Vacuolar H+ATPases (structure, function, assembly and regulation), cellular pH homeostasis, cellular stress responses, protein sorting, genomics, yeast as a model system
Postdoctoral Fellow: Institute of Molecular Biology, University of Oregon
PhD: Cornell University, 1987
All eukaryotic cells tightly control cellular pH. Proper control of cytoplasmic pH is essential for normal metabolism and cell growth, and acidification of organelles such as the lysosome, endosome, and Golgi apparatus is essential for protein sorting and degradation, ion homeostasis, and signal transduction. The vacuolar ATPase (V-ATPase) is one of the central players in pH control. All eukaryotic cells have V-ATPases of remarkably similar structure, and loss of V-ATPase function is lethal at early stages of development in higher eukaryotes and conditionally lethal in fungi.
The yeast V-ATPase has proven to be an excellent model for studies of V-ATPase structure, function, and regulation. Work in my laboratory addresses three major questions using yeast as a model system: 1) definition of functional and structural relationships among the fourteen subunits of the V-ATPase
2) regulation of the V-ATPase in vivo, 3) physiological implications of organelle acidification. We approach these questions using a combination of biochemical, genetic, molecular, and cell biological methods. Our studies of subunit structure and function combine traditional biochemistry and yeast genetics with insights from the growing number of complete eukaryotic genomes now available. Regulation of V-ATPases is proving to be rich and complex. Assembled V-ATPases can rapidly and reversibly dissociate in vivo in response to changes in growth conditions, and this appears to be a major regulatory mechanism. Current work is directed toward defining this signal transduction pathway and probing the possibility of crosstalk between V-ATPase regulation and other pathways and processes. Finally, V-ATPases are implicated in a number of unexpected roles, including resistance to oxidative stress. We seek to better understand these rolls and their links to overall cellular pH control.
Zhang Z, Zheng Y, Mazon H, Milgrom E, Kitagawa N, Kish-Trier E, Heck AJ, Kane PM, Wilkens S. Structure of the yeast vacuolar ATPase. J Biol Chem. 2008 Dec 19;283(51):35983-95. Epub 2008 Oct 27.
Chen S, Tarsio M, Kane PM, Greenberg ML. Cardiolipin mediates cross-talk between mitochondria and the vacuole. Mol Biol Cell. 2008 Dec;19(12):5047-58. Epub 2008 Sep 17.
Kane PM. The long physiological reach of the yeast vacuolar H+-ATPase. J Bioenerg Biomembr. 2007 Dec;39(5-6):415-21. Review.
Smardon AM, Kane PM. RAVE is essential for the efficient assembly of the C subunit with the vacuolar H(+)-ATPase. J Biol Chem. 2007 Sep 7;282(36):26185-94. Epub 2007 Jul 10.
Rizzo JM, Tarsio M, Martínez-Muñoz GA, Kane PM. Diploids heterozygous for a vma13Delta mutation in Saccharomyces cerevisiae highlight the importance of V-ATPase subunit balance in supporting vacuolar acidification and silencing cytosolic V1-ATPase activity. J Biol Chem. 2007 Mar 16;282(11):8521-32. Epub 2007 Jan 18.
Milgrom E, Diab H, Middleton F, Kane PM. Loss of vacuolar proton-translocating ATPase activity in yeast results in chronic oxidative stress. J Biol Chem. 2007 Mar 9;282(10):7125-36. Epub 2007 Jan 10.
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