David Pincus

Assistant Professor
Research Summary
David Pincus is an Assistant Professor in the Dept. of Molecular Genetics and Cell Biology. The Pincus lab is located in the Center for Physics of Evolving Systems on the 5th floor of GCIS. The Pincus Lab studies "System Mechanics of Cellular Stress Responses", defined as quantitative control processes cells employ to sense and respond to environmental and endogenous perturbations. David is trained in approaches in biochemistry, biophysics, genetics, and molecular, cell, computational, systems and synthetic biology. The lab uses budding yeast and cultured human cells as experimental models, and applies this toolkit to investigate three interconnected areas: 1) Hsf1, chaperones, and proteostasis networks 2) Stress responsive kinase signaling 3) Stress responsive gene expression The goal of the research program is to understand the establishment and maintenance of cell-level homeostasis.
Keywords
proteostasis, Hsf1, kinase, chaperone, Hsp70, Hsp40, Hsp90, Phosphorylation
Education
  • UC Berkeley, Berkeley, CA, BA Molecular & Cell Biology 12/2004
  • UCSF, San Francisco, CA, PhD Biochemistry 09/2012
  • Whitehead Institute, Cambridge, MA, 09/2018
Biosciences Graduate Program Association
Awards & Honors
  • 2007 - 2010 Graduate Research Felloship NSF
  • 2013 - 2015 Stewart Trust Cancer Fellowship Alexander and Margaret Stewart Trust
  • 2013 - 2018 Early Independence Award (DP5) NIH Office of the Director
Publications
  1. McCormick JW, Pincus D, Resnekov O, Reynolds KA. Strategies for Engineering and Rewiring Kinase Regulation. Trends Biochem Sci. 2019 Dec 19. View in: PubMed

  2. Bushkin GG, Pincus D, Morgan JT, Richardson K, Lewis C, Chan SH, Bartel DP, Fink GR. m6A modification of a 3' UTR site reduces RME1 mRNA levels to promote meiosis. Nat Commun. 2019 07 30; 10(1):3414. View in: PubMed

  3. Tye BW, Commins N, Ryazanova LV, Wühr M, Springer M, Pincus D, Churchman LS. Proteotoxicity from aberrant ribosome biogenesis compromises cell fitness. Elife. 2019 03 07; 8. View in: PubMed

  4. Chowdhary S, Kainth AS, Pincus D, Gross DS. Heat Shock Factor 1 Drives Intergenic Association of Its Target Gene Loci upon Heat Shock. Cell Rep. 2019 01 02; 26(1):18-28.e5. View in: PubMed

  5. Fanning S, Haque A, Imberdis T, Baru V, Barrasa MI, Nuber S, Termine D, Ramalingam N, Ho GPH, Noble T, Sandoe J, Lou Y, Landgraf D, Freyzon Y, Newby G, Soldner F, Terry-Kantor E, Kim TE, Hofbauer HF, Becuwe M, Jaenisch R, Pincus D, Clish CB, Walther TC, Farese RV, Srinivasan S, Welte MA, Kohlwein SD, Dettmer U, Lindquist S, Selkoe D. Lipidomic Analysis of a-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment. Mol Cell. 2019 03 07; 73(5):1001-1014.e8. View in: PubMed

  6. Pincus D, Pandey JP, Feder ZA, Creixell P, Resnekov O, Reynolds KA. Engineering allosteric regulation in protein kinases. Sci Signal. 2018 11 06; 11(555). View in: PubMed

  7. Pincus D, Anandhakumar J, Thiru P, Guertin MJ, Erkine AM, Gross DS. Genetic and epigenetic determinants establish a continuum of Hsf1 occupancy and activity across the yeast genome. Mol Biol Cell. 2018 12 15; 29(26):3168-3182. View in: PubMed

  8. Creixell P, Pandey JP, Palmeri A, Bhattacharyya M, Creixell M, Ranganathan R, Pincus D, Yaffe MB. Hierarchical Organization Endows the Kinase Domain with Regulatory Plasticity. Cell Syst. 2018 10 24; 7(4):371-383.e4. View in: PubMed

  9. Zheng X, Beyzavi A, Krakowiak J, Patel N, Khalil AS, Pincus D. Hsf1 Phosphorylation Generates Cell-to-Cell Variation in Hsp90 Levels and Promotes Phenotypic Plasticity. Cell Rep. 2018 03 20; 22(12):3099-3106. View in: PubMed

  10. Kayatekin C, Amasino A, Gaglia G, Flannick J, Bonner JM, Fanning S, Narayan P, Barrasa MI, Pincus D, Landgraf D, Nelson J, Hesse WR, Costanzo M. Translocon Declogger Ste24 Protects against IAPP Oligomer-Induced Proteotoxicity. Cell. 2018 03 22; 173(1):62-73.e9. View in: PubMed

