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Gene Review

STE6  -  ATP-binding cassette alpha-factor...

Saccharomyces cerevisiae S288c

Synonyms: Alpha-factor-transporting ATPase, Mating factor A secretion protein STE6, Multiple drug resistance protein homolog, P-glycoprotein, YKL209C
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Disease relevance of STE6


High impact information on STE6

  • Identification of revertants for the cystic fibrosis delta F508 mutation using STE6-CFTR chimeras in yeast [4].
  • Homologues of ste6 and CDC25 could regulate ras activity in other eukaryotic cells [5].
  • Epistatic interactions indicate that the ste6 gene functions upstream of ras1 [5].
  • Subsequent analysis revealed that the yeast P-glycoprotein is the product of the STE6 gene, a locus previously shown to be required in MATa cells for production of a-factor pheromone [6].
  • Mammalian tumours displaying multidrug resistance overexpress a plasma membrane protein (P-glycoprotein), which is encoded by the MDR1 gene and apparently functions as an energy-dependent drug efflux pump [6].

Chemical compound and disease context of STE6


Biological context of STE6

  • We also examined the phenotype of a mutant carrying an insertion mutation of the STE6 gene, the ste6::lacZ allele [8].
  • Negative regulation of STE6 gene expression by the alpha 2 product of Saccharomyces cerevisiae [8].
  • This observation suggests that the methyl group is likely to be a critical recognition determinant for the a-factor transporter, STE6, thus providing insight into the substrate specificity of STE6 and also supporting the hypothesis that carboxyl methylation can have a dramatic impact on protein-protein interactions [9].
  • Metabolic instability and constitutive endocytosis of STE6, the a-factor transporter of Saccharomyces cerevisiae [10].
  • A high degree of structural conservation between the STE6 and the HST6 loci with respect to DNA sequence, physical linkage and transcriptional arrangement indicates that HST6 is the C. albicans orthologue of the S. cerevisiae STE6 gene [11].

Anatomical context of STE6

  • The punctate pattern is consistent with the view that most of the STE6 molecules present in a cell at any given moment could be en route either to or from the plasma membrane [10].
  • We report here that STE6 is metabolically unstable in a wild-type strain, and that this instability is blocked in a pep4 mutant, suggesting that degradation of STE6 occurs in the vacuole and is dependent upon vacuolar proteases [10].
  • Saccharomyces cerevisiae STE6 gene product: a novel pathway for protein export in eukaryotic cells [12].
  • One model consistent with our results is that the degradation of Ste6p, the bulk of which is exposed to the cytosol, requires the activity of both the cytosolic proteasomal degradative machinery and the vacuolar lumenal proteases, acting in a synergistic fashion [13].
  • In contrast to wild-type Ste6, which was associated mainly with internal membranes, the ubiquitination-deficient mutants accumulated at the plasma membrane, as demonstrated by immunofluorescence and cell fractionation experiments [14].

Associations of STE6 with chemical compounds


Physical interactions of STE6

  • Overexpression of the soluble Ubp1 variant stabilizes the ATP-binding cassette-transporter Ste6, which is transported to the lysosome-like vacuole for degradation, and whose transport is regulated by ubiquitination [19].
  • The cis-acting GAL4 protein-binding site contained in the hairpin-TFO is targeted in vivo to the 5' upstream sequence of STE6 and CBT1 genes that are transcribed in opposite directions and share a poly(pu/py) sequence that can form triple helical structure [20].
  • Interestingly, yeast Pdr5p interacted with flavonoids recently found to bind to cancer cell P-glycoprotein and to the protozoan parasite multidrug transporter [21].
  • Ste6 is a very unstable protein (half-life 13 min) which is stabilized approximately 3-fold in a ubc4 ubc5 mutant, implicating the ubiquitin system in the degradation of Ste6 [22].
  • Thus, it appears that these mutations interfere with the ability of Ste6p to transport a-factor out of the MATa cell [23].

Regulatory relationships of STE6

  • We show that TRT2 acts as a barrier to repression, protecting the upstream CBT1 gene from the influence of the STE6 alpha2 operator in MATalpha cells [24].
  • The yeast a-factor mating peptide and its transporter Ste6 are normally expressed only in MATa haploid cells [25].
  • Similarly, glycerol enhanced protein levels of P-gp expressed under control of the GAL1 promoter [26].
  • Uptake of the ATP-binding cassette (ABC) transporter Ste6 into the yeast vacuole is blocked in the doa4 Mutant [27].

