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FAB1  -  1-phosphatidylinositol-3-phosphate 5-kinase

Saccharomyces cerevisiae S288c

Synonyms: 1-phosphatidylinositol 3-phosphate 5-kinase FAB1, PIPkin-III, Phosphatidylinositol 3-phosphate 5-kinase, Type III PIP kinase, YFR019W
 
 
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High impact information on FAB1

  • The PtdIns(3)P 5-kinase activity of Fab1p, which converts the product of the Vps34p PtdIns 3-kinase PtdIns(3)P into PtdIns(3,5)P2, also is required for cargo-selective sorting into the vacuole lumen [1].
  • Fab1p PtdIns(3)P 5-kinase function essential for protein sorting in the multivesicular body [1].
  • Atg18p is the most recently identified candidate for a Fab1p effector mediating the largely uncharacterized processes of vesicle fission and membrane recycling at the vacuole [2].
  • The Fab1 phosphatidylinositol kinase pathway in the regulation of vacuole morphology [2].
  • While it is has been shown that the lipid kinase Fab1p and its product phosphatidylinositol 3,5-bisphosphate, and not the mitogen-activated protein kinase Hog1p, are central to this regulatory pathway, key effectors still await identification [2].
 

Biological context of FAB1

  • Vac14 controls PtdIns(3,5)P(2) synthesis and Fab1-dependent protein trafficking to the multivesicular body [3].
  • Utilizing an endocytosis screen, we isolated a novel allele of FAB1 that contains a point mutation in the lipid kinase domain [4].
  • Fab1p is essential for PtdIns(3)P 5-kinase activity and the maintenance of vacuolar size and membrane homeostasis [5].
  • The major phenotypes resulting from Fab1p kinase inactivation include temperature-sensitive growth, vacuolar acidification defects, and dramatic increases in vacuolar size [5].
  • The presence of PtdIns(3)P in fab1 mutants, combined with previous data, indicate that PtdIns(3,5)P2 synthesis is a two step process, requiring the production of PtdIns(3)P by the Vps34p PtdIns 3-kinase and the subsequent Fab1p- dependent phosphorylation of PtdIns(3)P yielding PtdIns(3,5)P2 [5].
 

Anatomical context of FAB1

  • Svp1p is not involved in the contributions of FAB1/PtdIns(3,5)P2 to MVB sorting or to vacuole acidification and so additional PtdIns(3,5)P2 effectors must exist [6].
  • BACKGROUND: The PtdIns3P 5-kinase Fab1 makes PtdIns(3,5)P(2), a phosphoinositide essential for retrograde trafficking between the vacuole/lysosome and the late endosome and also for trafficking of some proteins into the vacuole via multivesicular bodies (MVB) [3].
  • We propose that Fab1p and Vac7p are components of a signal transduction pathway which functions to regulate the efflux or turnover of vacuolar membranes through the regulated production of PtdIns(3,5)P2 [5].
  • Immunofluorescent and fractionation studies of the epitope-tagged Mss4p suggest that Mss4p is localized on the plasma membrane, whereas Fab1p is reportedly localized on the vacuolar membrane [7].
  • The phosphoinositide kinase PIKfyve/Fab1p regulates terminal lysosome maturation in Caenorhabditis elegans [8].
 

Associations of FAB1 with chemical compounds

 

Regulatory relationships of FAB1

  • Genetic studies have indicated that Fab1 kinase is positively regulated by Vac7 and Vac14; deletion of either gene results in ablation of PtdIns(3,5)P2 synthesis and the formation of a grossly enlarged vacuole [13].
 

Other interactions of FAB1

  • Additionally, vac7Delta mutants have nearly undetectable levels of PtdIns(3,5)P(2), suggesting that Vac7 functions to regulate Fab1 kinase activity [9].
  • Like fab1 mutants, yeast lacking Vac14 have enlarged vacuoles that do not acidify correctly [3].
  • Two Saccharomyces cerevisiae genes, MSS4 and FAB1, are homologous to mammalian PtdIns(4)P 5Ks and PtdIns(5)P 4Ks [7].
  • Based on our studies, we hypothesize that whereas Vps34p is essential for anterograde trafficking of membrane and protein cargoes to the vacuole, Fab1p may play an important compensatory role in the recycling/turnover of membranes deposited at the vacuole [5].
  • However, whereas Rsp5 seems to be responsible for cargo ubiquitination, the precise role for Fab1 remains to be elucidated [14].
 

