The Role of Ypt/Rab GTPases in intra-cellular Trafficking
Intracellular trafficking is vital for the proper functioning of all eukaryotic cells. In this process, proteins and membranes are transported between intracellular compartments through multiple transport steps. Whereas the regulation of individual transport steps has been studied extensively, less is known about their coordination. Ypt/Rab GTPases have emerged as key regulators of individual transport steps. They are activated by guanine-nucleotide exchange factors (GEFs), and when in the active form, they interact with downstream effectors that mediate vesicular transport.
Our long-term goal is to elucidate how Ypt/Rab GTPases together with their GEFs coordinate multiple transport steps. Landmark discoveries about the mechanisms and machinery that underlie intracellular trafficking were made in yeast and shown to pertain to humans. Therefore, we will continue to use yeast as a model to address these complicated issues, because it allows utilizing sophisticated genetic approaches in combination with molecular and cellular methods. Furthermore, the relatively small number of players (e.g., 11 Ypts in yeast versus ~70 Rabs in humans) and the resultant simplified interaction networks make yeast an excellent model for studying the coordination of transport steps.
Our research focuses on coordinated activation of exocytic Ypts. In the exocytic pathway, proteins are transported from the endoplasmic reticulum (ER), through the Golgi, to the plasma membrane (PM). Two recycling loops regulate the level and quality of cargo at the beginning and the end of the exocytic pathway. At the ER, misfolded proteins are shuttled for degradation, and one major pathway is to lysosomes. At the PM, membrane proteins are recycled through endosomes either back to the Golgi or for degradation in lysosomes. In yeast, Ypt1 and the Ypt31/32 pair regulate all these transport steps, including the intersection of the exocytic pathway with the recycling loops. We are testing our hypothesis that activation of these Ypts is achieved by one modular GEF complex, TRAPP, which thereby coordinates all steps of the exocytic pathway.
Our research is relevant to human health because multiple essential processes depend on intracellular trafficking: e.g., secretion of proteins and peptides; presentation of receptors, ion channels and ion pumps on the outer-cell membrane; and internalization of ligands and receptors. Because the interaction of cells with their environment is dependent on intracellular trafficking, impairment of this process affects every system in the human body, including the development and functioning of the brain, heart, and immune system.
Selected Publications:
Segev, N. (2001) Review: Ypt and Rab GTPases: Insight into Functions through
Novel Interactions. Curr Opin Cell Biol. 13(4):500-11. PMID: 11454458
Segev, N. (2001) Review: The Ypt/Rab family of small GTPases. Science’s
Signal Tranduction Knowledge Environment (STKE), http://www.stke.org PMID: 11579231
Chen, S., Chen, S., Tokarev, A., Liu, F., Jedd, G., and Segev, N. (2005). Ypt31/32, and their novel F-Box effector protein, Rcy1, regulate protein recycling. Mol. Biol. Cell. 16:178-192. PMID: 15537705
Morozova, N., Liang, Y., Tokarev, A., Chen, S., Cox, R., Andrejic, J., Lipatova, Z., Sciora, V., Emr, S., and Segev, N. (2006). TRAPP II subunits are required for the specificity switch of a dual-Ypt/Rab GEF. Nature Cell Biology, 8(11):1263-9. PMID: 17041589
Cox, R.,, Chen, S., Yoo, E., and Segev, N. (2007). Conservation of the TRAPPII-specific subunits of a Ypt/Rab exchanger complex. BMC Evolutionary Biology, 7:12. PMID: 17274825
Liang, Y., Morozova, N., Tokarev, A., Mullholland, J., and Segev, N. (2007) The role of Trs65 in the Ypt/Rab GEF function of the TRAPP II complex. Mol. Biol. Cell. 18(7):2533-41. PMID: 17475775
Lipatova, Z., Tokarev, A., Jin, Y., Mullholland, J., Weisman, L., and Segev, N. (2008) Direct interaction between a myosin V motor and the Rab GTPases Ypt31/32 is required for polarized secretion. Mol. Biol. Cell. 19(10): 4177-87. PMID: 18653471
Sacher, M., Kim, Y-G., Lavie, A., Oh, B-H., Segev, N. (2008) Review: The TRAPP complex: Insights into its architecture and function. Traffic, 9 (12): 2032-2042. PMID: 18801063
Tokarev A., Taussig, D., Sundaram, G., Lipatova, Z., Liang, Y., Mulholland, J., and Segev, N. (2009) TRAPPII complex assembly requires Trs33 or Tr65. Traffic 10 (12):1831-44. PMID: 19843283
Segev N. (2011) GTPases in intracellular trafficking: an overview. Semin Cell Dev Biol. 22(1): 1-2. Review. PMID: 21145981
Segev N. (2011) Coordination of intracellular transport steps by GTPases. Semin Cell Dev Biol. 22(1): 33-8. Review. PMID: 21130177
Chen, S.C., Shah, A. H., and Segev, N. (2011) Ypt31/32 GTPases and their F-box effector Rcy1 regulate ubiquitination of recycling proteins. Cellular Logistics 1 (1) 21-31. PMID: 21686101
Books and Editorials:
Segev, N. (2009) Editor: Trafficking Inside Cells: Pathways, Mechanisms and Regulation. Publisher: Landes Bioscience and Springer Science + Business Media; http://www.eurekah.com
Tokarev, A., Alfonso, A. and Segev, N. (2009) Overview of Intracellular Compartments and Pathways. In Trafficking Inside Cells: Pathways, Mechanisms and Regulation. Publisher: Landes Bioscience and Springer Science + Business Media.
Donaldson, J. and Segev N. (2009) Regulation and Coordination of Intracellular Trafficking: An Overview. In Trafficking Inside Cells: Pathways, Mechanisms and Regulation. Publisher: Landes Bioscience and Springer Science + Business Media.
Segev, N. (2011) Launching Cellular Logistics: Editorial. Cell Logist. 2011 Jan;1(1):1-2. PMID: 21686096
Segev N. (2011) Editorial: Focusing on Arf GAPs. Cell Logist. Mar;1(2):47-48.
PMID: 21686251 |
