Research Summary

I have spent 33 years doing research in therapeutic sciences and biotechnology development, first 16 years at Genentech and then 8 years at Sunesis (a company I founded) prior to joining UCSF 9 years ago. At Genentech, my group was among the first to develop gain-of-function engineering of enzymes and proteins by site-directed mutagenesis and phage display. At Sunesis, we developed novel technologies for fragment-based drug discovery, notably the site-directed approach Tethering. My lab at UCSF has developed the N-terminomics technology to characterize the caspase products cleaved during apoptosis. We currently have what we believe is the largest database of proteins that are cleaved by caspases (~2,000 targets in all), as well as targets cleaved in specific cells and their precise cleavage sites identified. More recently, we have extended our proteomics work to serum using the subtiligase tagging technology. This has allowed us to dive to very low abundance proteins in serum. We have also engineered a new small molecule activated protease, called the SNIPer. We have built a catalytic tagging device called the NEDDylator to interrogate molecular binding partners in cellular pathways involving E3 ligases. Recently, we have developed a motif-specific scaffold strategy for producing synthetic monoclonal antibodies specific to post-translational modifications. I am also Director of the Small Molecule Discovery Center (SMDC) at UCSF, a core facility that offers UCSF researchers access to modern small molecule discovery technologies including high-throughput screening, fragment-based drug discovery, and hit-to-lead medicinal chemistry. We have also built the Antibiome Center for generation of renewable recombinant antibodies to the proteome.

Research Funding

  • September 24, 2014 - August 31, 2019 - Antibody Research Technology Center , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P41CA196276
  • June 16, 2014 - May 31, 2019 - Affinity-directed tagging of protein binding partners in signaling , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01CA191018
  • April 1, 2007 - July 31, 2016 - Global Analysis of Proteolysis in Apoptosis , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01GM081051
  • March 1, 2014 - February 29, 2016 - Generation of recombinant thiopeptides to target antimicrobial-resistant bacteria , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21AI111662

Education

University of California, Berkeley, CA, B.A., 1973, Biochemistry
Washington State University, Ph.D., 1979, Biochemistry
Washington State University, Postdoc, 1979-1980, Chemistry
Stanford University Medical School, Postdoc, 1980-1982, Biochemistry

Honors & Awards

  • 1979-1981
    Damon M. Runyon - Walter Winchell Postdoctoral Fellowship
  • 1990
    Pfizer Award (given by the American Chemical Society for achievements in enzyme chemistry)
  • 1998
    Recipient of the Christian B. Anfinsin Award presented by the Protein Society
  • 1998
    Recipient of the Vincent du Vignead Award given by the American Peptide Society
  • 1999
    Elected Member to the National Academy of Sciences
  • 2003
    Recipient of the Hans Neurath Award given by the Protein Society
  • 2006
    Perlman Lecture Award of the ACS biotechnology Division
  • 2017
    Named to first cohort of Chan Zuckerberg Biohub Investigators

