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Gene Review

STE2  -  Ste2p

Saccharomyces cerevisiae S288c

Synonyms: Pheromone alpha factor receptor, YFL026W
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Disease relevance of STE2

  • In this study, we tested whether desensitization requires signaling in three different receptors, beta2-adrenergic receptor (beta2AR) in S49 lymphoma cells, alpha-factor pheromone receptor (Ste2p) in Saccharomyces cerevisiae LM102 cells, and dopamine D3 receptor (D3R) in HEK-293 cells [1].
  • Biological synthesis of regions of Ste2p fused to a leader protein in Escherichia coli yielded milligram quantities of polypeptides that corresponded to one or two transmembrane domains [2].

High impact information on STE2

  • Protein ubiquitination is required for stimulated endocytosis of Ste2p, as internalization is 5- to 15-fold slower in ubc mutants that lack multiple ubiquitin-conjugating enzymes [3].
  • Thus, ubiquitination of Ste2p itself is required for ligand-stimulated endocytosis [3].
  • Binding of alpha factor to Ste2p, a G protein-coupled plasma membrane receptor, activates a signal transduction pathway and stimulates endocytosis of the receptor-ligand complex [3].
  • In a C-terminal truncated form of Ste2p that is rapidly ubiquitinated and endocytosed in response to ligand binding, a single lysine to arginine substitution in its cytoplasmic tail eliminates both ubiquitination and internalization [3].
  • We describe a system to assess retrieval to the ER in yeast cells making use of a dilysine-tagged Ste2 protein [4].

Chemical compound and disease context of STE2


Biological context of STE2

  • These results are consistent with the idea that STE2 encodes an alpha-factor receptor and STE3 encodes an a-factor receptor, and suggest that both alpha- and a-factors may generate an exchangeable signal(s) within haploid cells [6].
  • On the other hand, expression of STE2 in an a/alpha diploid cell did not affect the alpha-factor insensitive phenotype [6].
  • Induction of STE2 expression using the GAL1 promoter both in a wild-type MATalpha strain and in a MATalpha ste3 strain caused transient cell-cycle arrest and changes in morphology ('shmoo'-like phenotype) in a manner similar to alpha cells responding to alpha-factor [6].
  • In further support of this idea, a chemically synthesized version of the STE2 MCM1 binding site had UAS activity, but the activity was neither stimulated by pheromone nor reduced in ste12 mutants [7].
  • The single and multiple mutants were characterized in terms of their effects on the repression of the glucose-repressible SUC2 gene and the a mating-type gene STE2 [8].

Anatomical context of STE2

  • Here, we report that the alpha-factor receptor, a GPCR that is the product of the STE2 gene in the yeast Saccharomyces cerevisiae, is oligomeric in intact cells and membranes [9].
  • Here we have used subcellular fractionation and fluorescence resonance energy transfer (FRET) experiments to show that oligomerization of a GPCR (alpha-factor receptor; STE2 gene product) of the yeast Saccharomyces cerevisiae occurs in the endoplasmic reticulum [10].
  • The temperature-sensitive alleles ysl2-307 and ysl2-316 are specifically defective in ligand-induced degradation of Ste2p and alpha-factor and exhibit vacuole fragmentation directly upon a shift to 37 degrees C. In living cells, green fluorescent protein (GFP)-Ysl2p colocalizes with endocytic elements that accumulate FM4-64 [11].
  • In contrast, akr1 delta cells cannot carry out ligand-mediated endocytosis of Ste2p [12].
  • Using a new double-labeling technique we have colocalized antibodies against Ste2p and carboxypeptidase Y to this compartment, thereby identifying these compartments as prevacuolar late endosomes [13].

Associations of STE2 with chemical compounds

  • Conditions were devised to demonstrate GTP-regulated coupling between the yeast STE2-encoded receptor and its cognate guanine nucleotide-binding protein (G protein) [14].
  • Inhibition of the growth arresting effect of STE4 by the delta C6 mutant is not due to competition at the effector site, but rather involves an intrinsic activity of STE2 that is dependent on SCG1 [15].
  • Under conditions of complete solubilization, the major form of the STE2 gene product detected was a glycoprotein with an apparent molecular weight of 49,000 [16].
  • To demonstrate that the membrane constituent responsible for alpha-factor binding was the STE2 polypeptide, specific antibodies were generated and used to identify STE2-related polypeptides by radiolabeling, immunoprecipitation, and polyacrylamide gel electrophoresis [16].
  • Dimethyl sulfate, DNase I and micrococcal nuclease DNA cleavage were combined with the ligation-mediated polymerase chain reaction to obtain high resolution maps of the promoter regions for two cell-type-specific genes: the a-specific STE2 gene and the alpha-specific STE3 gene [17].

