Function and regulation of calcium and manganese homeostasis and signaling by secretory pathway calcium-ATPases

Ca2+ and Mn2+ ions are important signaling molecules and co-factors for many enzymes, carrying out many essential biological functions in the cells. Dysregulation of Ca2+ and/or Mn 2+ homeostasis leads to defects in many aspects of physiological processes, causing various diseases including cancers. Secretory Pathway Ca2+ -ATPases (SPCA) regulate Ca2+ and Mn2+ content in the Golgi store, and their secretion through the secretory pathways.;In this thesis we identified a unique function of SPCA2 in regulation of Ca2+ signaling which is necessary for oncogenic activities of breast cancer cells, and investigated the roles of SPCA1 in Mn2+ detoxification in liver cells. Chapter 1 is an introduction and a review of the biological functions of Ca2+, Mn2+ ions as well as SPCA pumps. Chapter II identifies a novel Ca2+ signaling pathway mediated by SPCA2 and a Ca2+-channel Orail, which is necessary for breast cancer cell proliferation and tumorigenesis. Next, chapter III uncovers the molecular mechanism of SPCA2-Orail interaction and activation. Chapter IV reveals vesicular distribution of SPCA1 proteins and their functions of Mn2+ transporting in rat liver and liver-derived polarized cells. Finally, Chapter V summarizes the reagents and methods used for the experiments presented in the thesis.