Investigating the Mechanisms of pH-dependent Protein Regulation

Transient changes in intracellular pH (pHi) regulate normal cell behaviors such as migration, differentiation, proliferation, and apoptosis. While pHi dynamics regulate normal cell biology, dysregulated pHi is associated with cancer and neurological disorders. There are a few characterized pHi-associated cell behaviors that have identified pH sensitive proteins (pH sensors) with known mechanisms of pH sensing; however, for many pHi-associated processes the essential pH sensing proteins are unknown. In recent years, the first pH sensor with pH-dependent abundance was identified (ß-catenin). In conjunction with established roles for protein abundance in regulating biological processes and disease phenotypes, it is crucial to understand how pHi dynamics drive broad proteomic changes. Additionally, neither global gene expression profiles nor the cellular proteome have ever been explored in the context of pHi. The use of global transcriptomic and proteomic approaches can identify gene expression and protein abundance differences that are regulated by pHi, providing a holistic view of pH-sensitive pathways and proteins that regulate pH-dependent cell phenotypes. By identifying the pathways and proteins that are regulated by changes in pHi, we will more rapidly characterize novel pH sensors and determine the mechanisms by which pHi regulates cell phenotype. Identification of new pH-sensitive proteins and pathways could reveal new therapeutic targets associated with diseases where pHi is dysregulated, including cancer (increased pHi) and neurodegeneration (decreased pHi).