Selected Publications

  1. Zhao N, Chopra S, Trepka K, Wang YH, Sakhamuri S, Hooshdaran N, Kim H, Zhou J, Lim SA, Leung KK, Egusa EA, Zhu J, Zhang L, Foye A, Sriram R, Chan E, Seo Y, Feng FY, Small EJ, Chou J, Wells JA, Aggarwal R, Evans MJ. CUB Domain-Containing Protein 1 (CDCP1) Is a Target for Radioligand Therapy in Castration-Resistant Prostate Cancer, including PSMA Null Disease. Clin Cancer Res. 2022 07 15; 28(14):3066-3075.  View on PubMed
  2. Ferguson ID, Patiño-Escobar B, Tuomivaara ST, Lin YT, Nix MA, Leung KK, Kasap C, Ramos E, Nieves Vasquez W, Talbot A, Hale M, Naik A, Kishishita A, Choudhry P, Lopez-Girona A, Miao W, Wong SW, Wolf JL, Martin TG, Shah N, Vandenberg S, Prakash S, Besse L, Driessen C, Posey AD, Mullins RD, Eyquem J, Wells JA, Wiita AP. The surfaceome of multiple myeloma cells suggests potential immunotherapeutic strategies and protein markers of drug resistance. Nat Commun. 2022 07 15; 13(1):4121.  View on PubMed
  3. Jiang Z, Kuo YH, Zhong M, Zhang J, Zhou XX, Xing L, Wells JA, Wang Y, Arkin MR. Adaptor-Specific Antibody Fragment Inhibitors for the Intracellular Modulation of p97 (VCP) Protein-Protein Interactions. J Am Chem Soc. 2022 07 27; 144(29):13218-13225.  View on PubMed
  4. Li Z, Ferguson L, Deol KK, Roberts MA, Magtanong L, Hendricks JM, Mousa GA, Kilinc S, Schaefer K, Wells JA, Bassik MC, Goga A, Dixon SJ, Ingolia NT, Olzmann JA. Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability. Nat Chem Biol. 2022 07; 18(7):751-761.  View on PubMed
  5. Solomon PE, Kirkemo LL, Wilson GM, Leung KK, Almond MH, Sayles LC, Sweet-Cordero EA, Rosenberg OS, Coon JJ, Wells JA. Discovery Proteomics Analysis Determines That Driver Oncogenes Suppress Antiviral Defense Pathways Through Reduction in Interferon-β Autocrine Stimulation. Mol Cell Proteomics. 2022 07; 21(7):100247.  View on PubMed
  6. Gramespacher JA, Cotton AD, Burroughs PWW, Seiple IB, Wells JA. Roadmap for Optimizing and Broadening Antibody-Based PROTACs for Degradation of Cell Surface Proteins. ACS Chem Biol. 2022 05 20; 17(5):1259-1268.  View on PubMed
  7. Kirkemo LL, Elledge SK, Yang J, Byrnes JR, Glasgow JE, Blelloch R, Wells JA. Cell-surface tethered promiscuous biotinylators enable comparative small-scale surface proteomic analysis of human extracellular vesicles and cells. Elife. 2022 03 08; 11.  View on PubMed
  8. Martinko AJ, Simonds EF, Prasad S, Ponce A, Bracken CJ, Wei J, Wang YH, Chow TL, Huang Z, Evans MJ, Wells JA, Hill ZB. Switchable assembly and function of antibody complexes in vivo using a small molecule. Proc Natl Acad Sci U S A. 2022 03 01; 119(9).  View on PubMed
  9. Rettko NJ, Campisi J, Wells JA. Engineering Antibodies Targeting p16 MHC-Peptide Complexes. ACS Chem Biol. 2022 03 18; 17(3):545-555.  View on PubMed
  10. Byrnes JR, Weeks AM, Shifrut E, Carnevale J, Kirkemo L, Ashworth A, Marson A, Wells JA. Hypoxia Is a Dominant Remodeler of the Effector T Cell Surface Proteome Relative to Activation and Regulatory T Cell Suppression. Mol Cell Proteomics. 2022 04; 21(4):100217.  View on PubMed
  11. Lim SA, Zhou J, Martinko AJ, Wang YH, Filippova EV, Steri V, Wang D, Remesh SG, Liu J, Hann B, Kossiakoff AA, Evans MJ, Leung KK, Wells JA. Targeting a proteolytic neoepitope on CUB domain containing protein 1 (CDCP1) for RAS-driven cancers. J Clin Invest. 2022 02 15; 132(4).  View on PubMed
  12. Glasgow JE, Byrnes JR, Barbee SD, Moreau JM, Rosenblum MD, Wells JA. Identifying and antagonizing the interactions between layilin and glycosylated collagens. Cell Chem Biol. 2022 04 21; 29(4):597-604.e7.  View on PubMed
  13. Carruthers JE, Wells J, Gupta A, Kallon D, Cox A, Pina N, Yaqoob MM, Rajakariar R. Response to Vaccination Against SARS-CoV-2 in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis With Renal Involvement. Front Med (Lausanne). 2021; 8:817845.  View on PubMed
  14. Samelson AJ, Tran QD, Robinot R, Carrau L, Rezelj VV, Kain AM, Chen M, Ramadoss GN, Guo X, Lim SA, Lui I, Nuñez JK, Rockwood SJ, Wang J, Liu N, Carlson-Stevermer J, Oki J, Maures T, Holden K, Weissman JS, Wells JA, Conklin BR, TenOever BR, Chakrabarti LA, Vignuzzi M, Tian R, Kampmann M. BRD2 inhibition blocks SARS-CoV-2 infection by reducing transcription of the host cell receptor ACE2. Nat Cell Biol. 2022 01; 24(1):24-34.  View on PubMed
  15. Fong KP, Molnar KS, Agard N, Litvinov RI, Kim OV, Wells JA, Weisel JW, DeGrado WF, Bennett JS. Cleavage of talin by calpain promotes platelet-mediated fibrin clot contraction. Blood Adv. 2021 12 14; 5(23):4901-4909.  View on PubMed
  16. Ma Y, Chen K, Xia F, Atwal R, Wang H, Ahmed SU, Cardarelli L, Lui I, Duong B, Wang Z, Wells JA, Sidhu SS, Kelley SO. Phage-Based Profiling of Rare Single Cells Using Nanoparticle-Directed Capture. ACS Nano. 2021 12 28; 15(12):19202-19210.  View on PubMed
  17. Samelson AJ, Tran QD, Robinot R, Carrau L, Rezelj VV, Mac Kain A, Chen M, Ramadoss GN, Guo X, Lim SA, Lui I, Nunez J, Rockwood SJ, Wang J, Liu N, Carlson-Stevermer J, Oki J, Maures T, Holden K, Weissman JS, Wells JA, Conklin BR, TenOever BR, Chakrabarti LA, Vignuzzi M, Tian R, Kampmann M. BRD2 inhibition blocks SARS-CoV-2 infection by reducing transcription of the host cell receptor ACE2. bioRxiv. 2021 Sep 20.  View on PubMed
  18. Muller YD, Ferreira LMR, Ronin E, Ho P, Nguyen V, Faleo G, Zhou Y, Lee K, Leung KK, Skartsis N, Kaul AM, Mulder A, Claas FHJ, Wells JA, Bluestone JA, Tang Q. Precision Engineering of an Anti-HLA-A2 Chimeric Antigen Receptor in Regulatory T Cells for Transplant Immune Tolerance. Front Immunol. 2021; 12:686439.  View on PubMed
  19. Cotton AD, Wells JA, Seiple IB. Biotin as a Reactive Handle to Selectively Label Proteins and DNA with Small Molecules. ACS Chem Biol. 2021 Aug 19.  View on PubMed
  20. Kang E, Kadoch C, Rubenstein JL, Lanier LL, Wells JA. A functional mammalian display screen identifies rare antibodies that stimulate NK cell-mediated cytotoxicity. Proc Natl Acad Sci U S A. 2021 08 03; 118(31).  View on PubMed

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