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Small molecule inhibition of ZAP‐70 kinase activity
Author(s) -
Levin Susan E,
Zhang Chao,
Shokat Kevan,
Weiss Arthur
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.lb64-d
Subject(s) - t cell receptor , t cell , signal transduction , microbiology and biotechnology , kinase , tyrosine kinase , biology , function (biology) , immune system , immunology
ZAP‐70 (zeta‐associated protein of 70 kDA) is a cytoplasmic protein tyrosine kinase that is required for T cell receptor (TCR) signaling. Both mice and humans deficient in the gene fail to develop functional T cells demonstrating the necessity of this gene for proper T cell development and T cell function. Although there are mice and cell lines available that are deficient in ZAP‐70 expression, there is currently no specific inhibitor for this kinase to assess the function of ZAP‐70 at later stages of development or in mature T cells. We have recently generated a mutant ZAP‐70 allele that retains its kinase activity but is sensitive to two PP1 analogs and thereby can be specifically inhibited upon addition of the analogs. Due to the requirement of ZAP‐70 in TCR signal transduction, it has been assumed that an inhibitor of ZAP‐70 would be valuable in the clinical setting as an immunosuppressant and for treatment of immune related disorders. The generation and study of this ZAP‐70 allele and inhibitor in vivo and in stable cell lines will allow us to determine the clinical usefulness of a ZAP‐70 inhibitor as well as gain a more sophisticated and complete understanding of ZAP‐70's function during T cell signaling. This study was funded by HHMI (AW) and a NSF predoctoral fellowship (SEL).