J. David Castle, PhD
Molecular and cellular analysis of protein sorting and membrane trafficking
Research in the Castle laboratory mainly addresses cellular mechanisms that regulate membrane trafficking, which is a controlling element in the nature and duration of cell signaling and in expediting cell migration. They have been focusing most of their attention on a family of membrane proteins known as Secretory Carrier Membrane Proteins (SCAMPs) that they discovered here at the University of Virginia . Mammals express five known isoforms of SCAMPs, which may work individually or in collaboration to regulate vesicle formation and fusion events throughout the cell surface recycling system. SCAMPs 1 and 2 function in exocytosis and in pheochromocytoma (PC12) cells SCAMP2 interacts with the small GTPase Arf6 and with phospholipase D1 and links their function to formation of exocytotic fusion pores. These studies have been conducted collaboratively with James Casanova (Cancer Center and Department of Cell Biology). Studies in collaboration with David Cafiso (Cancer Center Department of Chemistry), examine the role of SCAMP's in regulating the role local distribution of the polyphosphoinositide PI4,5P2, which is well known to be required for initiating both exocytosis and endocytosis. Another one of the SCAMPs, SCAMP3 is of special interest because it interacts with E3 ubiquitin ligases that regulate the trafficking of growth factor receptors including the EGF receptor. The lab is currently pursuing studies to investigate whether SCAMP3 contributes to organizing a membrane trafficking event within endosomes that distinguishes whether growth factor receptors are down-regulated via targeting for lysosomal degradation or are recycled to the plasma membrane for extended function in cell signaling. The polyphosphoinositides, PI-3P and PI3,5P2, which contribute critically to trafficking at this level, may be regulated by SCAMP3. Better understanding of the dynamics of growth factor receptors may provide new insight into mechanisms that control cell proliferation and that are subject to dysregulation in certain cancers.