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.
Judy Ashouri, MD
Byron Au-Yeung, PhD
Adam Courtney, PhD
Ynes Helou, PhD
Lyn Hsu, PhD
Wan-Lin Lo, PhD
Lin Shen, PhD
Marianne Mollenauer (Lab Manager)
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.