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.

Research Funding

  • May 18, 2020 - June 30, 2021 - Defining the Unique Properties of the Distinct Signaling Machinery Used by the TCR, Principal Investigator. Sponsor: NIH/NIAID, Sponsor Award ID: P01AI091580
  • July 1, 1978 - June 30, 2021 - Medical Scientist Training Program, Co-Principal Investigator. Sponsor: NIH/NIGMS, Sponsor Award ID: T32GM007618
  • December 8, 2015 - November 30, 2020 - The cell and molecular mechanisms underlying CD28 costimulation, Principal Investigator. Sponsor: NIH/NIAID, Sponsor Award ID: R37AI114575
  • December 8, 2015 - November 30, 2020 - The cell and molecular mechanisms underlying CD28 costimulation, Principal Investigator. Sponsor: NIH/NIAID, Sponsor Award ID: R01AI114575

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.  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.  View on PubMed
  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.  View on PubMed
  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.  View on PubMed
  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.  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.  View on PubMed
  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.  View on PubMed
  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.  View on PubMed
  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.  View on PubMed
  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.  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.  View on PubMed
  12. Courtney AH, Lo WL, Weiss A TCR Signaling: Mechanisms of Initiation and Propagation.  View on PubMed
  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.  View on PubMed
  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.  View on PubMed
  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.  View on PubMed
  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.  View on PubMed
  17. Ashouri JF, Weiss A Endogenous Nur77 Is a Specific Indicator of Antigen Receptor Signaling in Human T and B Cells.  View on PubMed
  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.  View on PubMed
  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.  View on PubMed
  20. Weiss A Human LAT mutation results in immune deficiency and autoimmunity but also raises questions about signaling pathways.  View on PubMed

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