Research Summary

Research Summary
I have studied signal transduction in lymphocytes for more than 40 years.  Early work led to the characterization of mechanisms of T cell antigen receptor signaling, including the identification of the cytoplasmic domain of the zeta chain as a receptor signaling module.  Our development of zeta chain chimeric receptors that could signal led to the development of CAR-T cells.  More recently we have a 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 co-founder of Nurix Therapeutics, Inc., which seeks to develop therapeutics for various malignancies by targeting ubiquitin ligases. 

Research Funding

  • June 1, 2021 - May 31, 2026 - Academic Rheumatology and Clinical Immunology , Principal Investigator . Sponsor: NIH, Sponsor Award ID: T32AR079068
  • December 8, 2015 - November 30, 2025 - The cell and molecular mechanisms underlying CD28 costimulation , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R37AI114575
  • July 15, 2011 - June 30, 2021 - Defining the Unique Properties of the Distinct Signaling Machinery Used by the TCR , Principal Investigator . Sponsor: NIH, Sponsor Award ID: P01AI091580
  • July 1, 1978 - June 30, 2021 - Medical Scientist Training Program , Co-Principal Investigator . Sponsor: NIH, 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: R01AI114575
  • May 1, 2017 - April 30, 2018 - FASEB SRC on Signal Transduction in the Immune System , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R13AI131578
  • May 1, 2015 - April 30, 2016 - FASEB SRC on Signal Transduction in the Immune System , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R13AI118149
  • March 1, 1980 - February 28, 2015 - A Synchroton Radiation Structural Biology Resource , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P41RR001209
  • September 25, 2009 - August 31, 2013 - An allosteric inhibitor of ZAP-70 as a novel therapeutic for autoimmune disease , Principal Investigator . Sponsor: NIH, Sponsor Award ID: RC2AR058947
  • January 1, 1900 - July 31, 2012 - Immune Tolerance and Autoimmunity , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P01AI035297
  • February 15, 2006 - January 31, 2012 - Function of the RPTP CD148 in the Hematopoietic Lineage , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AI066120
  • February 20, 1997 - January 31, 2006 - FUNCTION OF THE VAV PROTOONCOGENE , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01CA072531
  • September 30, 1999 - August 31, 2003 - HUMAN IMMUNE CELL MATURATION DURING ONTOGENY AND INFECTI , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P01AI045865
  • June 1, 2002 - May 31, 2003 - Conference Proposal: Receptors and Signal Transduction , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R13CA094912
  • February 1, 1988 - November 30, 2001 - LCK AND CD45 IN T CELL RECEPTOR SIGNAL TRANSDUCTION , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01GM039553
  • February 1, 1992 - January 31, 1996 - FUNCTION OF THE CD28 MOLECULE , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01GM044493

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. Nguyen TTT, Lu W, Zhu WS, Ansel KM, Liang HE, Weiss A. Stimulation of ectopically expressed muscarinic receptors induces IFN-γ but suppresses IL-2 production by inhibiting activation of pAKT pathways in primary T cells. Proc Natl Acad Sci U S A. 2023 06 20; 120(25):e2300987120.  View on PubMed
  2. Lu W, Helou YA, Shrinivas K, Liou J, Au-Yeung BB, Weiss A. The phosphatidylinositol-transfer protein Nir3 promotes PI(4,5)P2 replenishment in response to TCR signaling during T cell development and survival. Nat Immunol. 2023 01; 24(1):136-147.  View on PubMed
  3. Yuan-Li Tsai, Marcel Arias Badia, Theresa A Kadlecek, Neel H Shah, Lawrence Fong, Arthur Weiss. Overcoming inhibitory constraints to TCR signaling by targeting the pH-sensitive phosphatase suppressor of T-cell receptor signaling 1 (STS1). The Journal of Immunology. 2022 May 1; 208(1_Supplement):166.14-166.14.  View on PubMed
  4. Wen Lu, Ynes A Helou, Byron B Au-Yeung, Krishna Shrinivas, Jen Liou, Arthur Weiss. The phosphatidylinositol-transfer protein Nir3 modulates T cell development and function. The Journal of Immunology. 2022 May 1; 208(1_Supplement):166.12-166.12.  View on PubMed
  5. Ashouri JF, Lo WL, Nguyen TTT, Shen L, Weiss A. ZAP70, too little, too much can lead to autoimmunity. Immunol Rev. 2022 05; 307(1):145-160.  View on PubMed
  6. Huang F, Nguyen TT, Echeverria I, Rakesh R, Cary DC, Paculova H, Sali A, Weiss A, Peterlin BM, Fujinaga K. Reversible phosphorylation of cyclin T1 promotes assembly and stability of P-TEFb. Elife. 2021 11 25; 10.  View on PubMed
  7. Lu W, Skrzypczynska KM, Weiss A. Acute Csk inhibition hinders B cell activation by constraining the PI3 kinase pathway. Proc Natl Acad Sci U S A. 2021 10 26; 118(43).  View on PubMed
  8. Jeffrey Bluestone, Arthur Weiss. Frank W. Fitch, M.D. Ph.D., 1929–2021. The Journal of Immunology. 2021 Jun 15; 206(12):2769-2772.  View on PubMed
  9. Nguyen TTT, Wang ZE, Shen L, Schroeder A, Eckalbar W, Weiss A. Cbl-b deficiency prevents functional but not phenotypic T cell anergy. J Exp Med. 2021 07 05; 218(7).  View on PubMed
  10. Lo WL, Weiss A. Adapting T Cell Receptor Ligand Discrimination Capability via LAT. Front Immunol. 2021; 12:673196.  View on PubMed
  11. Shen L, Matloubian M, Kadlecek TA, Weiss A. A disease-associated mutation that weakens ZAP70 autoinhibition enhances responses to weak and self-ligands. Sci Signal. 2021 02 02; 14(668).  View on PubMed
  12. Byron B Au-Yeung, Arthur Weiss, Wendy Zinzow-Kramer. Basal TCR signaling drives the functional heterogeneity of naïve CD4+ T cells. The Journal of Immunology. 2020 May 1; 204(1_Supplement):150.2-150.2.  View on PubMed
  13. Wendy M. Zinzow-Kramer, Arthur Weiss, Byron B Au-Yeung. CD4+ T cells are more sensitive to inhibition of TCR signaling under Th17 polarizing conditions. The Journal of Immunology. 2020 May 1; 204(1_Supplement):80.6-80.6.  View on PubMed
  14. Ynes Helou, Byron B Au-Yeung, Arthur Weiss. The phosphatidinositol-transfer protein Nir3 is a modulator of T cell development. The Journal of Immunology. 2020 May 1; 204(1_Supplement):61.12-61.12.  View on PubMed
  15. 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
  16. 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.  View on PubMed
  17. 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).  View on PubMed
  18. 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.  View on PubMed
  19. 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
  20. 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.  View on PubMed

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