Research Summary

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.

Research Funding

  • June 1, 2016 - May 31, 2022 - Roles for Intracellular pH Dynamics in Cancer , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01CA197855
  • July 1, 2015 - June 30, 2019 - Regulation of Epithelial Plasticity , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01GM116384
  • July 1, 2013 - June 30, 2015 - Retention of somatic mutations in cancers by changes in pH sensing , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21CA178706
  • January 1, 1993 - May 31, 2015 - Mechanisms of Receptor Regulated Na+-H+ Exchange , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01GM047413
  • August 1, 1999 - November 30, 2013 - Actions of the Sodium-Hydrogen Exchanger Subtype, NHE1 , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01GM058642
  • February 1, 2007 - September 30, 2011 - Mechanotransduction in Fibroblast , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01GM071526
  • September 21, 1987 - December 31, 2002 - SIGNALING MECHANISMS OF SOMATOSTATIN RECEPTORS , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01DK040259
  • May 1, 1989 - April 30, 1993 - MECHANISMS REGULATING INTESTINAL NEUROTENSIN EXPRESSION , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01DK041371
  • September 21, 1987 - March 31, 1993 - REGULATION OF NEUROTENSIN-CONTAINING ENTERIC CELLS , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R29DK040259
  • September 1, 1986 - January 1, 1900 - VIP RELEASE FROM ENTERIC NEURONS IN CULTURE , Principal Investigator . Sponsor: NIH, Sponsor Award ID: F32DK007662
  • September 1, 1985 - January 1, 1900 - VIP RELEASE FROM ENTERIC NEURONS IN CULTURE , Principal Investigator . Sponsor: NIH, Sponsor Award ID: F32AM007662

Education

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

Honors & Awards

  • 2022
    UCSF Annual Academic Senate Faculty Research Lecture Translational Science Award
  • 2020-present
    Editorial Board, Current Opinion in Cell Biology
  • 2020
    Excellence in Research and Mentoring Award, John Greene Society of School of Dentistry Students
  • 2020,2021
    Annual Student Invited Speaker. 2020 Department of Biochemistry and Molecular Biology, Johns Hopkins University; 2021 Program in Molecular Cell Biology, Brown University
  • 2019
    Keynote Speaker, International Society for Cancer Metabolism (ISCaM) meeting, Portugal
  • 2018-present
    Scientific Advisory Board European Consortium on pH and Ion Transport in Pancreatic Cancer
  • 2018
    Invited speaker and panel participant for NIH Strategic Workshop on Imaging Subcellular to Cellular Cancer Biology
  • 2017
    Keynote Speaker, Hunter Conference on Cell Biology, Australia
  • 2017-present
    Associate Editor, Molecular Biology of the Cell
  • 2016-2021
    Scientific Advisory Board Max Planck Institute for Experimental Medicine
  • 2016
    NIH Workshop on Advancing Women in Independent Careers, Speaker
  • 2016-2019
    Chair, Women in Cell Biology (WICB) for American Society of Cell Biology (ASCB)
  • 2013
    Faculty Research Lecture Award, UCSF School of Dentistry
  • 2013-present
    UCSF Discovery Fellows Advisory Council
  • 2012
    Outstanding Faculty Mentor Award, UCSF Postdoctoral Scholars Association
  • 2012
    Elected AAAS Fellow
  • 2010-2022
    Leland A. and Gladys K. Barber Endowed Chair in Dentistry
  • 2008
    Annual Student Invited Speaker, Molecular and Cellular Biochemistry, University of Kentucky
  • 2001-2003
    Vice-chair/Chair, Gordon Research Conference on Molecular Pharmacology
  • 1998
    Innovation in Basic Sciences Award, UCSF
  • 1997-present
    Editorial Board, American Journal of Physiology: Cell Physiology and Journal of Molecular Signaling
  • 1995-2000
    Established Investigator, American Heart Association
  • 1986
    Joseph P. Healy Research Award, University of Massachusetts Medical Center

