Diane L. Barber, PhD
Leland and Gladys Barber Endowed Chair in Dentistry, UCSF
Professor and Chair, Department of Cell and Tissue Biology, UCSF
A major aspect our research program is determining in molecular detail how intracellular (cytoplasmic) pH (pHi) dynamics regulates cell behaviors, with a focus on epithelial plasticity. Although pHi was previously thought to be relatively constant as a homeostatic mechanism, we now know that pHi changes during normal cell cycle progression, cell migration, and cell differentiation. Moreover, pHi is dysregulated in diseases, including being constitutively increased in cancers and decreased in neurodegenerative disorders. The molecular mechanisms mediating pHi-regulated cell behaviors, however, remain understudied and largely unknown. Our work bridges protein electrostatics and structure with cell biology to reveal how pHi dynamics regulates cell behaviors through protonation of titrating amino acids as a post-translational modification to regulate protein structure and function (Schönichen et al., 2013 Ann Rev Biophys. 42:289). We have revealed the design principles and functions of “pH sensors” described as endogenous proteins regulated within the cellular pH range, including guanine nucleotide exchange factors regulating cell polarity (Frantz et al., 2007 J Cell Biol. 179:403), cofilin controlling actin assemblies (Frantz et al., 2008 J Cell Biol. 183:865), b-catenin regulating tumorigenesis (White et al., 2018 J Cell Biol. 217:3965), and talin (Srivastava et al., 2008 Proc Natl Acad Sci. 105:14436) and the focal adhesion kinase FAK (Choi et al., 2013 J Cell Biol. 202:849) controlling cell-substrate adhesion.
We also found that increased pHi is necessary for adult and embryonic stem cell differentiation as well as lineage specification (Ulmschneider et al., 2016 J Cell Biol. 215:345-355; Benitez et al., 2019 Dev Biol. 452:127s; Liu et al., bioRxiv https://doi.org/10.1101/2021.10.28.466337). Through our work we developed new genetically encoded pHi biosensors that we used in clonal cells (Choi et al., 2013 J Cell Biol. 202:849) as well as in model organisms (Grillo-Hill et al., 2015 eLife. 4:e03270; Ulmschneider et al., 2016 J Cell Biol. 215:345-355). Our recent new direction is addressing questions on the role of lysosome pH (pHlys) dynamics in cancers and neurodegenerative disorders. These studies include generating the first genetically encoded and ratiometric pHlys biosensor (Webb, et al., 2021 Mol Biol Cell 32:131). The high impact our pioneering work bridging protein electrostatics and cell biology is highlighted by our publication h-index of 46.
University of California, Davis, B.S., 1975, Biological Sciences
University of California, Davis, M.S., 1977, Physiology
University of California, Los Angeles, Ph.D., 1985, Anatomy