J. David Castle
- BA, Carleton College, Northfield, MN
- PhD, Rockefeller University, New York, NY
- Postdoc, Yale Univ. Sch. of Med., New Haven, CT
- Postdoc, Univ. of California, Berkeley, CA
- Professor, Cell Biology
- Phone: 434-924-1786
- Email: email@example.com
- Website: http://www.faculty.virginia.edu/castlelab/home.php
Intracellular cholesterol and the regulation of insulin secretion and membrane trafficking.
The longstanding interest of my laboratory is on the regulation of membrane trafficking in the secretory and endocytic pathways. A new direction that is a major focus of our research concerns cholesterol regulation in insulin’s secretory pathway. Following upon collaborative studies (Sturek et al, 2010) that were conducted with Lynn Hedrick’s laboratory (now located at La Jolla Institute of Allergy and Immunology), we are examining how ATP binding cassette proteins ABCG1 and ABCA1 and other proteins that control intracellular cholesterol distribution collaborate to regulate the formation and function of insulin storage granules. It is now appreciated that phospholipid and cholesterol dynamics play major roles in regulating membrane trafficking during both secretion and endocytosis. This area is relatively underexplored even though there is growing appreciation that cholesterol dysregulation is a component of a broad spectrum of diseases -- metabolic, neurodegenerative, and cancer. In our particular case, the ABC transporters being studied are significant to type-2 diabetes as their expression is altered in disease models and is required for endocrine pancreatic actions of selected antidiabetic drugs.
We also maintain an interest in the function of Secretory Carrier Membrane Proteins (SCAMPs), a family of proteins that were discovered in my laboratory. Our work has been focused along two lines: 1) deciphering the complementary roles of SCAMPs 1 and 2 in exo-endocytic coupling during secretion by neuroendocrine cells including those derived from adrenal medulla and endocrine pancreatic islets; and 2) analysis of the function of SCAMP3 in regulating endocytic sorting of epidermal growth factor receptor (EGFR). Our most recent achievement regarding SCAMP1 is a demonstration that it is a key component controlling fusion pore closure and thereby determining the magnitude of export of stored hormone in response to cellular stimulation (Zhang and Castle, 2011). This regulatory role appears to involve an indirect coupling to the GTPase dynamin that mediates membrane scission. With respect to SCAMP3, we and our collaborators have recently shown that its levels govern the rate at which EGFR is degraded in response to EGF stimulation. SCAMP3's role appears focused in sorting endosomes where it is able to interact with components of the ESCRT (Endosomal Sorting Complex Required for Transport) machinery that function in down regulation of growth factor receptors (Aoh et al, 2009; Falguieres et al, 2012). The particular role of SCAMP3 in supporting down regulation versus recycling of EGFR may be determined by its reversible ubiquitylation.
Finally, my laboratory contributes to a collaborative Program Project headed by Professor Lukas Tamm in the Department of Molecular Physiology and Biological Physics and Center for Membrane Biology. These studies are addressing structural dynamics of presynaptic membrane fusion.
- Schiel J, Simon G, Zaharris C, Weisz J, Castle D, Wu C, Prekeris R. FIP3-endosome-dependent formation of the secondary ingression mediates ESCRT-III recruitment during cytokinesis. Nature cell biology. 2012;14(10): 1068-78. PMID: 23000966
- Falguières T, Castle D, Gruenberg J. Regulation of the MVB pathway by SCAMP3. Traffic (Copenhagen, Denmark). 2011;13(1): 131-42. PMID: 21951651
- Zhang J, Castle D. Regulation of fusion pore closure and compound exocytosis in neuroendocrine PC12 cells by SCAMP1. Traffic (Copenhagen, Denmark). 2011;12(5): 600-14. PMID: 21272170 | PMCID: PMC3085939
- Sturek J, Castle J, Trace A, Page L, Castle A, Evans-Molina C, Parks J, Mirmira R, Hedrick C. An intracellular role for ABCG1-mediated cholesterol transport in the regulated secretory pathway of mouse pancreatic beta cells. The Journal of clinical investigation. 2010;120(7): 2575-89. PMID: 20530872 | PMCID: PMC2898593
- Aoh Q, Castle A, Hubbard C, Katsumata O, Castle J. SCAMP3 negatively regulates epidermal growth factor receptor degradation and promotes receptor recycling. Molecular biology of the cell. 2009;20(6): 1816-32. PMID: 19158374 | PMCID: PMC2655259
- Liao H, Zhang J, Shestopal S, Szabo G, Castle A, Castle D. Nonredundant function of secretory carrier membrane protein isoforms in dense core vesicle exocytosis. American journal of physiology. Cell physiology. 2008;294(3): C797-809. PMID: 18171723
- Balasubramanian N, Scott D, Castle J, Casanova J, Schwartz M. Arf6 and microtubules in adhesion-dependent trafficking of lipid rafts. Nature cell biology. 2007;9(12): 1381-91. PMID: 18026091 | PMCID: PMC2715295
- Liao H, Ellena J, Liu L, Szabo G, Cafiso D, Castle D. Secretory carrier membrane protein SCAMP2 and phosphatidylinositol 4,5-bisphosphate interactions in the regulation of dense core vesicle exocytosis. Biochemistry. 2007;46(38): 10909-20. PMID: 17713930
- Castle A, Castle D. Ubiquitously expressed secretory carrier membrane proteins (SCAMPs) 1-4 mark different pathways and exhibit limited constitutive trafficking to and from the cell surface. Journal of cell science. 2005;118 3769-80. PMID: 16105885
- Liu L, Liao H, Castle A, Zhang J, Casanova J, Szabo G, Castle D. SCAMP2 interacts with Arf6 and phospholipase D1 and links their function to exocytotic fusion pore formation in PC12 cells. Molecular biology of the cell. 2005;16(10): 4463-72. PMID: 16030257 | PMCID: PMC1237056