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


Professional Experience

  • 1979-1980
    Postdoctoral Fellow, Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland
  • 1980-1982
    Resident, Department of Medicine, University of California, San Francisco (UCSF)
  • 1982-1984
    Fellow in Rheumatology/Clinical Immunology, UCSF
  • 1982-1985
    Associate, Howard Hughes Medical Institute, UCSF
  • 1984-1985
    Instructor, Department of Medicine, Division of Rheumatology/Clinical Immunology, UCSF
  • 1985-1989
    Assistant Investigator, Howard Hughes Medical Institute, UCSF
  • 1985-1989
    Assistant Professor of Medicine, Microbiology and Immunology, UCSF
  • 1987-2011
    Chief, Division of Rheumatology/Clinical Immunology, Department of Medicine, UCSF
  • 1989-1993
    Associate Professor or Medicine, Microbiology and Immunology, UCSF
  • 1989-1994
    Associate Investigator, Howard Hughes Medical Institute, UCSF
  • 1991-present
    Ephraim P. Engleman Distinguished Professor of Rheumatology, UCSF
  • 1992-present
    Professor of Medicine, Microbiology and Immunology, UCSF
  • 1993-present
    Investigator, Howard Hughes Medical Institute, UCSF
  • 1998-2005
    Associate Director, The Rosalind Russell Medical Research Center for Arthritis, UCSF
  • 2002-2006
    Director, Medical Scientist Training Program (MSTP), UCSF
  • 2007-2010
    Co-Director, Institute for Molecular Medicine, UCSF

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

Selected Publications

  1. 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 Oct 22; 12(604).
    View on PubMed
  2. 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 Oct 14.
    View on PubMed
  3. 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 Sep 10; 116(37):18517-18527.
    View on PubMed
  4. 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 May 06; 218(5):1619-1633.
    View on PubMed
  5. 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.
    View on PubMed
  6. 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.
    View on PubMed
  7. Jean K Chung, Laura M Nocka, Qi Wang, Theresa A Kadlecek, Arthur Weiss, John Kuriyan, Jay T Groves. Switch-like activation of Bruton's tyrosine kinase by membrane-mediated dimerization. . 2018 Mar 17; 284000.
    View on PubMed
  8. 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.
    View on PubMed
  9. Neel H Shah, Mark Löbel, Arthur Weiss, John Kuriyan. Fine-tuning of substrate preferences of the Src-family kinase Lck revealed through a high-throughput specificity screen. . 2018 Jan 19; 250753.
    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. 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.
    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. Mol Cell. 2017 Aug 03; 67(3):498-511.e6.
    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. J Exp Med. 2017 03 06; 214(3):833-849.
    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. J Immunol. 2017 03 15; 198(6):2445-2456.
    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. SLAS Discov. 2017 03; 22(3):324-331.
    View on PubMed
  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.
    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. Immunity. 2016 12 20; 45(6):1232-1244.
    View on PubMed
  19. Adam H. Courtney, Theresa A. Kadlecek, Byron Au-Yeung, Arthur Weiss. Abstract A074: A Zap70-dependent negative feedback loop governs Lck activation by CD45. . 2016 Nov 1; a074-a074.
    View on PubMed
  20. 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.
    View on PubMed

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