University of California San Francisco
Helen Diller Family Comprehensive Cancer Center
Jason E. Gestwicki, PhD

Jason E. Gestwicki, PhD

Associate Professor, Pharmaceutical Chemistry, UCSF

Cancer Center Program Memberships

Experimental Therapeutics

Research Summary

The Gestwicki Laboratory is interested in molecular chaperones, protein homeostasis and protein misfolding disorders. To approach the big questions in this area, we use a chemical biology strategy that includes the discovery and optimization of new chemical inhibitors. We use these chemical probes to acutely perturb chaperone functions, revealing how these systems normally protect from cancer and neurodegeneration. Many of our chemical probes target allosteric and protein-protein interaction sites on the molecular chaperones and we have a significant interest in discovering inhibitors of "difficult" targets. We hope to better understand the logic of protein folding and misfolding and use this information to design more effective therapies.

Education

State University of New York - Fredonia, B.S., 1997, Chemistry
University of Wisconsin – Madison (with Laura L. Kiessling), PhD, 2002, Biochemistry
Stanford University (with Gerald R. Crabtree), 2005, Post-doctoral, Chemical Biology


Professional Experience

  • 2013 – present
    University of California at San Francisco Associate Professor in Residence, Department of Pharmaceutical Chemistry Associate Professor, Institute for Neurodegenerative Diseases
  • 2011 - 2013
    University of Michigan Associate Professor, Departments of Pathology and Biological Chemistry William B. Pratt Collegiate Professor, Life Sciences Institute Director, Center for Chemical Genomics (CCG)
  • 2005 – 2011
    University of Michigan Assistant Professor, Departments of Pathology and Biological Chemistry Research Assistant Professor, Life Sciences Institute

Honors & Awards

  • 2015
    UCSF School of Pharmacy, Excellence in Teaching
  • 2014
    Named “Young Innovator” at UCSF
  • 2012
    Elected Fellow, American Association for the Advancement of Science (AAAS)
  • 2009
    National Science Foundation CAREER award
  • 2006
    McKnight Foundation Brain Disorders Award (with Andrew Lieberman and William Pratt)
  • 2005
    Biological Sciences Scholar (University of Michigan)
  • 2001
    Sigrid Liermo Award (Departmental Service; UW Madison)
  • 1998
    National Institutes of Health Biotechnology Training Program Fellowship

