (1997) [Pubmed]
  5. Activation of the phosphatidylinositol 3-kinase Vps34 by a G protein alpha subunit at the endosome. Slessareva, J.E., Routt, S.M., Temple, B., Bankaitis, V.A., Dohlman, H.G. Cell (2006) [Pubmed]
  6. Trans-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors. Yvert, G., Brem, R.B., Whittle, J., Akey, J.M., Foss, E., Smith, E.N., Mackelprang, R., Kruglyak, L. Nat. Genet. (2003) [Pubmed]
  7. SGV1 encodes a CDC28/cdc2-related kinase required for a G alpha subunit-mediated adaptive response to pheromone in S. cerevisiae. Irie, K., Nomoto, S., Miyajima, I., Matsumoto, K. Cell (1991) [Pubmed]
  8. FUS3 encodes a cdc2+/CDC28-related kinase required for the transition from mitosis into conjugation. Elion, E.A., Grisafi, P.L., Fink, G.R. Cell (1990) [Pubmed]
  9. Stoichiometry of G protein subunits affects the Saccharomyces cerevisiae mating pheromone signal transduction pathway. Cole, G.M., Stone, D.E., Reed, S.I. Mol. Cell. Biol. (1990) [Pubmed]
  10. The yeast G-protein homolog is involved in the mating pheromone signal transduction system. Fujimura, H.A. Mol. Cell. Biol. (1989) [Pubmed]
  11. Signal transduction by a nondissociable heterotrimeric yeast G protein. Klein, S., Reuveni, H., Levitzki, A. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  12. Functional expression of the yeast alpha-factor receptor in Xenopus oocytes. Yu, L., Blumer, K.J., Davidson, N., Lester, H.A., Thorner, J. J. Biol. Chem. (1989) [Pubmed]
  13. N-myristoylation is required for function of the pheromone-responsive G alpha protein of yeast: conditional activation of the pheromone response by a temperature-sensitive N-myristoyl transferase. Stone, D.E., Cole, G.M., de Barros Lopes, M., Goebl, M., Reed, S.I. Genes Dev. (1991) [Pubmed]
  14. Regulation of membrane and subunit interactions by N-myristoylation of a G protein alpha subunit in yeast. Song, J., Hirschman, J., Gunn, K., Dohlman, H.G. J. Biol. Chem. (1996) [Pubmed]
  15. Differential regulation of G protein alpha subunit trafficking by mono- and polyubiquitination. Wang, Y., Marotti, L.A., Lee, M.J., Dohlman, H.G. J. Biol. Chem. (2005) [Pubmed]
  16. GPA1Val-50 mutation in the mating-factor signaling pathway in Saccharomyces cerevisiae. Miyajima, I., Arai, K., Matsumoto, K. Mol. Cell. Biol. (1989) [Pubmed]
  17. GPA1, a haploid-specific essential gene, encodes a yeast homolog of mammalian G protein which may be involved in mating factor signal transduction. Miyajima, I., Nakafuku, M., Nakayama, N., Brenner, C., Miyajima, A., Kaibuchi, K., Arai, K., Kaziro, Y., Matsumoto, K. Cell (1987) [Pubmed]
  18. G protein mutations that alter the pheromone response in Saccharomyces cerevisiae. Stone, D.E., Reed, S.I. Mol. Cell. Biol. (1990) [Pubmed]
  19. CNLAC1 is required for extrapulmonary dissemination of Cryptococcus neoformans but not pulmonary persistence. Noverr, M.C., Williamson, P.R., Fajardo, R.S., Huffnagle, G.B. Infect. Immun. (2004) [Pubmed]
  20. Separate roles for N- and C-termini of the STE4 (beta) subunit of the Saccharomyces cerevisiae G protein in the mediation of the growth arrest. Lack of growth-arresting activity of mammalian beta gamma complexes. Coria, R., Ongay-Larios, L., Birnbaumer, L. Yeast (1996) [Pubmed]
  21. Golf complements a GPA1 null mutation in Saccharomyces cerevisiae and functionally couples to the STE2 pheromone receptor. Crowe, M.L., Perry, B.N., Connerton, I.F. J. Recept. Signal Transduct. Res. (2000) [Pubmed]
  22. The yeast G protein alpha subunit Gpa1 transmits a signal through an RNA binding effector protein Scp160. Guo, M., Aston, C., Burchett, S.A., Dyke, C., Fields, S., Rajarao, S.J., Uetz, P., Wang, Y., Young, K., Dohlman, H.G. Mol. Cell (2003) [Pubmed]
  23. Switch-domain mutations in the Saccharomyces cerevisiae G protein alpha-subunit Gpa1p identify a receptor subtype-biased mating defect. DeSimone, S.M., Kurjan, J. Mol. Gen. Genet. (1998) [Pubmed]
  24. G1 cyclins CLN1 and CLN2 repress the mating factor response pathway at Start in the yeast cell cycle. Oehlen, L.J., Cross, F.R. Genes Dev. (1994) [Pubmed]
  25. Site-directed mutations altering the CAAX box of Ste18, the yeast pheromone-response pathway G gamma subunit. Whiteway, M.S., Thomas, D.Y. Genetics (1994) [Pubmed]
  26. Identification and characterization of a mutation affecting the division arrest signaling of the pheromone response pathway in Saccharomyces cerevisiae. Fujimura, H. Genetics (1990) [Pubmed]
  27. The N terminus of Saccharomyces cerevisiae Sst2p plays an RGS-domain-independent, Mpt5p-dependent role in recovery from pheromone arrest. Xu, B.E., Skowronek, K.R., Kurjan, J. Genetics (2001) [Pubmed]
  28. Sequence elements that contribute to the degradation of yeast G alpha. Schauber, C., Chen, L., Tongaonkar, P., Vega, I., Madura, K. Genes Cells (1998) [Pubmed]
  29. Beta and gamma subunits of a yeast guanine nucleotide-binding protein are not essential for membrane association of the alpha subunit but are required for receptor coupling. Blumer, K.J., Thorner, J. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  30. Role of STE genes in the mating factor signaling pathway mediated by GPA1 in Saccharomyces cerevisiae. Nakayama, N., Kaziro, Y., Arai, K., Matsumoto, K. Mol. Cell. Biol. (1988) [Pubmed]
  31. Interactions between the ankyrin repeat-containing protein Akr1p and the pheromone response pathway in Saccharomyces cerevisiae. Kao, L.R., Peterson, J., Ji, R., Bender, L., Bender, A. Mol. Cell. Biol. (1996) [Pubmed]
  32. 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]
  33. Pheromone action regulates G-protein alpha-subunit myristoylation in the yeast Saccharomyces cerevisiae. Dohlman, H.G., Goldsmith, P., Spiegel, A.M., Thorner, J. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  34. Cloning of a Cryptococcus neoformans gene, GPA1, encoding a G-protein alpha-subunit homolog. Tolkacheva, T., McNamara, P., Piekarz, E., Courchesne, W. Infect. Immun. (1994) [Pubmed]
  35. Histone deacetylases in Trypanosoma brucei: two are essential and another is required for normal cell cycle progression. Ingram, A.K., Horn, D. Mol. Microbiol. (2002) [Pubmed]
  36. The inducible N-acetylglucosamine catabolic pathway gene cluster in Candida albicans: discrete N-acetylglucosamine-inducible factors interact at the promoter of NAG1. Kumar, M.J., Jamaluddin, M.S., Natarajan, K., Kaur, D., Datta, A. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
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