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Fungal-Specific Mechanisms of Ras -Mediated Morphogenetic Signaling in Aspergillus fumigatus

Fungal-Specific Mechanisms of Ras -Mediated Morphogenetic Signaling in Aspergillus fumigatus. Jarrod Fortwendel, PhD Assistant Professor Dept. of Microbiology and Immunology University of South Alabama. The Ras GTPase: A Binary Switch.

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Fungal-Specific Mechanisms of Ras -Mediated Morphogenetic Signaling in Aspergillus fumigatus

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  1. Fungal-Specific Mechanisms of Ras-Mediated Morphogenetic Signaling in Aspergillus fumigatus Jarrod Fortwendel, PhD Assistant Professor Dept. of Microbiology and Immunology University of South Alabama

  2. The Ras GTPase: A Binary Switch • Conserved GTPase protein that controls growth and differentiation • Binary switch: • Active (GTP) and inactive (GDP) • Controlled by interaction with: • GTPase activating protein (GAP) • Guanine exchange factor (GEF) • Ras is found mutated in up to 30% of all human cancers • Ras pathways are focus of anti-cancer therapies

  3. A. fumigatusRashomologs • A. fumigatusencodes 2 Ras proteins: • RasA: • Major Ras protein in fungi • RasB : • Fungal specific Ras homolog • Minor role in growth and asexual development RasAhomologs are critical to morphogenesis and virulence in all fungi

  4. Spatiotemporal Ras Regulation is Required for Morphogenesis Fortwendel J R et al. Eukaryotic Cell 2008;7:1530-1539

  5. Spatiotemporal Ras Regulation is Required for Morphogenesis GDP RasA RasA GTP Deregulation Fortwendel J R et al. Eukaryotic Cell 2011;10:611-615

  6. Ras Protein Maturation – Post-translational Lipidation Plasma Membrane RasA --CC--C RasA --CC--CAAX FTase RasA --CC--C PATs ER/Golgi Membrane

  7. Ras Protein Maturation – Post-translational Lipidation Plasma Membrane RasA --CC--C RasA --CC--CAAX FTase RasA --CC--C Farnesyltransferase Inhibitors Palmitoyltransferase Inhibitors PATs ER/Golgi Membrane

  8. Spatiotemporal Ras Regulation is Required for Morphogenesis RasA --CC--CAAX Fortwendel J R et al. Eukaryotic Cell 2012;11:966-977

  9. Spatiotemporal Ras Regulation is Required for Morphogenesis RasA --CC--CAAX Farnesyltransferase deletion WT Δram1 Ram1-C’

  10. Spatiotemporal Ras Regulation is Required for Virulence Fortwendel J R et al. Eukaryotic Cell 2012;11:966-977 ΔrasA and palmitoylation-deficient mutants exhibit reduced virulence

  11. Summary of RasA Functions • Conserved aspects required for Ras pathway function • Regulation of localization and activity controls processes that support filamentous growth Fortwendel J R et al. Eukaryotic Cell 2011;10:611-615

  12. Future Questions/Directions • Do fungal-specific Ras domains contribute to Ras-mediated growth and virulence? • Are there fungal-specific attributes of Ras network signaling that contribute to hyphal morphogenesis? RasA

  13. Acknowledgements University of South Alabama Rachel Lovingood, M.S. Tiffany Norton HaideeCustodio, M.D. Past labs: Bill Steinbach, M.D. (Duke) -Praveen Juvvadi, Ph.D. Judy Rhodes, Ph.D. (Cincinnati) Funding - NIH/NIAID K22 - K22AI089766 R01 - R01AI106925

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