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| T cell signaling: Giving HPK1 the SLP
Hematopoietic progenitor kinase 1 (HPK1) diminishes T cell receptor (TCR) signaling activity and T cell proliferation by phosphorylating the adaptor protein SLP-76. HPK1, also called MAP4K1, activates the JNK/SAPK signaling pathway in hematopoietic progenitor cells. HPK1 interacts with numerous T cell receptor (TCR) adaptor proteins and is phosphorylated by the tyrosine kinases Lck and Zap70 after TCR activation. In Nature Immunology Shui et al. now demonstrate that HPK1 in turn phosphorylates the adaptor protein SLP-76, leading to negative feedback regulation of TCR signaling and consequently inhibition of T cell proliferation.
The authors created MAP4K1 knock-out mice and analyzed the consequences for T cell function and TCR signaling. While the development of T cells in MAP4K1-/- mice appeared normal, in vitro-stimulated knock-out T cells were hyperproliferative. Furthermore, the T cells also hyperproliferated in vivo and the increased production of interleukins indicated that TCR signaling was enhanced. The mice showed exacerbated autoimmunity, as indicated by an increased sensitivity to the induction of a multiple sclerosis-like condition. Thus, as well as inhibiting T cell proliferation, HPK1 downregulates self antigen-specific T-cell activation. The authors observed that HPK1 did not alter JNK signaling in MAP4K1-/- T cells, which lead to the conclusion that — in contrast to hematopoietic progenitor cells — HPK1 activity does not target the JNK pathway. On the other hand, Erk activation was enhanced after TCR stimulation in the MAP4K1-/- T cells. The Erk signaling pathway is known to be another downstream component of TCR signaling, and Erk signaling itself can be downregulated by the TCR adaptor protein SLP-76. Next, the authors observed that SLP-76 was phosphorylated in vitro by wild-type HPK1, but not by a kinase-inactive mutant. In keeping with this, SLP-76 phosphorylation was reduced in MAP4K1-/- T cells. Sequence analysis predicted that phosphorylation of SLP-76 creates several potential binding sites for 14-3-3 adaptor proteins. Indeed, the interaction between non-phosphorylated SLP 76 and 14-3-3τ, a negative regulator of TCR signaling, was weak in vitro and in MAP4K1-/- T cells. Taken together, these data show that HPK1 phosphorylates SLP-76, thus facilitating binding to 14-3-3τ. The complex is involved in the downregulation of Erk signaling, which leads to a decrease in TCR signaling and T-cell proliferation. This study elucidates a new regulatory mechanism of T cell–mediated immune responses focused on HPK1 as a central modulator of upstream TCR signaling. Mirko von Elstermann References | |
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