Regulation of Protein/Vesicle Trafficking in Epithelial Cells in Health and Disease
Dennis Brown is the Director of the MGH Program in Membrane Biology (PMB) which brings together investigators from several areas of research related to protein trafficking and cell signaling in normal and disease states, including diabetic nephropathy. The theme of the PMB is to understand how endocytotic mechanisms (including clathrin and caveolae-mediated processes) and endosomal pathways interact with accessory proteins (e. g., small GTPases, SNAREs, adaptors) and with the cytoskeleton (e. g., microtubules, actin, and PDZ proteins) in physiological and pathophysiological conditions to regulate the trafficking of membrane proteins that are important to epithelial cell function in different organs. Experimental models used range from in vitro systems using purified proteins and membrane vesicles (endosomes, Golgi, plasma membrane), to transfected cell cultures, to whole animal models including transgenic mice and diabetic rats and mice. The aim of the Program is to understand how physiologically-relevant processes that regulate fluid and electrolyte transport, acid-base sensing, albumin internalization and trafficking, and other metabolic events are regulated at the cell and molecular levels and how they are disrupted by disease. Representative projects include: 1) dissecting the mechanism by which water channel (aquaporin 2) trafficking occurs in renal epithelial cells in response to vasopressin to regulate the urinary concentrating mechanism; 2) understanding the pathways and proteins involved in the recycling of a vacuolar (V-type) H+ATPase in renal and urogenital tract to regulate renal acid-base secretion and urinary tract acidification; 3) Elucidating the role of the V-ATPase and a soluble adenylyl cyclase as endosomal and extracellular pH sensors in epithelial cells; 4) Dissecting the respective roles of changes in glomerular albumin permeability versus proximal tubule uptake of albumin in the development of albuminuria during diabetic nephropathy.
1. Hurtado-Lorenzo, A., Skinner, M., El Annan, J., Futai, M., Sun-Wada, G. H., Bourgoin, S., Casanova, J., Wildeman, A., Bechoua, S., Ausiello, D. A., Brown, D., and Marshansky, V. V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway. Nat Cell Biol 8: 124-136, 2006.
2. Russo, L. M., Del Re, E., Brown, D., and Lin, H. Y. Evidence for a role of transforming growth factor –b1 in the induction of postglomerular albuminuria in diabetic nephropathy. Amelioration by soluble TGF-b type II receptor. Diabetes 56:380-388, 2007.
3. Lu, H. A. J., Sun,T-X., Yi X-H., Bouley, R., McLaughlin, M., Van Hoek, A., and Brown, D. Heat-shock protein 70 (Hsp/Hsc70) is an aquaporin-2 interacting protein and is involved in AQP2 endocytosis. J. Biol. Chem., 282: 28721-28732, 2007.
4. Russo, L. M., Sandoval, R. M., McKee, M., Osicka, T. M., Collins, A. B., Brown, D., Molitoris, B. A., and Comper, W. D. The normal kidney filters nephrotic levels of albumin retrieved by proximal tubule cells: retrieval is disrupted in nephrotic states. Kidney Int. 71: 504-513, 2007.
5. Shum, W. W. C., Da Silva, N., McKee, M., Smith, P. J. S., Brown, D., and Breton, S. Epithelial basal cells are luminal hormone sensors. Cell, 135: 1108-1117, 2008. PMCID: PMC2646085
6.Liu, L., Brown, D., McKee, M., Lebrasseur, N. K., Yang, D., Albrecht, K. H., Ravid, K., Pilch, P. F. Deletion of Cavin/PTRF causes global loss of caveolae, dyslipidemia and glucose intolerance. Cell Metab. 8: 310-317, 2008.
Hasler, U., Nunes, P., Bouley, R., Lu, H. A. J., Matsuzaki., T. and Brown, D. Acute hypertonicity alters aquaporin-2 trafficking and induces a MAP kinase-dependent accumulation at the plasma membrane of renal epithelial cells. J. Biol. Chem., 283: 26643-26661, 2008. PMCID: PMC2581738
7. Russo, L. M., Sandoval, R. M., McKee, M., Campos, S. B., Molitoris, B. A., Comper, W. A. and Brown, D. Impaired tubular uptake explains albuminuria in early diabetic nephropathy. J. Am. Soc. Nephrol. 20: 489-494, 2009. PMCID: PMC2653682.
8. Brown, D., Breton, S., Ausiello, D. A., and Marshansky, V. Sensing, signaling and sorting events in kidney epithelial cell physiology. Traffic 10: 275-284, 2009. PMCID: PMC2896909