Physical interactions of STE2

  • We find that MCM1 binds in vivo in a-cells to a 16 bp P-box sequence located in the STE2 UAS [17].
  • Golf complements a GPA1 null mutation in Saccharomyces cerevisiae and functionally couples to the STE2 pheromone receptor [18].

Enzymatic interactions of STE2

  • Temperature-sensitive rsp5 mutants were unable to ubiquitinate or to internalize Ste2p at the nonpermissive temperature [19].

Regulatory relationships of STE2

  • Mutations in STE12 known to block STE2 mRNA accumulation also resulted in an absence of receptors [20].
  • The mating defects of the ste2 deletion mutant and the temperature-sensitive ste4-3 mutant were also suppressed by overexpression of wild-type STE5 [21].
  • The AFR1 mutants were also defective when expressed as fusions to STE2, the alpha-factor receptor, indicating that the mutant Afr1 proteins are defective in function and not in co-localizing with receptors [22].
  • Third, MATa cells expressing a truncated but functional STE2 gene (in which the COOH-terminal 135-hydrophilic residues were deleted) produced a protein detected by cross-linking to 35S-alpha-factor of apparent molecular weight 33,000, close to the size expected for the predicted abbreviated STE2 polypeptide [16].
  • The original D2S gene and an elongated D2S gene with an N-terminal fusion to the first 24 amino acids of the STE2 gene from S. cerevisiae were introduced into the episomal yeast expression vector YEp51 under the control of the GAL10 promoter [23].

Other interactions of STE2

  • These results suggest that the GPA1 protein functions downstream of the STE2 receptor [24].
  • The results presented here are consistent with a model in which an a-specific gene product other than Ste2p detects the presence of the a-factor receptor and blocks signaling by inhibiting the function of Ste4p [25].
  • Defects at one step (requiring the STE2 gene are suppressed (directly or indirectly) by mutation sst2-1, whereas defects at the other step (requiring the STE5 gene) are suppressed by the ros1-1 mutation [20].
  • Likewise, the loss of STE12 function reduced lacZ expression driven by the wild-type STE2 fragment [7].
  • Other yeast genes with PREs, e.g., STE2 and BAR1, are more modestly inducible and have additional UAS elements contributing to the overall activity [26].

Analytical, diagnostic and therapeutic context of STE2

  • The sensitivity of the bioassay was increased by deletion of the STE2 gene, which encodes the yeast alpha-mating pheromone receptor [27].
  • Western-blot analysis of membranes prepared from transformed yeast cells producing either the receptor protein alone or the receptor fusion protein revealed apparent molecular masses of 40 kDa (D2S receptor alone) and 42 kDa (STE2/D2S receptor fusion protein) [23].
  • Northern blot analysis revealed that transcription of the a-specific gene STE2 and the haploid-specific locus RME1 in these transformants is repressed to the same level as in wild-type MATa/MAT alpha cells [28].
  • We studied the ligand-induced endocytosis of the yeast alpha-factor receptor Ste2p by immuno-electron microscopy [13].
  • Specifically, in akr1 delta mutants, newly synthesized receptor is accessible to exogenous protease, and by indirect immunofluorescence, the receptor is located at the cell surface. akr1 delta cells are also defective for endocytosis of the alpha-factor receptor (Ste2p) [12].


