University of California San Francisco
Helen Diller Family Comprehensive Cancer Center
Arthur Weiss, MD, PhD

Arthur Weiss, MD, PhD

Professor, Departments of Medicine, Microbiology and Immunology; Investigator, Howard Hughes Medical Institute, UCSF
Ephraim P. Engleman Distinguished Professorship, UCSF

Cancer Center Program Memberships

Cancer Immunology

Research Summary

I have studied signal transduction in lymphocytes for more than 30 years, with a recent focused interest in the role of cytoplasmic tyrosine kinases and transmembrane phosphatases, molecules critically important in normal lymphocyte responses to pathogens and in responses to tumors. Mutations of some of these molecules within the hematopoietic lineage can lead to malignant transformation. I have studied the influence of dysregulation of tyrosine kinases, particularly of ZAP-70, and phosphatases such as CD45 and CD148 in mouse models of lymphoproliferation, a frequent precursor of malignant transformation. My lab discovered ZAP-70, demonstrated its importance in T cell antigen receptor signaling, and was one of the first to report ZAP-70 mutations as a cause of human SCID. We have also collaborated with Tom Kipps (UCSD) on the expression of ZAP-70 in human Chronic Lymphocytic Leukemia (CLL) as a prognostic marker and have studied its role in CLL cells. We have established several mouse models of ZAP-70, Csk, and CD45 mutant alleles to understand the consequences of these alleles on lymphocyte signaling.

During my career, I have served on the Scientific Advisory Boards of several biotechnology companies. Two have successful FDA-approved therapies for malignancies. Sunitinib, whose early development occurred at Sugen and then at Pfizer, has been approved for renal cell carcinoma, gastrointestinal stromal tumors, and neuroendocrine pancreatic tumors. Plexxikon developed Vemurafinib, a pioneering targeted therapeutic for melanomas harboring the BRAF V600E mutation, which occurs in approximately half of melanoma patients. I am a cofounder of Nurix, Inc., which seeks to develop therapeutics for various malignancies by targeting ubiquitin ligases.

Education

University of Chicago, Chicago, IL, Ph.D., 1978, Immunology
University of Chicago, Chicago, IL, M.D., 1979, Medicine

Honors & Awards

  • 1997
    Lee C. Howley Prize, Arthritis Foundation
  • 1998
    Forty-First Faculty Research Lecturer, UCSF
  • 2001
    American Association of Immunologist-Huang Foundation Meritorious Career Award
  • 2003
    Fellow, American Academy of Arts and Sciences
  • 2004
    Member, National Academy of Sciences
  • 2004
    Fellow, American Academy of Microbiology
  • 2004
    Member, Institute of Medicine
  • 2004
    Distinguished Investigator Award, American College of Rheumatology
  • 2012
    Lifetime Achievement Award, American Association of Immunology
  • 2012
    UCSF Lifetime Achievement in Mentoring Award
  • 2017
    Associate Member, European Molecular Biology Organization
  • 2018
    Howard and Martha Holley Research Prize in Rheumatology
  • 2019
    AAI Distinguished Fellow, American Association of Immunologists
  • 2019
    Establishment of the Art Weiss Lectureship in Immunology and Rheumatology
  • 2019
    William B. Coley Award for Distinguished Research in Basic Immunology, Cancer Research Institute

