Michael Forgac, Ph.D.

Our laboratory is focused on understanding the regulation and function of the vacuolar ATPases (V-ATPases) in normal and disease processes. The V-ATPases are a family of ATP-driven proton pumps which function in such processes as intracellular membrane traffic, bone resorption and renal acidification, as well as in many disease processes, including viral infection, bone disease and cancer. Our laboratory is employing a variety of biochemical, genetic and cell biological approaches to understand how assembly of the V-ATPases is regulated in mammalian cells and the role that V-ATPases play in nutrient sensing and energy homeostasis. In particular, we are interested in their role in controlling two central regulators of cell growth and metabolism, namely AMPK and mTOR. We are also investigating the role of V-ATPases in tumor cell invasion and survival using both in vitro cell culture models and in vivo mouse models, with the ultimate aim of developing therapeutic agents to inhibit tumor growth and metastasis. The long term aim of this work is to explore the V-ATPase as a potential therapeutic target in treating human diseases such as neurodegenerative diseases and cancer. The V-ATPases are large, multisubunit complexes composed of two domains. The peripheral V1 domain carries out ATP hydrolysis while the integral V0 domain is responsible for proton translocation. We are investigating how V-ATPase activity is controlled in vivo, and have recently demonstrated that regulated assembly of the V-ATPase in lysosomes occurs in mammalian cells in response to changes in glucose and amino acid availability. These changes appear to be important in the homeostatic response of cells to nutrient starvation. We have also demonstrated that highly invasive breast tumor cells over-express isoforms of subunit a that are able to target V-ATPases to the cell surface and that these plasma membrane V-ATPases play a critical role in enhancing the invasiveness of the highly metastatic cells. We are exploring whether disrupting these plasma membrane-targeting isoforms of the V-ATPase are able to inhibit breast cancer metastasis in vivo.