Selected Publications

  1. Freilich R, Arhar T, Abrams JL, Gestwicki JE. Protein-Protein Interactions in the Molecular Chaperone Network. Acc Chem Res. 2018 Apr 03.
    View on PubMed
  2. Min SW, Sohn PD, Li Y, Devidze N, Johnson JR, Krogan NJ, Masliah E, Mok SA, Gestwicki JE, Gan L. SIRT1 Deacetylates Tau and Reduces Pathogenic Tau Spread in a Mouse Model of Tauopathy. J Neurosci. 2018 Apr 11; 38(15):3680-3688.
    View on PubMed
  3. Taylor IR, Dunyak BM, Komiyama T, Shao H, Ran X, Assimon VA, Kalyanaraman C, Rauch JN, Jacobson MP, Zuiderweg ERP, Gestwicki JE. High Throughput Screen for Inhibitors of Protein-Protein Interactions in a Reconstituted Heat Shock Protein 70 (Hsp70) Complex. J Biol Chem. 2018 Feb 02.
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  4. Young ZT, Mok SA, Gestwicki JE. Therapeutic Strategies for Restoring Tau Homeostasis. Cold Spring Harb Perspect Med. 2018 Jan 02; 8(1).
    View on PubMed
  5. Cesa LC, Shao H, Srinivasan SR, Tse E, Jain C, Zuiderweg ERP, Southworth DR, Mapp AK, Gestwicki JE. X-linked inhibitor of apoptosis protein (XIAP) is a client of heat shock protein 70 (Hsp70) and a biomarker of its inhibition. J Biol Chem. 2018 Feb 16; 293(7):2370-2380.
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  6. Srinivasan SR, Cesa LC, Li X, Julien O, Zhuang M, Shao H, Chung J, Maillard I, Wells JA, Duckett CS, Gestwicki JE. Heat Shock Protein 70 (Hsp70) Suppresses RIP1-Dependent Apoptotic and Necroptotic Cascades. Mol Cancer Res. 2018 Jan; 16(1):58-68.
    View on PubMed
  7. Rauch JN, Olson SH, Gestwicki JE. Interactions between Microtubule-Associated Protein Tau (MAPT) and Small Molecules. Cold Spring Harb Perspect Med. 2017 Jul 05; 7(7).
    View on PubMed
  8. Pricer R, Gestwicki JE, Mapp AK. From Fuzzy to Function: The New Frontier of Protein-Protein Interactions. Acc Chem Res. 2017 Mar 21; 50(3):584-589.
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  9. Zuiderweg ER, Hightower LE, Gestwicki JE. The remarkable multivalency of the Hsp70 chaperones. Cell Stress Chaperones. 2017 Mar; 22(2):173-189.
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  10. Rauch JN, Tse E, Freilich R, Mok SA, Makley LN, Southworth DR, Gestwicki JE. BAG3 Is a Modular, Scaffolding Protein that physically Links Heat Shock Protein 70 (Hsp70) to the Small Heat Shock Proteins. J Mol Biol. 2017 01 06; 429(1):128-141.
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  11. Costa MDC, Ashraf NS, Fischer S, Yang Y, Schapka E, Joshi G, McQuade TJ, Dharia RM, Dulchavsky M, Ouyang M, Cook D, Sun D, Larsen MJ, Gestwicki JE, Todi SV, Ivanova MI, Paulson HL. Unbiased screen identifies aripiprazole as a modulator of abundance of the polyglutamine disease protein, ataxin-3. Brain. 2016 11 01; 139(11):2891-2908.
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  12. Zuiderweg ER, Gestwicki JE. Backbone and methyl resonance assignments of the 42 kDa human Hsc70 nucleotide binding domain in the ADP state. Biomol NMR Assign. 2017 04; 11(1):11-15.
    View on PubMed
  13. Gabai VL, Yaglom JA, Wang Y, Meng L, Shao H, Kim G, Colvin T, Gestwicki J, Sherman MY. Anticancer Effects of Targeting Hsp70 in Tumor Stromal Cells. Cancer Res. 2016 10 15; 76(20):5926-5932.
    View on PubMed
  14. Young ZT, Rauch JN, Assimon VA, Jinwal UK, Ahn M, Li X, Dunyak BM, Ahmad A, Carlson GA, Srinivasan SR, Zuiderweg ER, Dickey CA, Gestwicki JE. Stabilizing the Hsp70-Tau Complex Promotes Turnover in Models of Tauopathy. Cell Chem Biol. 2016 Aug 18; 23(8):992-1001.
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  15. Rauch JN, Zuiderweg ER, Gestwicki JE. Non-canonical Interactions between Heat Shock Cognate Protein 70 (Hsc70) and Bcl2-associated Anthanogene (BAG) Co-Chaperones Are Important for Client Release. J Biol Chem. 2016 09 16; 291(38):19848-57.
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  16. Ouimet CM, Shao H, Rauch JN, Dawod M, Nordhues B, Dickey CA, Gestwicki JE, Kennedy RT. Protein Cross-Linking Capillary Electrophoresis for Protein-Protein Interaction Analysis. Anal Chem. 2016 Aug 16; 88(16):8272-8.
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  17. Dunyak BM, Gestwicki JE. Peptidyl-Proline Isomerases (PPIases): Targets for Natural Products and Natural Product-Inspired Compounds. J Med Chem. 2016 Nov 10; 59(21):9622-9644.
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  18. Sabnis AJ, Guerriero CJ, Olivas V, Sayana A, Shue J, Flanagan J, Asthana S, Paton AW, Paton JC, Gestwicki JE, Walter P, Weissman JS, Wipf P, Brodsky JL, Bivona TG. Combined chemical-genetic approach identifies cytosolic HSP70 dependence in rhabdomyosarcoma. Proc Natl Acad Sci U S A. 2016 08 09; 113(32):9015-20.
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  19. Morozova K, Clement CC, Kaushik S, Stiller B, Arias E, Ahmad A, Rauch JN, Chatterjee V, Melis C, Scharf B, Gestwicki JE, Cuervo AM, Zuiderweg ER, Santambrogio L. Structural and Biological Interaction of hsc-70 Protein with Phosphatidylserine in Endosomal Microautophagy. J Biol Chem. 2016 08 26; 291(35):18096-106.
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  20. Martin MD, Baker JD, Suntharalingam A, Nordhues BA, Shelton LB, Zheng D, Sabbagh JJ, Haystead TA, Gestwicki JE, Dickey CA. Inhibition of Both Hsp70 Activity and Tau Aggregation in Vitro Best Predicts Tau Lowering Activity of Small Molecules. ACS Chem Biol. 2016 07 15; 11(7):2041-8.
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