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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

Ynes Helou, PhD

Lyn Hsu, PhD 

Wan-Lin Lo, PhD

Lin Shen, PhD

Graduate Students

Kasia Skrzypczynska

Geoff Smith

Research Technicians

Amrit Kaur

Terri Kadlecek 

Marianne Mollenauer (Lab Manager)

Al Roque 

Kerri Tam 

Administrative Assistant

Ray Herrman

Selected Publications

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. Feb;15(2):393-401, 2014. PMCID: PMC3946925.

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.  Nature Immunol. Apr;15(4):393-401. doi: 10.1038/ni.2846. 2014. PMCID: PMC3996831.

Phee, H., Au-Yeung, B.B., Pryshchep, O., O'Hagan, K.L., Fairbairn, S.G., 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. May 13;3:e02270. dol: 10.7554/eLife.02270. 2014. PMCID: PMC4017645.

Au-Yeung, B.B., Melichar, H.J., Ross, J.O., Cheng, D.A., Zikherman, J., Shokat, K.M., Robey, E.A., and Weiss, A.  Quantitative and temporal requirements revealed for Zap70 catalytic activity during T cell development.  Nat. Immunol. 15:687-694, 2014.  PMCID: PMC4095875.

Au-Yeung, B.B., Zikherman, J., Mueller, J.L., Ashouri, J.F., Matloubian, M., Cheng, D.A., Chen, Y., Shokat, K.M., and Weiss, A.  A sharp T-cell antigen receptor signaling threshold for T-cell proliferation.  Proc. Natl. Acad. Sci. USA.  Aug 18, 2014.  pii: 201413726.  PMID:  25136127. PMCID: PMC4156735.

Tian, R., Wang, H., Gish, G.D., Petsalaki, E., Pasculescu, A., Shi, Y., Mollenauer, M., Bagshaw, R.D., Yosef, N., Hunter, T., Gingras, A.-C., Weiss, A., Pawson, T.  Combinatorial proteomic analysis of intercellular signaling applied to the CD28 T-cell costimulatory receptor. Proc. Natl. Acad. Sci. USA. March 31, 2015 ;112(13):E1594-603. doi: 10.1073/pnas.1503286112. Epub 2015 Mar 17.  PMID:  25829543.