Other interactions of STE6

  • RPD3 is required for both full repression and full activation of transcription of target genes including PHO5, STE6, and TY2 [28].
  • Examination of STE6 localization by indirect immunofluorescence indicates that STE6 is found in a punctate, possibly vesicular, intracellular pattern, distinct from the rim-staining pattern characteristic of PMA1 [10].
  • In order to understand how SIN3 functions in STE6 regulation, we have performed a genetic analysis [29].
  • Mutations in AXL1, STE6 and FUS3 were identified in the screen [30].
  • Expression of MFA1 and STE6 is sufficient for mating type-independent secretion of yeast a-factor, but not mating competence [25].

Analytical, diagnostic and therapeutic context of STE6


  1. Mutational analysis of the yeast a-factor transporter STE6, a member of the ATP binding cassette (ABC) protein superfamily. Berkower, C., Michaelis, S. EMBO J. (1991) [Pubmed]
  2. The organized chromatin domain of the repressed yeast a cell-specific gene STE6 contains two molecules of the corepressor Tup1p per nucleosome. Ducker, C.E., Simpson, R.T. EMBO J. (2000) [Pubmed]
  3. RNF2 interacts with the linker region of the human P-glycoprotein. Rao, P.S., Mallya, K.B., Srivenugopal, K.S., Balaji, K.C., Rao, U.S. Int. J. Oncol. (2006) [Pubmed]
  4. Identification of revertants for the cystic fibrosis delta F508 mutation using STE6-CFTR chimeras in yeast. Teem, J.L., Berger, H.A., Ostedgaard, L.S., Rich, D.P., Tsui, L.C., Welsh, M.J. Cell (1993) [Pubmed]
  5. Homologous activators of ras in fission and budding yeast. Hughes, D.A., Fukui, Y., Yamamoto, M. Nature (1990) [Pubmed]
  6. The yeast STE6 gene encodes a homologue of the mammalian multidrug resistance P-glycoprotein. McGrath, J.P., Varshavsky, A. Nature (1989) [Pubmed]
  7. Differential sensitivity of plant and yeast MRP (ABCC)-mediated organic anion transport processes towards sulfonylureas. Forestier, C., Frangne, N., Eggmann, T., Klein, M. FEBS Lett. (2003) [Pubmed]
  8. Negative regulation of STE6 gene expression by the alpha 2 product of Saccharomyces cerevisiae. Wilson, K.L., Herskowitz, I. Mol. Cell. Biol. (1984) [Pubmed]
  9. Nucleotide sequence of the yeast STE14 gene, which encodes farnesylcysteine carboxyl methyltransferase, and demonstration of its essential role in a-factor export. Sapperstein, S., Berkower, C., Michaelis, S. Mol. Cell. Biol. (1994) [Pubmed]
  10. Metabolic instability and constitutive endocytosis of STE6, the a-factor transporter of Saccharomyces cerevisiae. Berkower, C., Loayza, D., Michaelis, S. Mol. Biol. Cell (1994) [Pubmed]
  11. A Ste6p/P-glycoprotein homologue from the asexual yeast Candida albicans transports the a-factor mating pheromone in Saccharomyces cerevisiae. Raymond, M., Dignard, D., Alarco, A.M., Mainville, N., Magee, B.B., Thomas, D.Y. Mol. Microbiol. (1998) [Pubmed]
  12. Saccharomyces cerevisiae STE6 gene product: a novel pathway for protein export in eukaryotic cells. Kuchler, K., Sterne, R.E., Thorner, J. EMBO J. (1989) [Pubmed]
  13. Role for the ubiquitin-proteasome system in the vacuolar degradation of Ste6p, the a-factor transporter in Saccharomyces cerevisiae. Loayza, D., Michaelis, S. Mol. Cell. Biol. (1998) [Pubmed]
  14. The linker region of the ABC-transporter Ste6 mediates ubiquitination and fast turnover of the protein. Kölling, R., Losko, S. EMBO J. (1997) [Pubmed]
  15. Functional interactions between synthetic alkyl phospholipids and the ABC transporters P-glycoprotein, Ste-6, MRP, and Pgh 1. Ruetz, S., Brault, M., Dalton, W., Gros, P. Biochemistry (1997) [Pubmed]
