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TRAF3 regulation of inhibitory signaling pathways in B and T lymphocytes by kinase and phosphatase localization
Author(s) -
Wallis Alicia M.,
Bishop Gail A.
Publication year - 2018
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.2mir0817-339rr
Subject(s) - protein tyrosine phosphatase , biology , microbiology and biotechnology , signal transduction , phosphatase , jak stat signaling pathway , kinase , tyrosine kinase , phosphorylation
This brief review presents current understanding of how the signaling adapter protein TRAF3 can both induce and block inhibitory signaling pathways in B and T lymphocytes, via association with kinases and phosphatases, and subsequent regulation of their localization within the cell. In B lymphocytes, signaling through the interleukin 6 receptor (IL‐6R) induces association of TRAF3 with IL‐6R‐associated JAK1, to which TRAF3 recruits the phosphatase PTPN22 (protein tyrosine phosphatase number 22) to dephosphorylate JAK1 and STAT3, inhibiting IL‐6R signaling. An important biological consequence of this inhibition is restraining the size of the plasma cell compartment, as their differentiation is IL‐6 dependent. Similarly, in T lymphocytes, interleukin 2 receptor (IL‐2R) signaling recruits TRAF3, which in turn recruits the phosphatase TCPTP (T cell protein tyrosine phosphatase) to dephosphorylate JAK3. The resulting inhibition of IL‐2R signaling limits the IL‐2‐dependent size of the T regulatory cell (Treg) compartment. TRAF3 also inhibits type 1 IFN receptor (IFNαR) signaling to T cells by this mechanism, restraining expression of IFN‐stimulated gene expression. In contrast, TRAF3 association with two inhibitors of TCR signaling, C‐terminal Src kinase (Csk) and PTPN22, promotes their localization to the cytoplasm, away from the membrane TCR complex. TRAF3 thus enhances TCR signaling and downstream T cell activation. Implications are discussed for these regulatory roles of TRAF3 in lymphocytes, as well as potential future directions.