RAF3 restrains CSK to enhance T cell receptor (TCR) signaling

Previous research in our lab has focused on the role of TNF receptor associated factor 3 (TRAF3) in lymphocyte activation. Our group previously produced a T cell-conditional (CD4-Cre) TRAF3-/- mouse, which demonstrated that TRAF3 plays an important positive role in TCR signaling and T cell functions. The goal of my research is to delineate how TRAF3 regulates TCR signaling. Preliminary data has indicated that after TCR engagement, TRAF3 associates with the TCR complex, and TRAF3-/- cells display a marked reduction in the early phosphorylation of Lck and CD3-zeta activation sites. This role for TRAF3 in proximal TCR signaling events led us to hypothesize that TRAF3 regulates TCR signaling through CSK, a T cell membrane-localized protein that binds to and inhibits Src family kinases, such as Lck. Ongoing experiments are testing the prediction that TRAF3 sequesters CSK in the cytoplasm to restrain its ability to inhibit TCR-associated Lck activation.

Wallis AM, Bishop GA. TRAF3 regulation of inhibitory signaling pathways in B and T lymphocytes by kinase and phosphatase localization. J Leukoc Biol. 2018 Jan 17. doi: 10.1002/JLB.2MIR0817-339RR. [Epub ahead of print] Review. PubMed PMID: 29345428.

Wallis AM, Wallace EC, Hostager BS, Yi Z, Houtman JCD, Bishop GA. TRAF3 enhances TCR signaling by regulating the inihibitors Csk and PTPN22. Sci Rep. 7:2081, 2017.

Mambetsariev N, Lin WW, Wallis AM, Stunz LL, Bishop GA. TRAF3 deficiency promotes metabolic reprogramming in B cells. Sci Rep. 2016 Oct 18;6:35349. doi:10.1038/srep35349. PubMed PMID: 27752131; PubMed Central PMCID: PMC5082756.

Yi Z, Wallis AM, Bishop GA. Roles of TRAF3 in T cells: many surprises. Cell Cycle. 2015;14(8):1156-63. doi: 10.1080/15384101.2015.1021524. PubMed PMID:25723057.