Selected Publications

  1. Meyer NP, Singh T, Kutys ML, Nystul TG, Barber DL. Arp2/3 complex activity enables nuclear YAP for naïve pluripotency of human embryonic stem cells. Elife. 2024 Sep 25; 13.  View on PubMed
  2. Kisor KP, Ruiz DG, Jacobson MP, Barber DL. A role for pH dynamics regulating transcription factor DNA binding selectivity. bioRxiv. 2024 May 21.  View on PubMed
  3. Tsai YL, Arias-Badia M, Kadlecek TA, Lwin YM, Srinath A, Shah NH, Wang ZE, Barber D, Kuriyan J, Fong L, Weiss A. TCR signaling promotes formation of an STS1-Cbl-b complex with pH-sensitive phosphatase activity that suppresses T cell function in acidic environments. Immunity. 2023 12 12; 56(12):2682-2698.e9.  View on PubMed
  4. Liu Y, Reyes E, Castillo-Azofeifa D, Klein OD, Nystul T, Barber DL. Intracellular pH dynamics regulates intestinal stem cell lineage specification. Nat Commun. 2023 06 23; 14(1):3745.  View on PubMed
  5. Kyle Kisor, Diane Barber. pH dynamics regulates transcription factor-DNA binding. Biophysical Journal. 2023 Feb 1; 122(3):214a-215a.  View on PubMed
  6. Aloisio FM, Barber DL. Arp2/3 complex activity is necessary for mouse ESC differentiation, times formative pluripotency, and enables lineage specification. Stem Cell Reports. 2022 06 14; 17(6):1318-1333.  View on PubMed
  7. Sesanto R, Kuehn JF, Barber DL, White KA. Low pH Facilitates Heterodimerization of Mutant Isocitrate Dehydrogenase IDH1-R132H and Promotes Production of 2-Hydroxyglutarate. Biochemistry. 2021 06 29; 60(25):1983-1994.  View on PubMed
  8. Manoli SS, Kisor K, Webb BA, Barber DL. Ethyl isopropyl amiloride decreases oxidative phosphorylation and increases mitochondrial fusion in clonal untransformed and cancer cells. Am J Physiol Cell Physiol. 2021 07 01; 321(1):C147-C157.  View on PubMed
  9. Webb BA, Aloisio FM, Charafeddine RA, Cook J, Wittmann T, Barber DL. pHLARE: a new biosensor reveals decreased lysosome pH in cancer cells. Mol Biol Cell. 2021 01 15; 32(2):131-142.  View on PubMed
  10. Luna LA, Lesecq Z, White KA, Hoang A, Scott DA, Zagnitko O, Bobkov AA, Barber DL, Schiffer JM, Isom DG, Sohl CD. An acidic residue buried in the dimer interface of isocitrate dehydrogenase 1 (IDH1) helps regulate catalysis and pH sensitivity. Biochem J. 2020 08 28; 477(16):2999-3018.  View on PubMed
  11. Liu Y, White KA, Barber DL. Intracellular pH Regulates Cancer and Stem Cell Behaviors: A Protein Dynamics Perspective. Front Oncol. 2020; 10:1401.  View on PubMed
  12. Barber DL, Trepat X. Editorial overview: Cell dynamics: Integrating cell dynamics across scales. Curr Opin Cell Biol. 2020 10; 66:130-132.  View on PubMed
  13. Bradley Webb, Anne Dosey, Torsten Wittmann, Justin Kollmann, Diane Barber. Filament assembly by the liver phosphofructokinase-1, the “gatekeeper” of glycolysis. The FASEB Journal. 2020 Apr 1; 34(S1):1-1.  View on PubMed
  14. White KA, Kisor K, Barber DL. Intracellular pH dynamics and charge-changing somatic mutations in cancer. Cancer Metastasis Rev. 2019 06; 38(1-2):17-24.  View on PubMed
  15. Benitez M, Tatapudy S, Liu Y, Barber DL, Nystul TG. Drosophila anion exchanger 2 is required for proper ovary development and oogenesis. Dev Biol. 2019 08 15; 452(2):127-133.  View on PubMed
  16. Charafeddine RA, Cortopassi WA, Lak P, Tan R, McKenney RJ, Jacobson MP, Barber DL, Wittmann T. Tau repeat regions contain conserved histidine residues that modulate microtubule-binding in response to changes in pH. J Biol Chem. 2019 05 31; 294(22):8779-8790.  View on PubMed
  17. White KA, Grillo-Hill BK, Esquivel M, Peralta J, Bui VN, Chire I, Barber DL. β-Catenin is a pH sensor with decreased stability at higher intracellular pH. J Cell Biol. 2018 11 05; 217(11):3965-3976.  View on PubMed
  18. Rana MK, Aloisio FM, Choi C, Barber DL. Formin-dependent TGF-β signaling for epithelial to mesenchymal transition. Mol Biol Cell. 2018 06 15; 29(12):1465-1475.  View on PubMed
  19. Bradley Webb, Annie Dosey, Torsten Wittmann, Justin Kollman, Diane Barber. The Glycolytic Enzyme Phosphofructokinase-1 Assembles into Filaments. Biophysical Journal. 2018 Feb 1; 114(3):228a.  View on PubMed
  20. Tatapudy S, Aloisio F, Barber D, Nystul T. Cell fate decisions: emerging roles for metabolic signals and cell morphology. EMBO Rep. 2017 12; 18(12):2105-2118.  View on PubMed

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