Selected Publications

  1. Laura M. Nocka, Jean K. Chung, Aubrianna Decker, Theresa Kadlecek, Arthur Weiss, John Kuriyan, Jay T. Groves. Bruton's Tyrosine Kinase Membrane Dynamics and Signaling. Biophysical Journal. 2020 Feb 1; 118(3):560a-561a.
    View on PubMed
  2. Raman S. Ganti, Wan-Lin Lo, Darren McAffee, Jay T. Groves, Arthur Weiss, Arup K. Chakraborty. How the T Cell Signaling Network Processes Information to Discriminate between Self and Cognate Ligands. Biophysical Journal. 2020 Feb 1; 118(3):245a.
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  3. Courtney AH, Shvets AA, Lu W, Griffante G, Mollenauer M, Horkova V, Lo WL, Yu S, Stepanek O, Chakraborty AK, Weiss A. CD45 functions as a signaling gatekeeper in T cells. Sci Signal. 2019 10 22; 12(604).
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  4. Lo WL, Shah NH, Rubin SA, Zhang W, Horkova V, Fallahee IR, Stepanek O, Zon LI, Kuriyan J, Weiss A. Slow phosphorylation of a tyrosine residue in LAT optimizes T cell ligand discrimination. Nat Immunol. 2019 11; 20(11):1481-1493.
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  5. Ashouri JF, Hsu LY, Yu S, Rychkov D, Chen Y, Cheng DA, Sirota M, Hansen E, Lattanza L, Zikherman J, Weiss A. Reporters of TCR signaling identify arthritogenic T cells in murine and human autoimmune arthritis. Proc Natl Acad Sci U S A. 2019 09 10; 116(37):18517-18527.
    View on PubMed
  6. Wang Y, Huynh W, Skokan TD, Lu W, Weiss A, Vale RD. CRACR2a is a calcium-activated dynein adaptor protein that regulates endocytic traffic. J Cell Biol. 2019 05 06; 218(5):1619-1633.
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  7. Nagy Z, Vögtle T, Geer MJ, Mori J, Heising S, Di Nunzio G, Gareus R, Tarakhovsky A, Weiss A, Neel BG, Desanti GE, Mazharian A, Senis YA. The Gp1ba-Cre transgenic mouse: a new model to delineate platelet and leukocyte functions. Blood. 2019 01 24; 133(4):331-343.
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  8. Lo WL, Shah NH, Ahsan N, Horkova V, Stepanek O, Salomon AR, Kuriyan J, Weiss A. Lck promotes Zap70-dependent LAT phosphorylation by bridging Zap70 to LAT. Nat Immunol. 2018 07; 19(7):733-741.
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  9. Shah NH, Löbel M, Weiss A, Kuriyan J. Fine-tuning of substrate preferences of the Src-family kinase Lck revealed through a high-throughput specificity screen. Elife. 2018 03 16; 7.
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  10. Mori J, Nagy Z, Di Nunzio G, Smith CW, Geer MJ, Al Ghaithi R, van Geffen JP, Heising S, Boothman L, Tullemans BME, Correia JN, Tee L, Kuijpers MJE, Harrison P, Heemskerk JWM, Jarvis GE, Tarakhovsky A, Weiss A, Mazharian A, Senis YA. Maintenance of murine platelet homeostasis by the kinase Csk and phosphatase CD148. Blood. 2018 03 08; 131(10):1122-1144.
    View on PubMed
  11. Smith GA, Taunton J, Weiss A. IL-2Rß abundance differentially tunes IL-2 signaling dynamics in CD4+ and CD8+ T cells. Sci Signal. 2017 Dec 19; 10(510).
    View on PubMed
  12. Courtney AH, Lo WL, Weiss A. TCR Signaling: Mechanisms of Initiation and Propagation. Trends Biochem Sci. 2018 02; 43(2):108-123.
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  13. Courtney AH, Amacher JF, Kadlecek TA, Mollenauer MN, Au-Yeung BB, Kuriyan J, Weiss A. A Phosphosite within the SH2 Domain of Lck Regulates Its Activation by CD45. Mol Cell. 2017 Aug 03; 67(3):498-511.e6.
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  14. Hsu LY, Cheng DA, Chen Y, Liang HE, Weiss A. Destabilizing the autoinhibitory conformation of Zap70 induces up-regulation of inhibitory receptors and T cell unresponsiveness. J Exp Med. 2017 03 06; 214(3):833-849.
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  15. Au-Yeung BB, Smith GA, Mueller JL, Heyn CS, Jaszczak RG, Weiss A, Zikherman J. IL-2 Modulates the TCR Signaling Threshold for CD8 but Not CD4 T Cell Proliferation on a Single-Cell Level. J Immunol. 2017 03 15; 198(6):2445-2456.
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  16. Visperas PR, Wilson CG, Winger JA, Yan Q, Lin K, Arkin MR, Weiss A, Kuriyan J. Identification of Inhibitors of the Association of ZAP-70 with the T Cell Receptor by High-Throughput Screen. SLAS Discov. 2017 03; 22(3):324-331.
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  17. Ashouri JF, Weiss A. Endogenous Nur77 Is a Specific Indicator of Antigen Receptor Signaling in Human T and B Cells. J Immunol. 2017 01 15; 198(2):657-668.
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  18. Skrzypczynska KM, Zhu JW, Weiss A. Positive Regulation of Lyn Kinase by CD148 Is Required for B Cell Receptor Signaling in B1 but Not B2 B Cells. Immunity. 2016 12 20; 45(6):1232-1244.
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  19. Shah NH, Wang Q, Yan Q, Karandur D, Kadlecek TA, Fallahee IR, Russ WP, Ranganathan R, Weiss A, Kuriyan J. An electrostatic selection mechanism controls sequential kinase signaling downstream of the T cell receptor. Elife. 2016 10 04; 5.
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  20. Weiss A. Human LAT mutation results in immune deficiency and autoimmunity but also raises questions about signaling pathways. J Exp Med. 2016 06 27; 213(7):1114.
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