Enhancement of lymphocyte responsiveness by a gain-of-function mutation of ZAP-70.

Molecular and Cellular Biology
Q Zhao, Arthur Weiss

Abstract

The protein tyrosine kinase ZAP-70 plays an essential role in T-cell activation and development. After T-cell receptor stimulation, ZAP-70 is associated with the receptor and is phosphorylated on many tyrosine residues, including tyrosine 292 (Y-292), in the region between the C-terminal SH2 domain and the kinase domain (interdomain B). Here we show that a mutation of Y-292 (292F) or deletion of interdomain B enhanced the ability of ZAP-70 to reconstitute B-cell receptor stimulation-dependent NF-AT induction in a B-cell line deficient in Syk. In contrast, in a T-cell line, expression of 292F led to basal NF-AT induction independent of T-cell receptor stimulation. These results demonstrate that the role of Y-292 is to negatively regulate the function of ZAP-70 in lymphocytes. This appears to be a dominant function of interdomain B because deletion of most of interdomain B also resulted in a mutant of ZAP-70 with enhanced ability to reconstitute Syk-deficient DT-40 B cells. Since our biochemical studies did not reveal an effect of the 292F mutation on either the kinase activity of ZAP-70 or on the ability of ZAP-70 to bind to the receptor, we propose a model in which Y-292 interacts with an inhibitory protein to negatively regula...Continue Reading

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Citations

Jun 23, 1998·The Journal of Biological Chemistry·L ZeitlmannW Kolanus
Jan 9, 1999·The Journal of Biological Chemistry·S MotoyaA Takeda
Feb 13, 1999·The Journal of Biological Chemistry·Z ZhangY C Liu
Dec 22, 1999·The Journal of Immunology : Official Journal of the American Association of Immunologists·K SadaR P Siraganian
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Oct 20, 2001·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·P Hasler, M Zouali
Apr 22, 2004·The Journal of Immunology : Official Journal of the American Association of Immunologists·Seiji GodaYoji Shimizu
Nov 15, 2007·Proceedings of the National Academy of Sciences of the United States of America·Lisa M MaierDavid A Hafler
Mar 18, 2009·Immunological Reviews·Byron B Au-YeungArthur Weiss
Mar 18, 2009·Immunological Reviews·Ulrike Lorenz
Feb 6, 2010·Seminars in Immunopathology·Alain FischerClaire Hivroz
Feb 12, 2000·Molecular and Cellular Biology·M López-LagoX R Bustelo
Feb 6, 2002·European Journal of Immunology·Vincenzo Di BartoloOreste Acuto
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Dec 14, 2017·Annual Review of Immunology·Byron B Au-YeungArthur Weiss
Apr 1, 1997·Current Opinion in Cell Biology·D Qian, A Weiss

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