Analytical, diagnostic and therapeutic context of FAB1

  • Additional sequence analysis of the Fab1p kinase domain, reveals that Fab1p defines a subfamily of putative PtdInsP kinases that is distinct from the kinases that synthesize PtdIns(4,5)P2 [5].

References

  1. 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]
  2. The Fab1 phosphatidylinositol kinase pathway in the regulation of vacuole morphology. Efe, J.A., Botelho, R.J., Emr, S.D. Curr. Opin. Cell Biol. (2005) [Pubmed]
  3. Vac14 controls PtdIns(3,5)P(2) synthesis and Fab1-dependent protein trafficking to the multivesicular body. Dove, S.K., McEwen, R.K., Mayes, A., Hughes, D.C., Beggs, J.D., Michell, R.H. Curr. Biol. (2002) [Pubmed]
  4. PtdIns(3,5)P2 is required for delivery of endocytic cargo into the multivesicular body. Shaw, J.D., Hama, H., Sohrabi, F., DeWald, D.B., Wendland, B. Traffic (2003) [Pubmed]
  5. Fab1p is essential for PtdIns(3)P 5-kinase activity and the maintenance of vacuolar size and membrane homeostasis. Gary, J.D., Wurmser, A.E., Bonangelino, C.J., Weisman, L.S., Emr, S.D. J. Cell Biol. (1998) [Pubmed]
  6. Svp1p defines a family of phosphatidylinositol 3,5-bisphosphate effectors. Dove, S.K., Piper, R.C., McEwen, R.K., Yu, J.W., King, M.C., Hughes, D.C., Thuring, J., Holmes, A.B., Cooke, F.T., Michell, R.H., Parker, P.J., Lemmon, M.A. EMBO J. (2004) [Pubmed]
  7. Phosphatidylinositol-4-phosphate 5-kinase localized on the plasma membrane is essential for yeast cell morphogenesis. Homma, K., Terui, S., Minemura, M., Qadota, H., Anraku, Y., Kanaho, Y., Ohya, Y. J. Biol. Chem. (1998) [Pubmed]
  8. The phosphoinositide kinase PIKfyve/Fab1p regulates terminal lysosome maturation in Caenorhabditis elegans. Nicot, A.S., Fares, H., Payrastre, B., Chisholm, A.D., Labouesse, M., Laporte, J. Mol. Biol. Cell (2006) [Pubmed]
  9. Regulation of Fab1 phosphatidylinositol 3-phosphate 5-kinase pathway by Vac7 protein and Fig4, a polyphosphoinositide phosphatase family member. Gary, J.D., Sato, T.K., Stefan, C.J., Bonangelino, C.J., Weisman, L.S., Emr, S.D. Mol. Biol. Cell (2002) [Pubmed]
  10. Phosphoinositide signaling: vac to the future in fab1 kinase regulation. DeWald, D.B. Curr. Biol. (2002) [Pubmed]
  11. Vac7p, a novel vacuolar protein, is required for normal vacuole inheritance and morphology. Bonangelino, C.J., Catlett, N.L., Weisman, L.S. Mol. Cell. Biol. (1997) [Pubmed]
  12. Novel PI(4)P 5-kinase homologue, Fab1p, essential for normal vacuole function and morphology in yeast. Yamamoto, A., DeWald, D.B., Boronenkov, I.V., Anderson, R.A., Emr, S.D., Koshland, D. Mol. Biol. Cell (1995) [Pubmed]
  13. Vacuole size control: regulation of PtdIns(3,5)P2 levels by the vacuole-associated Vac14-Fig4 complex, a PtdIns(3,5)P2-specific phosphatase. Rudge, S.A., Anderson, D.M., Emr, S.D. Mol. Biol. Cell (2004) [Pubmed]
  14. Multivesicular body sorting: ubiquitin ligase Rsp5 is required for the modification and sorting of carboxypeptidase S. Katzmann, D.J., Sarkar, S., Chu, T., Audhya, A., Emr, S.D. Mol. Biol. Cell (2004) [Pubmed]
 
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