A genetically selective inhibitor demonstrates a function for the kinase Zap70 in regulatory T cells independent of its catalytic activity

Howard Hughes Medical Institute, Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, Department of Microbiology and Immunology, University of California-San Francisco, California, USA.
Nature Immunology (Impact Factor: 20). 10/2010; 11(12):1085-92. DOI: 10.1038/ni.1955
Source: PubMed


To investigate the role of the kinase Zap70 in T cells, we generated mice expressing a Zap70 mutant whose catalytic activity can be selectively blocked by a small-molecule inhibitor. We found that conventional naive, effector and memory T cells were dependent on the kinase activity of Zap70 for their activation, which demonstrated a nonredundant role for Zap70 in signals induced by the T cell antigen receptor (TCR). In contrast, the catalytic activity of Zap70 was not required for activation of the GTPase Rap1 and inside-out signals that promote integrin adhesion. This Zap70 kinase-independent pathway was sufficient for the suppressive activity of regulatory T cells (T(reg) cells), which was unperturbed by inhibition of the catalytic activity of Zap70. Our results indicate Zap70 is a likely therapeutic target.

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Available from: Arthur Weiss, Jun 30, 2014
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    • "One possibility is the spatial segregation of TCR and Lck from phosphatases such as CD45 (Davis and Van Der Merwe, 2006; Rossy et al., 2012). Phosphorylated ITAMs serve as recruitment and activation sites for zeta chain-associated protein kinase of 70 kDa (ZAP-70), whose activity is essential in conventional T cells but not in regulatory T cells (Au-Yeung et al., 2010). "
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