Clare Boothe Luce Assistant Professor in the Department of Chemistry and Biochemistry
University of Notre Dame
The White Lab is studying how intracellular pH dynamics regulate proteins, pathways and cell behaviors, with approaches across experimental scales. We apply the results of our work to answer fundamental questions about the molecular mechanisms driving cancer cell behaviors and how those mechanisms can be exploited for more effective and safer cancer therapies.
Transient increases in intracellular pH (pHi) are necessary for normal cell processes of cell-cycle progression, migration, and differentiation while dysregulated pHi dynamics are linked to diseases such as neurodegeneration and cancer. While the effects of pHi on global cell behaviors is well established, the proteins and molecular mechanisms that drive these pH-sensitive responses are largely unknown. Furthermore, a lack of tools to directly, specifically, and spatiotemporally manipulate pHi has restricted experiments probing how pH dynamics alter individual cell behaviors. Finally, decreasing pHi can limit tumor progression in some models, but criteria to identify cancer subtypes or patients that would benefit from pHi-lowering drugs are critically needed.
A long-term goal of our research is to understand how protonation events are integrated to induce coordinated changes from proteins, to macromolecular assemblies, to cell behaviors and complex tissue-level effects. To address this goal, we are performing interdisciplinary research across experimental scales. At the molecular scale, we are identifying pH-sensing mechanisms utilized by both wildtype and mutant proteins. At the cellular scale, we are developing new optogenetic tools to spatiotemporally manipulate pHi in living cells to better understand how pHi changes are communicated between cells. At the evolutionary scale, we are interested in understanding how the constitutively increased pHi of cancer shapes the mutational landscape of human cancers.
- Sesanto R*, Kuehn JF*, Barber DL, White, K.A.. Low pH Facilitates Heterodimerization of Mutant Isocitrate Dehydrogenase IDH1-R132H and Promotes Production of 2Hydroxyglutarate. Biochemistry. 2021. PMID:34143606.
- Czowski BJ*, Romero-Moreno*, Trull KJ*, White, K.A.. Cancer and pH dynamics: Transcriptional regulation, proteostasis, and the need for new molecular tools. Cancers 12(10) 2760 (2020). PMID: 32992762.
- Luna, LA, Lesecq Z, White, K.A., 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 477(16):2999-3018 (2020). PMID: 32729927.
- White, K.A., Kisor K, Barber D. L. Intracellular pH dynamics and charge-changing somatic mutations in cancer. 2019 Cancer Metastasis Rev. 38(1-2):17-24. DOI: 10.1007/s10555-019-09791-8.
- White, K. A.; Grillo-Hill, B. K.; Esquivel, M.; Peralta, J.; Bui, V. N.; Chire, I.; Barber, D. L. "β-catenin is a pH sensor with decreased stability at higher intracellular pH." 2018 Journal of Cell Biology 217(11):3965. DOI: 10.1083/jcb.201712041
- Vercoulen, Y., Kondo, Y., Iwig, J.S., Janssen, A.B., White, K.A., Amini, M., Barber, D.L., Kuriyan, J., Roose, J.P. "A histidine pH sensor regulates activation of the Ras-specific guanine nucleotide exchange factor RasGRP1" 2017 eLife, 6, e29002. DOI: 10.7554/eLife.29002
- White, K.A., Ruiz, D.G., Szpiech, Z.A., Strauli, N.B., Hernandez, R.D., Jacobson, M.P., Barber, D.L. "Cancer-associated arginine-to-histidine mutations confer a gain in pH sensing to mutant proteins" 2017 Science Signaling, 10 (495), eaam9931. DOI: 10.1126/scisignal.aam9931
- Szpiech, Z.A., Strauli, N.B., White, K.A., Ruiz, D.G., Jacobson, M.P., Barber, D.L., Hernandez, R.D. "Prominent features of the amino acid mutation landscape in cancer" 2017 PLoS ONE, 12 (8), e0183273. DOI: 10.1371/journal.pone.0183273
- White, K.A., Grillo-Hill, B.K., Barber, D.L. "Cancer cell behaviors mediated by dysregulated pH dynamics at a glance" 2017 Journal of Cell Science, 130 (4), pp. 663-669. DOI: 10.1242/jcs.195297
- Webb, B.A., White, K.A., Grillo-Hill, B.K., Schönichen, A., Choi, C., Barber, D.L. "A histidine cluster in the cytoplasmic domain of the Na-H exchanger NHE1 confers pH-sensitive phospholipid binding and regulates transporter activity" 2016 Journal of Biological Chemistry, 291 (46), pp. 24096-24104. DOI: 10.1074/jbc.M116.736215