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Gene Review

VPS34  -  phosphatidylinositol 3-kinase VPS34

Saccharomyces cerevisiae S288c

Synonyms: Carboxypeptidase Y-deficient protein 15, END12, L9672.10, PEP15, PI3-kinase VPS34, ...
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High impact information on VPS34


Biological context of VPS34

  • Vac1p FYVE finger mutant missorting phenotypes were suppressed by a defective allele of VPS34 [6].
  • This rapid block in vacuolar protein sorting appears to be the result of loss of PtdIns 3-kinase activity since cellular PtdIns(3)P levels decrease dramatically in vps34 temperature-sensitive mutant cells that have been incubated at the nonpermissive temperature [7].
  • Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae [8].
  • Dominant missense mutations in a novel yeast protein related to mammalian phosphatidylinositol 3-kinase and VPS34 abrogate rapamycin cytotoxicity [9].
  • The nucleotide sequence of STT4 predicts a hydrophilic protein composed of 1,900 amino acid residues, with 26% sequence identity to the yeast VPS34 gene product and 27% to the catalytic subunit of mammalian phosphatidylinositol (PI) 3-kinase, respectively [10].

Anatomical context of VPS34


Associations of VPS34 with chemical compounds

  • A direct role for phosphoinositides in vesicular trafficking has been demonstrated by the identification of the yeast VPS34 gene encoding the phosphatidylinositol 3-kinase responsible for the synthesis of phosphatidylinositol 3-phosphate (PtdIns3P) [14].
  • Subcellular fractionation and sucrose density gradients indicate that Vps15p is responsible for the association of Vps34p with an intracellular membrane fraction [15].
  • Characterization of the PI 3-kinase activity of Vps34p demonstrates that it, unlike the mammalian p110 PI 3-kinase, is highly resistant to the PI 3-kinase inhibitors wortmannin and LY294002 [12].
  • Using an in vivo assay in yeast that detects Vps34 PI(3)K-dependent intracellular localization of a GFP reporter protein, and in vitro lipid-binding assays, we demonstrate that cysteine-rich RING domains of the FYVE finger subfamily bind specifically to Ptdlns phosphorylated exclusively at the D-3 position of the inositol ring [16].
  • Cholesterol sulfate and sulfatide inhibit the free catalytic subunit p110 alpha but fail to inhibit the homologous phosphatidylinositol 3-kinase from Saccharomyces cerevisiae (Vps34p), suggesting that these sulfated lipids act specifically on the mammalian phosphatidylinositol 3-kinase [17].

Physical interactions of VPS34


Regulatory relationships of VPS34

  • Consistent with this, mutations altering highly conserved residues in the lipid kinase domain of Vps34p lead to a dominant-negative phenotype resulting from titration of activating Vps15 proteins [7].
  • We propose that Vps34 regulates the CPY, Cvt, and macroautophagy pathways through distinct sets of PtdIns(3)P-binding effectors and that Vps34 promotes protein trafficking in the Cvt pathway through activation/localization of the effector protein Etf1 [19].

Other interactions of VPS34

  • In contrast, catalytically inactive Vps15p mutants do not produce a dominant mutant phenotype because they are unable to associate with Vps34p in a wild-type manner [7].
  • These results indicate that Vps30p functions as a subunit of a Vps34 PtdIns 3-kinase complex(es) [8].
  • They were identified by mass spectrometry to be Vps38p and Vps34p, a phosphatidylinositol (PtdIns) 3-kinase [8].
  • The vps34 and vps15 mutants displayed additional phenotypes such as defects in transport of proteinase A and proteinase B, implying the existence of another PtdIns 3-kinase complex(es) [8].
  • In contrast, deletions in genes that selectively confer vacuolar hydrolase sorting to the PVC or protein transport to the vacuole (i.e. VPS34 and VAM3, respectively) have no effect [20].

