Dr. Nava Segev
- PhD, Tel Aviv University, Israel
- Postdoctoral Research MIT, Cambridge MA (Advisor: David Botstein)
Regulation of Intracellular Trafficking byMolecular Switches and Cascades
Our research is aimed at understanding a basic cellular process, trafficking inside cells, in which proteins and membranes are shuttled between cellular organelles. This process is required for proper functioning of all cells, and therefore for every system of the human body. Elucidation of the mechanisms that regulate trafficking inside cells is relevant to a variety of diseases caused by impaired transport of substances that are either essential, such as insulin in diabetes, growth-factor receptors in cancer and CFTR in cystic fibrosis, or detrimental, such as b-amyloid in Alzheimer's disease.
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.