The Yeast Secretory Pathway
Our lab studies the selective recognition,
sorting and vesicle-mediated transport of proteins through the
secretory pathway. The long term objective is to identify
components of the cellular machinery that direct each stage of
the process. Toward this end, we have isolated a large collection
of yeast mutants that exhibit severe and specific defects in
protein delivery to the lysosome in yeast. The affected genes are
being cloned and several have been found to encode components of
the cell's protein sorting apparatus, including; a transmembrane
sorting receptor and a membrane-associated complex of two kinases
(Vps15 protein kinase and Vps34 phosphatidylinositol 3-kinase)
that regulate protein traffic to the lysosome. Our data
demonstrate that the Vps15 protein kinase and the Vps34 PtdIns
3-kinase are components of a signal transduction complex that
produces a second messenger, PI3P, which activates as yet unknown
effector molecule(s) required for an early step in the sorting
reaction (e.g., transport vesicle formation). These studies are
medically relevant as several serious lysosomal storage diseases
(e.g., I-cell disease, pseudo-Hurler polydystrophy) as well as
other diseases (e.g., osteoporosis and the progression of certain
types of cancer) are known to result from, or are correlated
with, mislocalization of lysosomal hydrolases.
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