Biological Sciences

Scott D. Emr Adjunct Professor of Biology, UCSD  Professor of Cellular and Molecular Medicine Investigator, Howard Hughes Medical Institute e-mail: semr@ucsd.edu Lab Homepage: Emr Lab

     An essential feature of all eukaryotic cells is their highly compartmentalized organization. Our lab is using yeast, a simple unicellular eukaryote, as a model genetic system to uncover the molecular machinery required to establish and maintain organelle identity. The fundamental similarities between the pathways and machinery that guide protein traffic in yeast as well as in mammalian cells has established yeast as an ideal organism for addressing such problems. In addition, the recent completion of the entire DNA sequence of the yeast genome further facilitates the identification and functional analysis of novel transport components. Much of the lab's effort has been directed toward identification of the cellular machinery required for sorting along the secretory, endocytic and autophagic pathways to the lysosome. Lysosomes play an important role in macromolecular turnover and in the degradation or down regulation of cell surface receptors (e.g., growth factor, cytokine and nutrient receptors) that are internalized by endocytosis. Defects in these pathways result in severe health problems. Several serious inherited lysosomal storage diseases (e.g., I-cell disease) as well as other diseases (e.g., osteoporosis, bleeding disorders and the progression of certain cancers) result
from, or are correlated with, defects in the sorting and transport of lysosomal proteins. To fully elucidate the molecular mechanisms that underlie these processes, we are employing a mutidisciplinary approach that involves the application of sophisticated genetic, molecular, biochemical and cell biological techniques. Through these approaches the lab has discovered a novel kinase signaling system that directs membrane trafficking decisions through a series of kinase and second messenger cascades, a new transport pathway (defects in which result in bleeding disorders), a set of vesicle docking complexes, and a multivalent adaptor complex that coordinates interactions essential for endocytosis. 

     Using a variety of genetic selection schemes, we have identified more than 50 genes that are required for biosynthetic and endocytic membrane trafficking. The affected genes in many of the mutants have been cloned and found to encode components of the protein sorting and regulatory machinery, including: a transmembrane sorting receptor (Vps10p), a rab-like GTPase (Vps21p) and associated regulator (Vps9p), a vesicle docking protein complex (Vps6p, Vps19p, Vps45p), and a membrane-associated protein and phosphoinositide kinase complex (Vps15p and Vps34p). Human homologs for several VPS genes are being characterized in the lab, including a tumor susceptibility gene. The Vps15 protein kinase and the Vps34 PI 3-kinase are components of a novel signal transduction complex that produces a lipid second messenger which activates a set of effector molecules recently identified in the lab that are required for distinct stages of vesicle-mediated sorting reactions. Through further genetic, molecular and biochemical reconstitution studies, we hope to elucidate the detailed signaling and regulatory mechanisms that ensure high fidelity protein and membrane trafficking in eukaryotic cells. 

     Babst, M., Wendland, B., Estepa, E.J. and Emr, S.D. (1998). The Vps4p AAA ATPase regulates membrane association of a Vps protein complex required for normal endosome function. EMBO J. 17:101-112. 

     Cowles, C. R., Odorizzi, G., Payne, G.S. and Emr, S.D. (1997). The AP-3 adaptor complex is essential for cargo-selective transport to the yeast vacuole. Cell 91:109-118. 

     Darsow, T., Rieder, S.E. and Emr, S.D. (1997). A multi-specificity syntaxin homologue, Vam3p, essential for autophagic and biosynthetic protein transport to the vacuole. J. Cell Biol. 138 :517-529.

     Seaman, N. J., Marcusson, E.B., Cereghino, J.L. and Emr, S.D. (1997). Endosome to Golgi retrieval of the vacuolar protein sorting receptor, Vps10p, requires the function of the VPS29, VPS30 and VPS35 gene products. J. Cell Biol. 137:79-92.