Diane Barber, PhD

Professor & Chair
Department of Cell & Tissue Biology
+1 415 476-3764

Our research aims to understand basic cell biology processes and how they are dysregulated in diseases. We bridge structural and cell biology to reveal the molecular mechanisms of cell behaviors, with a focus on behaviors relevant to cancer cell biology, stem cell differentiation and neurodegeneration. Within this context we are determining how protein behaviors and cell functions are regulated by intracellular pH (pHi) and actin filament dynamics.

Cancer cell biology Cancer cells have a higher pHi than normal cells, which we showed is necessary for disease progression. We revealed in molecular detail how increased pHi is necessary for directed cell migration for metastasis by identifying the design principles and functional significance of selective pH sensors, defined a proteins regulated by cellular changes in pH. We are now addressing questions on how increased pHi enables tumorigenic behaviors, glycolytic enzymes for metabolic programming and the selection and retention of recurrent somatic mutations. Contributing to these studies is our unique expertise in investigating pHi dynamics and pHi-regulated cell processes combined with innovative approaches, including optogenetic tools for modulating pHi, genetically encoded biosensors to rigorously quantify pHi dynamics in single cells and in vivo, and computational programs for identifying titrating networks of ionizable residues in proteins as well as amino acid mutation signatures in cancer databases.

Stem cell differentiation In collaboration with the Todd Nystul lab we are determining how pHi and actin filament dynamics regulate stem cell differentiation, which remains understudied relative to the current focus on transcriptional and epigenetic regulation. We recently showed that daughter cells have a higher pHi than naïve adult and embryonic stem cells, and that this increase in pHi is necessary for stem cell differentiation. A current objective is to identify pH sensors necessary for stem cell differentiation. We also are characterizing how remodeling of actin filaments is necessary for differentiation of naïve embryonic stem cells to the primed state with a focus on how actin dynamics is linked to transcriptional events.

Neurodegeneration As part of a 4-lab collaboration with the groups of Aimee Kao, Matt Jacobson and Torsten Wittmann, we are determining how dysregulated cellular pH dynamics enables pathologies associated with Alzheimer’s Disease. Our studies include resolving molecular mechanisms that can be therapeutically targeted to reverse the effects of decreased intracellular pH and increased lysosomal pH that are seen with neurodegeneration.

Representative publications

Choi, C.C., Webb, B.A., Chimenti, M., Jacobson, M.P. and Barber, D.L. A molecular mechanism for pH sensing by FAK in focal adhesion remodeling. J Cell Biol. 2013 202:849-59.

LeClaire, L.L., Rana, M.K., Baumgartner, M. and Barber, D.L. 2015 Arp2 phosphorylation: Functional significance and regulation by the Nck-interacting kinase NIK. J. Cell. Biol. 208:161-170.

Webb, B.A., Forouhar, F., Szu, F.E., Seetharaman J.,  Tong L., Barber, D.L. 2015 Crystal structures of human phosphofructokinase-1 and atomic basis of cancer mutations. Nature 523:111-114. *co-first authors, ** co-corresponding authors

Ulmschneider, B., Grillo-Hill, B.K., Benitez, M., Azimova, D., Barber. D.L., Nystul, T.G. 2016 Increased intracellular pH is necessary for adult epithelial and embryonic stem cell differentiation. J. Cell Biol. (in press).

Primary Thematic Area: 
Cancer Biology & Cell Signaling
Secondary Thematic Area: 
Developmental & Stem Cell Biology
Research Summary: 
We investigate basic cell biology and how it is dysregulated in diseases. We bridge structural and cell biology to resolve cell behaviors relevant to cancer, stem cells and neurodegeneration.

Websites

Featured Publications: 

Structural model and functional significance of pH-dependent talin-actin binding for focal adhesion remodeling.

Proceedings of the National Academy of Sciences of the United States of America

Srivastava J, Barreiro G, Groscurth S, Gingras AR, Goult BT, Critchley DR, Kelly MJ, Jacobson MP, Barber DL

Cofilin is a pH sensor for actin free barbed end formation: role of phosphoinositide binding.

The Journal of cell biology

Frantz C, Barreiro G, Dominguez L, Chen X, Eddy R, Condeelis J, Kelly MJ, Jacobson MP, Barber DL

Phosphorylation of the Arp2/3 complex is necessary to nucleate actin filaments.

The Journal of cell biology

LeClaire LL, Baumgartner M, Iwasa JH, Mullins RD, Barber DL

Dysregulated pH: a perfect storm for cancer progression.

Nature reviews. Cancer

Webb BA, Chimenti M, Jacobson MP, Barber DL

Considering protonation as a posttranslational modification regulating protein structure and function.

Annual review of biophysics

Schönichen A, Webb BA, Jacobson MP, Barber DL