  16. Farnesyl cysteine C-terminal methyltransferase activity is dependent upon the STE14 gene product in Saccharomyces cerevisiae. Hrycyna, C.A., Clarke, S. Mol. Cell. Biol. (1990) [Pubmed]
  17. The a-factor transporter (STE6 gene product) and cell polarity in the yeast Saccharomyces cerevisiae. Kuchler, K., Dohlman, H.G., Thorner, J. J. Cell Biol. (1993) [Pubmed]
  18. Distinct machinery is required in Saccharomyces cerevisiae for the endoplasmic reticulum-associated degradation of a multispanning membrane protein and a soluble luminal protein. Huyer, G., Piluek, W.F., Fansler, Z., Kreft, S.G., Hochstrasser, M., Brodsky, J.L., Michaelis, S. J. Biol. Chem. (2004) [Pubmed]
  19. The deubiquitinating enzyme Ubp1 affects sorting of the ATP-binding cassette-transporter Ste6 in the endocytic pathway. Schmitz, C., Kinner, A., Kölling, R. Mol. Biol. Cell (2005) [Pubmed]
  20. Targeted activation of transcription in vivo through hairpin-triplex forming oligonucleotide in Saccharomyces cerevisiae. Ghosh, M.K., Katyal, A., Chandra, R., Brahmachari, V. Mol. Cell. Biochem. (2005) [Pubmed]
  21. Prenyl-flavonoids as potent inhibitors of the Pdr5p multidrug ABC transporter from Saccharomyces cerevisiae. Conseil, G., Decottignies, A., Jault, J.M., Comte, G., Barron, D., Goffeau, A., Di Pietro, A. Biochemistry (2000) [Pubmed]
  22. The ABC-transporter Ste6 accumulates in the plasma membrane in a ubiquitinated form in endocytosis mutants. Kölling, R., Hollenberg, C.P. EMBO J. (1994) [Pubmed]
  23. Mutations within the first LSGGQ motif of Ste6p cause defects in a-factor transport and mating in Saccharomyces cerevisiae. Browne, B.L., McClendon, V., Bedwell, D.M. J. Bacteriol. (1996) [Pubmed]
  24. The Saccharomyces cerevisiae TRT2 tRNAThr gene upstream of STE6 is a barrier to repression in MATalpha cells and exerts a potential tRNA position effect in MATa cells. Simms, T.A., Miller, E.C., Buisson, N.P., Jambunathan, N., Donze, D. Nucleic Acids Res. (2004) [Pubmed]
  25. Expression of MFA1 and STE6 is sufficient for mating type-independent secretion of yeast a-factor, but not mating competence. Quinby, G.E., Dean, J.P., Deschenes, R.J. Curr. Genet. (1999) [Pubmed]
  26. Use of chemical chaperones in the yeast Saccharomyces cerevisiae to enhance heterologous membrane protein expression: high-yield expression and purification of human P-glycoprotein. Figler, R.A., Omote, H., Nakamoto, R.K., Al-Shawi, M.K. Arch. Biochem. Biophys. (2000) [Pubmed]
  27. Uptake of the ATP-binding cassette (ABC) transporter Ste6 into the yeast vacuole is blocked in the doa4 Mutant. Losko, S., Kopp, F., Kranz, A., Kölling, R. Mol. Biol. Cell (2001) [Pubmed]
  28. RPD3 encodes a second factor required to achieve maximum positive and negative transcriptional states in Saccharomyces cerevisiae. Vidal, M., Gaber, R.F. Mol. Cell. Biol. (1991) [Pubmed]
  29. Genetic interactions between SIN3 mutations and the Saccharomyces cerevisiae transcriptional activators encoded by MCM1, STE12, and SWI1. Wang, H., Reynolds-Hager, L., Stillman, D.J. Mol. Gen. Genet. (1994) [Pubmed]
  30. Combining mutations in the incoming and outgoing pheromone signal pathways causes a synergistic mating defect in Saccharomyces cerevisiae. Giot, L., DeMattei, C., Konopka, J.B. Yeast (1999) [Pubmed]
  31. Functional and physical interactions between partial molecules of STE6, a yeast ATP-binding cassette protein. Berkower, C., Taglicht, D., Michaelis, S. J. Biol. Chem. (1996) [Pubmed]
  32. Arabidopsis thaliana cDNA isolated by functional complementation shows homology to serine/threonine protein kinases. Covic, L., Lew, R.R. Biochim. Biophys. Acta (1996) [Pubmed]
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