  1. Relationship between the G protein signaling and homologous desensitization of G protein-coupled receptors. Barak, L.S., Gilchrist, J., Becker, J.M., Kim, K.M. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  2. Biosynthesis and biophysical analysis of domains of a yeast G protein-coupled receptor. Arevalo, E., Estephan, R., Madeo, J., Arshava, B., Dumont, M., Becker, J.M., Naider, F. Biopolymers (2003) [Pubmed]
  3. Ubiquitination of a yeast plasma membrane receptor signals its ligand-stimulated endocytosis. Hicke, L., Riezman, H. Cell (1996) [Pubmed]
  4. Coatomer is essential for retrieval of dilysine-tagged proteins to the endoplasmic reticulum. Letourneur, F., Gaynor, E.C., Hennecke, S., Démollière, C., Duden, R., Emr, S.D., Riezman, H., Cosson, P. Cell (1994) [Pubmed]
  5. Heterologous gene expression in a membrane-protein-specific system. Turner, G.J., Reusch, R., Winter-Vann, A.M., Martinez, L., Betlach, M.C. Protein Expr. Purif. (1999) [Pubmed]
  6. Common signal transduction system shared by STE2 and STE3 in haploid cells of Saccharomyces cerevisiae: autocrine cell-cycle arrest results from forced expression of STE2. Nakayama, N., Miyajima, A., Arai, K. EMBO J. (1987) [Pubmed]
  7. Relative contributions of MCM1 and STE12 to transcriptional activation of a- and alpha-specific genes from Saccharomyces cerevisiae. Hwang-Shum, J.J., Hagen, D.C., Jarvis, E.E., Westby, C.A., Sprague, G.F. Mol. Gen. Genet. (1991) [Pubmed]
  8. The isolation and characterization of missense mutants in the general repressor protein Ssn6 of Saccharomyces cerevisiae. Limbach, M.P., Zitomer, R.S. Mol. Gen. Genet. (2000) [Pubmed]
  9. G-protein-coupled receptors function as oligomers in vivo. Overton, M.C., Blumer, K.J. Curr. Biol. (2000) [Pubmed]
  10. The extracellular N-terminal domain and transmembrane domains 1 and 2 mediate oligomerization of a yeast G protein-coupled receptor. Overton, M.C., Blumer, K.J. J. Biol. Chem. (2002) [Pubmed]
  11. Yeast Ysl2p, homologous to Sec7 domain guanine nucleotide exchange factors, functions in endocytosis and maintenance of vacuole integrity and interacts with the Arf-Like small GTPase Arl1p. Jochum, A., Jackson, D., Schwarz, H., Pipkorn, R., Singer-Krüger, B. Mol. Cell. Biol. (2002) [Pubmed]
  12. The ankyrin repeat-containing protein Akr1p is required for the endocytosis of yeast pheromone receptors. Givan, S.A., Sprague, G.F. Mol. Biol. Cell (1997) [Pubmed]
  13. Visualization of receptor-mediated endocytosis in yeast. Mulholland, J., Konopka, J., Singer-Kruger, B., Zerial, M., Botstein, D. Mol. Biol. Cell (1999) [Pubmed]
  14. 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]
  15. STE2/SCG1-dependent inhibition of STE4-induced growth arrest by mutant STE4 delta C6 in the yeast pheromone response pathway. Coria, R., Saviñon-Tejeda, A.L., Birnbaumer, L. FEBS Lett. (1995) [Pubmed]
  16. The STE2 gene product is the ligand-binding component of the alpha-factor receptor of Saccharomyces cerevisiae. Blumer, K.J., Reneke, J.E., Thorner, J. J. Biol. Chem. (1988) [Pubmed]
  17. Genomic footprinting of the promoter regions of STE2 and STE3 genes in the yeast Saccharomyces cerevisiae. Ganter, B., Tan, S., Richmond, T.J. J. Mol. Biol. (1993) [Pubmed]
  18. 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]
  19. Domains of the Rsp5 ubiquitin-protein ligase required for receptor-mediated and fluid-phase endocytosis. Dunn, R., Hicke, L. Mol. Biol. Cell (2001) [Pubmed]
  20. Saccharomyces cerevisiae mutants unresponsive to alpha-factor pheromone: alpha-factor binding and extragenic suppression. Jenness, D.D., Goldman, B.S., Hartwell, L.H. Mol. Cell. Biol. (1987) [Pubmed]
  21. Mutational activation of the STE5 gene product bypasses the requirement for G protein beta and gamma subunits in the yeast pheromone response pathway. Hasson, M.S., Blinder, D., Thorner, J., Jenness, D.D. Mol. Cell. Biol. (1994) [Pubmed]
  22. Point mutations identify a conserved region of the saccharomyces cerevisiae AFR1 gene that is essential for both the pheromone signaling and morphogenesis functions. DeMattei, C.R., Davis, C.P., Konopka, J.B. Genetics (2000) [Pubmed]
  23. Heterologous expression of the human D2S dopamine receptor in protease-deficient Saccharomyces cerevisiae strains. Sander, P., Grünewald, S., Bach, M., Haase, W., Reiländer, H., Michel, H. Eur. J. Biochem. (1994) [Pubmed]
  24. 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]
  25. Receptor inhibition of pheromone signaling is mediated by the Ste4p Gbeta subunit. Kim, J., Couve, A., Hirsch, J.P. Mol. Cell. Biol. (1999) [Pubmed]
  26. Pheromone response elements are necessary and sufficient for basal and pheromone-induced transcription of the FUS1 gene of Saccharomyces cerevisiae. Hagen, D.C., McCaffrey, G., Sprague, G.F. Mol. Cell. Biol. (1991) [Pubmed]
  27. Pharmacological characterization of the rat A2a adenosine receptor functionally coupled to the yeast pheromone response pathway. Price, L.A., Strnad, J., Pausch, M.H., Hadcock, J.R. Mol. Pharmacol. (1996) [Pubmed]
  28. The role of cysteine residues in the homeodomain protein Mat alpha 2 in mating-type control of Saccharomyces cerevisiae. Mukai, Y., Ohno-Yamashita, Y., Oshima, Y., Harashima, S. Mol. Gen. Genet. (1997) [Pubmed]
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