Analytical, diagnostic and therapeutic context of VPS34


  1. 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]
  2. Fab1p PtdIns(3)P 5-kinase function essential for protein sorting in the multivesicular body. Odorizzi, G., Babst, M., Emr, S.D. Cell (1998) [Pubmed]
  3. Receptor-mediated protein sorting to the vacuole in yeast: roles for a protein kinase, a lipid kinase and GTP-binding proteins. Stack, J.H., Horazdovsky, B., Emr, S.D. Annu. Rev. Cell Dev. Biol. (1995) [Pubmed]
  4. Phosphatidylinositol 4-kinase: gene structure and requirement for yeast cell viability. Flanagan, C.A., Schnieders, E.A., Emerick, A.W., Kunisawa, R., Admon, A., Thorner, J. Science (1993) [Pubmed]
  5. Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting. Schu, P.V., Takegawa, K., Fry, M.J., Stack, J.H., Waterfield, M.D., Emr, S.D. Science (1993) [Pubmed]
  6. The phosphatidylinositol 3-phosphate binding protein Vac1p interacts with a Rab GTPase and a Sec1p homologue to facilitate vesicle-mediated vacuolar protein sorting. Tall, G.G., Hama, H., DeWald, D.B., Horazdovsky, B.F. Mol. Biol. Cell (1999) [Pubmed]
  7. Vesicle-mediated protein transport: regulatory interactions between the Vps15 protein kinase and the Vps34 PtdIns 3-kinase essential for protein sorting to the vacuole in yeast. Stack, J.H., DeWald, D.B., Takegawa, K., Emr, S.D. J. Cell Biol. (1995) [Pubmed]
  8. Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. Kihara, A., Noda, T., Ishihara, N., Ohsumi, Y. J. Cell Biol. (2001) [Pubmed]
  9. Dominant missense mutations in a novel yeast protein related to mammalian phosphatidylinositol 3-kinase and VPS34 abrogate rapamycin cytotoxicity. Cafferkey, R., Young, P.R., McLaughlin, M.M., Bergsma, D.J., Koltin, Y., Sathe, G.M., Faucette, L., Eng, W.K., Johnson, R.K., Livi, G.P. Mol. Cell. Biol. (1993) [Pubmed]
  10. A novel gene, STT4, encodes a phosphatidylinositol 4-kinase in the PKC1 protein kinase pathway of Saccharomyces cerevisiae. Yoshida, S., Ohya, Y., Goebl, M., Nakano, A., Anraku, Y. J. Biol. Chem. (1994) [Pubmed]
  11. Assortment of phosphatidylinositol 3-kinase complexes--Atg14p directs association of complex i to the pre-autophagosomal structure in Saccharomyces cerevisiae. Obara, K., Sekito, T., Ohsumi, Y. Mol. Biol. Cell (2006) [Pubmed]
  12. Vps34p required for yeast vacuolar protein sorting is a multiple specificity kinase that exhibits both protein kinase and phosphatidylinositol-specific PI 3-kinase activities. Stack, J.H., Emr, S.D. J. Biol. Chem. (1994) [Pubmed]
  13. Membrane transport in Caenorhabditis elegans: an essential role for VPS34 at the nuclear membrane. Roggo, L., Bernard, V., Kovacs, A.L., Rose, A.M., Savoy, F., Zetka, M., Wymann, M.P., Müller, F. EMBO J. (2002) [Pubmed]
  14. Retromer function in endosome-to-Golgi retrograde transport is regulated by the yeast Vps34 PtdIns 3-kinase. Burda, P., Padilla, S.M., Sarkar, S., Emr, S.D. J. Cell. Sci. (2002) [Pubmed]
  15. A membrane-associated complex containing the Vps15 protein kinase and the Vps34 PI 3-kinase is essential for protein sorting to the yeast lysosome-like vacuole. Stack, J.H., Herman, P.K., Schu, P.V., Emr, S.D. EMBO J. (1993) [Pubmed]
  16. Phosphatidylinositol(3)-phosphate signaling mediated by specific binding to RING FYVE domains. Burd, C.G., Emr, S.D. Mol. Cell (1998) [Pubmed]
  17. Modulation of the substrate specificity of the mammalian phosphatidylinositol 3-kinase by cholesterol sulfate and sulfatide. Woscholski, R., Kodaki, T., Palmer, R.H., Waterfield, M.D., Parker, P.J. Biochemistry (1995) [Pubmed]
  18. The phosphatidylinositol 3-kinase Vps34p of the human pathogenic yeast Candida albicans is a multifunctional protein that interacts with the putative vacuolar H+ -ATPase subunit Vma7p. Eck, R., Nguyen, M., Günther, J., Künkel, W., Zipfel, P.F. Int. J. Med. Microbiol. (2005) [Pubmed]
  19. Novel PtdIns(3)P-binding protein Etf1 functions as an effector of the Vps34 PtdIns 3-kinase in autophagy. Wurmser, A.E., Emr, S.D. J. Cell Biol. (2002) [Pubmed]
  20. Dynamin and clathrin are required for the biogenesis of a distinct class of secretory vesicles in yeast. Gurunathan, S., David, D., Gerst, J.E. EMBO J. (2002) [Pubmed]
  21. Nonradioactive analysis of phosphatidylinositides and other anionic phospholipids by anion-exchange high-performance liquid chromatography with suppressed conductivity detection. Nasuhoglu, C., Feng, S., Mao, J., Yamamoto, M., Yin, H.L., Earnest, S., Barylko, B., Albanesi, J.P., Hilgemann, D.W. Anal. Biochem. (2002) [Pubmed]
  22. Characterization of VPS34, a gene required for vacuolar protein sorting and vacuole segregation in Saccharomyces cerevisiae. Herman, P.K., Emr, S.D. Mol. Cell. Biol. (1990) [Pubmed]
  23. Molecular cloning and biochemical characterization of a Drosophila phosphatidylinositol-specific phosphoinositide 3-kinase. Linassier, C., MacDougall, L.K., Domin, J., Waterfield, M.D. Biochem. J. (1997) [Pubmed]
  24. Inositide signalling in Chlamydomonas: characterization of a phosphatidylinositol 3-kinase gene. Molendijk, A.J., Irvine, R.F. Plant Mol. Biol. (1998) [Pubmed]
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