A genetically selective inhibitor demonstrates a function for the kinase Zap70 in regulatory T cells independent of its catalytic activity
A genetically selective inhibitor demonstrates a function for the kinase Zap70 in regulatory T cells independent of its catalytic activity
Byron B Au-Yeung., et al. 2010. Nat Immunol. 11(12):1089-92
Speaker: Chia-Yun Wu (吳佳芸) Time: 14:10~15:00, Apr. 20, 2011
Commentator: Dr. Li-Jin Hsu (徐麗君 老師) Place: Room 611
Abstract:
Transgenic knockout mice are an effective model to study the kinase function in the T cell receptor (TcR) signaling pathway. However there are problems such as the low number of mature T cells, genetic compensation and redundancy of function, and not reversible of gene transfer. To solve those problems, developing specific small-molecule kinase inhibitor is ongoing field to find out the real catalytic activity function of kinase in T cell responses. Previous studies showed Zap70 mutant that still has catalytic activity in T cell line can be specifically inhibited by analog of small-molecule inhibitor PP11. However the catalytic activity role of Zap70 in T cell responses still has some unknown gaps. In this study, the authors generated mice expressing a Zap70 mutant (AS) transgene which catalytic activity can be specifically inhibited by PP1 analog (3-MB-PP1). They found that the catalytic activity of Zap70 is required for transducing TcR activation signal mediating the inositol -1,3,4-trisphosphate-calcium flux and the diacylglycerol-mitogen activated protein kinase (MAPK) pathways, T cell proliferation, memory T cell response and TH1、TH2 and cytotoxic T lymphocytes effector function. But, the suppressive activity of Treg is independent on the catalytic activity of Zap70. Phosphorylated Zap70 could interact with adaptor protein CrK II, which associates with guanine nucleotide exchanger factor C3G for GTPase Rap1 that joins the integrin inside-out signaling for cell adhesion2. Indeed, Zap70 associated with CrK II to active Rap1 for enhancing cellular adhesion in Treg cells no matter 3-MB-PP1 present or not. In summary, the suppression activity of Treg cell is independent on the catalytic activity of Zap70, in there the Zap70 is suggested as an scaffolding protein to interact with integrin signaling for cell adhesion that enhancing the close to target cells to carry out suppression function.
References:
- Levin, S.E., et al. Inhibition of ZAP-70 kinase activity via an analog-sensitive allele blocks T cell receptor and CD28 superagonist signaling. J. Biol. Chem. 283, 15419–15430 (2008).
- Gelkop, S., et al. T cell activation-induced CrkII binding to the Zap70 protein tyrosine kinase is mediated by Lck-dependent phosphorylation of Zap70 tyrosine 315. J. Immunol. 175, 8123–8132 (2005).