  11. Solís EJ, Pandey JP, Zheng X, Jin DX, Gupta PB, Airoldi EM, Pincus D, Denic V. Defining the Essential Function of Yeast Hsf1 Reveals a Compact Transcriptional Program for Maintaining Eukaryotic Proteostasis. Mol Cell. 2018 02 01; 69(3):534. View in: PubMed

  12. Krakowiak J, Zheng X, Patel N, Feder ZA, Anandhakumar J, Valerius K, Gross DS, Khalil AS, Pincus D. Hsf1 and Hsp70 constitute a two-component feedback loop that regulates the yeast heat shock response. Elife. 2018 02 02; 7. View in: PubMed

  13. Zheng X, Pincus D. Serial Immunoprecipitation of 3xFLAG/V5-tagged Yeast Proteins to Identify Specific Interactions with Chaperone Proteins. Bio Protoc. 2017 Jun 20; 7(12). View in: PubMed

  14. Pincus D, Resnekov O, Reynolds KA. An evolution-based strategy for engineering allosteric regulation. Phys Biol. 2017 04 28; 14(2):025002. View in: PubMed

  15. Truttmann MC, Zheng X, Hanke L, Damon JR, Grootveld M, Krakowiak J, Pincus D, Ploegh HL. Unrestrained AMPylation targets cytosolic chaperones and activates the heat shock response. Proc Natl Acad Sci U S A. 2017 01 10; 114(2):E152-E160. View in: PubMed

  16. Zheng X, Krakowiak J, Patel N, Beyzavi A, Ezike J, Khalil AS, Pincus D. Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation. Elife. 2016 11 10; 5. View in: PubMed

  17. Pincus D. Size doesn't matter in the heat shock response. Curr Genet. 2017 May; 63(2):175-178. View in: PubMed

  18. Solís EJ, Pandey JP, Zheng X, Jin DX, Gupta PB, Airoldi EM, Pincus D, Denic V. Defining the Essential Function of Yeast Hsf1 Reveals a Compact Transcriptional Program for Maintaining Eukaryotic Proteostasis. Mol Cell. 2016 07 07; 63(1):60-71. View in: PubMed

  19. van Anken E, Pincus D, Coyle S, Aragón T, Osman C, Lari F, Gómez Puerta S, Korennykh AV, Walter P. Specificity in endoplasmic reticulum-stress signaling in yeast entails a step-wise engagement of HAC1 mRNA to clusters of the stress sensor Ire1. Elife. 2014 Dec 30; 3:e05031. View in: PubMed

  20. Damon JR, Pincus D, Ploegh HL. tRNA thiolation links translation to stress responses in Saccharomyces cerevisiae. Mol Biol Cell. 2015 Jan 15; 26(2):270-82. View in: PubMed

  21. Pincus D, Ryan CJ, Smith RD, Brent R, Resnekov O. Assigning quantitative function to post-translational modifications reveals multiple sites of phosphorylation that tune yeast pheromone signaling output. PLoS One. 2013; 8(3):e56544. View in: PubMed

  22. Vidal SE, Pincus D, Stewart-Ornstein J, El-Samad H. Formation of subnuclear foci is a unique spatial behavior of mating MAPKs during hyperosmotic stress. Cell Rep. 2013 Feb 21; 3(2):328-34. View in: PubMed

  23. Fordyce PM, Pincus D, Kimmig P, Nelson CS, El-Samad H, Walter P, DeRisi JL. Basic leucine zipper transcription factor Hac1 binds DNA in two distinct modes as revealed by microfluidic analyses. Proc Natl Acad Sci U S A. 2012 Nov 06; 109(45):E3084-93. View in: PubMed

  24. Thomson TM, Benjamin KR, Bush A, Love T, Pincus D, Resnekov O, Yu RC, Gordon A, Colman-Lerner A, Endy D, Brent R. Scaffold number in yeast signaling system sets tradeoff between system output and dynamic range. Proc Natl Acad Sci U S A. 2011 Dec 13; 108(50):20265-70. View in: PubMed

  25. Pincus D, Chevalier MW, Aragón T, van Anken E, Vidal SE, El-Samad H, Walter P. BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response. PLoS Biol. 2010 Jul 06; 8(7):e1000415. View in: PubMed

  26. Pincus D, Benjamin K, Burbulis I, Tsong AE, Resnekov O. Reagents for investigating MAPK signalling in model yeast species. Yeast. 2010 Jul; 27(7):423-30. View in: PubMed

  27. Aragón T, van Anken E, Pincus D, Serafimova IM, Korennykh AV, Rubio CA, Walter P. Messenger RNA targeting to endoplasmic reticulum stress signalling sites. Nature. 2009 Feb 05; 457(7230):736-40. View in: PubMed

  28. Yu RC, Pesce CG, Colman-Lerner A, Lok L, Pincus D, Serra E, Holl M, Benjamin K, Gordon A, Brent R. Negative feedback that improves information transmission in yeast signalling. Nature. 2008 Dec 11; 456(7223):755-61. View in: PubMed