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Arthur Weiss, MD, PhD

Arthur Weiss, MD, PhD
Investigator, Howard Hughes Medical Institute
Ephraim P. Engleman Distinguished Professor
Department of Medicine, Division of Rheumatology
Department of Microbiology and Immunology
Research Summary:
Signal transduction in lymphocytes

The response of lymphocytes to antigen which initiates an antigen specific immune response also represents a unique opportunity to study how complex molecular interactions between cells can lead to developmental decisions, cell differentiation and proliferation. We are interested in understanding how receptors involved in antigen recognition can initiate signal transduction events that regulate cell responses in the immune system. We know that receptors involved in antigen recognition functionally interact with tyrosine kinases and phosphatases, enzymes that regulate protein phosphorylation, to induce signaling pathways that regulate cellular responses and gene expression.  We are using genetically selective small molecule inhibitors of kinases together with phosphatase mutants to study how thresholds for the initiation of immune responses are set and how feedback circuits influence responses.  We would like to understand how the tyrosine kinases and phosphatases in these pathways are regulated and how they control cellular responses in development, in normal immune responses and in autoimmune diseases such as lupus and rheumatoid arthritis.

Lab Members

Postdoctoral Fellows

Judy Ashouri, MD

Byron Au-Yeung, PhD

Adam Courtney, PhD

Henrik Flach, PhD 

Tanya Freedman, PhD

Lyn Hsu, PhD 

Wan-Lin Lo, PhD

Boryana Manz, PhD

Ying-Xim Tan 

Haopeng Wang, PhD

Graduate Students

Kasia Skrzypczynska

Geoff Smith

Research Technicians

Yiling Chen 

Terri Kadlecek 

Marianne Mollenauer (Lab Manager)

Al Roque 

Kerri Tam 

Administrative Assistant

Ray Herrman

Selected Publications

Deindl S, Kadlecek TA, Brdicka T, Cao X, Weiss A, Kuriyan J.   Structural basis for the inhibition of the tyrosine kinase activity of ZAP-70.  Cell.  2007;129:735-46.

Zhu JW, Brdicka T, Katsumoto TR, Lin J,  Weiss A.  Structurally distinct phosphatases CD45 and CD148 both regulate B cell and macrophage immunoreceptor signaling.  Immunity.  2008;28:183-96.  

Das J, Ho M, Zikherman J, Govern C, Yang M, Weiss A, Chakraborty AK, Roose JP. Digital signaling and hysteresis characterize Ras activation in lymphoid cells.  Cell. 2009;136:337-51. 

Zikherman J, Jenne C, Watson S, Doan K, Raschke W, Goodnow CC, Weiss A.  CD45-Csk phosphatase-kinase titration uncouples basal and inducible T cell receptor signaling during thymic development.  Immunity. 2010;32:342-54. 

Phee H, Dzhagalov I, Mollenauer M, Wang Y, Irvine DJ, Robey E, Weiss A.  Regulation of thymocyte positive selection and motility by GIT2.  Nat Immunol.  2010 Jun;11(6):503-11. 

Au-Yeung BB, Levin SE, Zhang C, Hsu LY, Cheng DA, Killeen N, Shokat K, Weiss A.  A genetically selective inhibitor demonstrates a function for the kinase Zap70 in regulatory T cells independent of its catalytic activity.  Nat Immunol. 2010 Dec;11(12):1085-92.

Limnander A, Depeille P, Freedman TS, Liou J, Leitges M, Kurosaki T, Roose JP, Weiss A.  Stim1, PKC, and RasGRP proteins set a threshold for pro-apoptotic Erk signaling during B cell development.  Nat Immunol.2011 May;12(5):425-33.

Zikherman, J., Parameswaran, R., and Weiss. A.   Endogenous antigen tunes responsiveness of antigen recepor signaling in B cells but not T cells.  Nature. 489:160-164.  2012. 

Mukherjee, S., Zhu, J., Zikherman, J., Parameswaran, R., Kadlecek, T.A., Wang, Q., Au-Yeung, B., Ploegh, H., Kuriyan, J., Das, J.*, Weiss, A.*  Monovalent and multivalent ligation of the B cell receptor exhibit differential dependence upon Syk and Src family kinases.  Sci. Signal.  2013.  Jan 1;6(256):ra1 *co-corresponding authors

Katzumoto, T.R., Kudo, M, Chen, C., Sundaram, A., Callahan, E., Zhu, J., Lin, J., Rosen, C.E., Manz, B., Lee, J.W., Matthay, M.A., Huang, X., Sheppard, D., and Weiss, A.  The phosphatase CD148 promotes airway hyperresponsiveness through SRC family kinases.  J. Clin. Invest., 2013. 123:2037-48.   

Yan, Q., Barros, T., Visperas, P.R., Deindl, S., Kadlecek, T.A., Weiss, A., and Kuriyan, J.  Structural basis for activation of ZAP-70 by phosphorylation of the SH2-kinase linker.  Mol. Cell. Biol., 2013 Jun;33(11):2188-201.

Tan, Y.-X., Manz, B.N., Freedman, T.S., Zhang, C., Shokat, K.M., and Weiss, A.  Inhibition of the kinase Csk in thymocytes reveals a requirement for actin remodeling in the initiation of full TCR signaling.  Nat. Immunol.  2013  15:186-94  

Wang, H., Flach, H., Onizawa, M., Wei, L., McManus, M.T., and Weiss, A.  Negative regulation of Hif1a expression and Th17 differentiation by the hypoxia-regulated microRNA miR-210.  Nat. Immunol.  2014. Apr;15(4):393-401.

Jenkins, M.R., Stinchcombe, J.C., Au-Yeung, B.B., Asano, Y., Ritter, A.T., Weiss A., Griffiths, G.M. Distinct structural and catalytic roles for Zap70 in formation of the immunological synapse in CTL.  eLife.  2014 Jan 1;3:e01310. 

Phee, H., Au-Yeung, B., Pryshchep, O., O'Hagan, K., Fairbairn, S., Radu, M., Kosoff, R., Mollenauer, M., Cheng, D., Chernoff, J., and Weiss, A.  Pak2 is required for actin cytoskeleton remodeling, TCR signaling, and normal thymocyte development and maturation.  Elife 2014 May 13;3:e02270.  DOI: 10.7554/eLife.02270.