The kinase, SH3, and SH2 domains of Lck play critical roles in T-cell activation after ZAP-70 membrane localization.

Molecular and Cellular Biology
S YamasakiM Iwashima

Abstract

Antigenic stimulation of the T-cell antigen receptor initiates signal transduction through the immunoreceptor tyrosine-based activation motifs (ITAMs). When its two tyrosines are phosphorylated, ITAM forms a binding site for ZAP-70, one of the cytoplasmic protein tyrosine kinases essential for T-cell activation. The signaling process that follows ZAP-70 binding to ITAM has been analyzed by the construction of fusion proteins that localize ZAP-70 to the plasma membrane. We found that membrane-localized forms of ZAP-70 induce late signaling events such as activation of nuclear factor of activated T cells without any stimulation. This activity was observed only when Lck was expressed and functional. In addition, each mutation that affects the function of Lck in the kinase, Src homology 2 (SH2), and SH3 domains greatly impaired the signaling ability of the chimeric protein. Therefore, Lck functions in multiple manners in T-cell activation for the steps following ZAP-70 binding to ITAM.

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Citations

Dec 29, 2004·FEBS Letters·Kazuyuki IwaiMakio Iwashima
Dec 6, 2014·International Immunology·Y Jeffrey Chiang, Richard J Hodes
Mar 28, 2002·Proceedings of the National Academy of Sciences of the United States of America·Makio IwashimaToru Koike
Apr 3, 2003·Immunological Reviews·Takashi Saito, Sho Yamasaki
Jan 27, 2009·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Stamatina E ZiembaAllen J Rosenspire
Jul 23, 2011·Molecular Biology Reports·Liu Yonggang, Xia Xueshan
Jan 9, 1999·The Journal of Biological Chemistry·S MotoyaA Takeda
Jun 6, 1997·The Journal of Biological Chemistry·S YamasakiM Iwashima
Sep 21, 2001·Molecular and Cellular Biology·M C VeríE Bonvini
Nov 6, 1998·The Journal of Experimental Medicine·L HaughnM Julius
Feb 22, 2000·The Journal of Biological Chemistry·K V SalojinT L Delovitch
Jan 6, 2001·The Journal of Immunology : Official Journal of the American Association of Immunologists·V P PatelM C Miceli
Jun 1, 1997·Current Opinion in Immunology·T Kurosaki
Jun 6, 2000·Advanced Drug Delivery Reviews·Z Eshhar, C J Fitzer-Attas
Apr 4, 2003·Journal of Medicinal Chemistry·Daniel R GoldbergNeil Moss
Nov 1, 2005·Cellular Signalling·Atsuki FukushimaMakio Iwashima

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