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Jason Duex

Mentor: Lois Weisman, Ph.D.
Lab Phone: 335-8548

The role of phosphatidylinositol 3,5-bisphosphate (PI3,5P2) in vacuole morphology and the hyperosmotic stimulation response.

Type 2 diabetes is a result of a defect in the signal transduction pathway that relays extracellular insulin stimulation to the internal mobilization of glucose transporters (GLUT4, GLUT1) to the plasma membrane. Recent results with mammalian Fab1 (mFab1) closely parallel our yeast Fab1p studies and strongly suggest that mFab1, and its product PI3,5P2, may be important in glucose transporter translocation upon insulin stimulus. First, mFab1 messenger RNA levels are elevated in insulin target tissues. Second, hyperosmotic shock (which in yeast causes a 20-fold elevation in PI3,5P2 levels) causes GLUT4 translocation to the plasma membrane in both adipocyte and muscle cell-lines. Third, loss of mFab1/Fab1p function in both tissue culture cells and yeast leads to the same phenotype, namely formation of large, translucent vacuoles. Fourth, inhibition of mFab1 activity results in a block of insulin-induced GLUT4 translocation and a dramatic decrease in glucose uptake into 3T3-L1 adipocytes. Our laboratory and others have recently found that PI3,5P2 exists at very low levels in unperturbed cells. In our work with yeast, we have discovered that cells defective in PI3,5P2 production display large, unlobed vacuoles (lysosomes) and are defective in retrograde traffic out of the vacuole. Most notably, it has been shown that PI3,5P2 rapidly increases 20-fold in response to hyperosmotic shock. These results strongly suggest that activation of mFab1/Fab1p provides the major contribution to the increase in PI3,5P2. We have recently identified a number of candidate genes that likely play a role in mFab1/Fab1p activation. Future studies will be focused on characterizing the role of these candidate proteins as well as identifying changes to the mFab1/Fab1p protein itself.

Jin N, Chow CY, Liu L, Zolov SN, Bronson R, Davisson M, Petersen JL, Zhang Y, Park S, Duex JE, Goldowitz D, Meisler MH, Weisman LS. VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P(2) in yeast and mouse. EMBO J. 2008 Dec 17;27(24):3221-34. Epub 2008 Nov 27. PubMed PMID:19037259; PubMed Central PMCID: PMC2600653.

Duex JE, Nau JJ, Kauffman EJ, Weisman LS. Phosphoinositide 5-phosphatase Fig 4p is required for both acute rise and subsequent fall in stress-induced phosphatidylinositol 3,5-bisphosphate levels. Eukaryot Cell. 2006 Apr;5(4):723-31. PubMed PMID: 16607019; PubMed Central PMCID: PMC1459661.

Duex JE, Tang F, Weisman LS. The Vac14p-Fig4p complex acts independently of Vac7p and couples PI3,5P2 synthesis and turnover. J Cell Biol. 2006 Feb 27;172(5):693-704. Epub 2006 Feb 21. PubMed PMID: 16492811; PubMed Central PMCID:PMC2063702.

Bonangelino CJ, Nau JJ, Duex JE, Brinkman M, Wurmser AE, Gary JD, Emr SD, Weisman LS. Osmotic stress-induced increase of phosphatidylinositol 3,5-bisphosphate requires Vac14p, an activator of the lipid kinase Fab1p. J Cell Biol. 2002 Mar 18;156(6):1015-28. Epub 2002 Mar 11. PubMed PMID: 11889142; PubMed Central PMCID: PMC2173454.

Wang YX, Kauffman EJ, Duex JE, Weisman LS. Fusion of docked membranes requires the armadillo repeat protein Vac8p. J Biol Chem. 2001 Sep 14;276(37):35133-40. Epub 2001 Jul 5. PubMed PMID: 11441010.

Catlett NL, Duex JE, Tang F, Weisman LS. Two distinct regions in a yeast myosin-V tail domain are required for the movement of different cargoes. J Cell Biol. 2000 Aug 7;150(3):513-26. PubMed PMID: 10931864; PubMed Central PMCID:PMC2175197.

Honors and Awards

  • 1999, Second place, Poster Contest, Midwest Yeast Convention, Chicago; 2000, First place, Poster
  • Genetics Society of America 2002, American Society for Cell Biology, 2002
  • Chosen for 10 Minute Talk, Steenbock International Symposium on Intracellular Protein and Lipid Traf