Involvement of phosphatidylinositol 3-kinase in NFAT activation in T cells.

The Journal of Biological Chemistry
T JascurT Mustelin

Abstract

Phosphatidylinositol 3-kinase (PI3-K) has been implicated in the regulation of cell proliferation in many cell types. We have previously shown that in T cells the PI3-K inhibitor, wortmannin, interferes with activation of the mitogen-activated kinase, Erk2, after T cell receptor (TcR) stimulation. To further explore the involvement of PI3-K in T cell activation, we created a set of potentially dominant negative PI3-K constructs comprising individual or tandem domains of the regulatory p85 subunit and tested their effect on downstream signaling events like Erk2 activation and transcription from an NFAT (nuclear factor of activated T cells) element taken from the interleukin-2 promoter. Following TcR stimulation, activation of Erk2 was only inhibited by a previously described truncated form of p85 that cannot bind the catalytic subunit, but not by other constructs of p85. In contrast, several mutant p85 alleles had dramatic effects on NFAT activation. Most interestingly, the N-terminal SH2 domain had an inhibitory effect, whereas a mutant p85 containing only the two SH2 domains enhanced basal NFAT activity in a Ras-dependent manner. Ionomycin induced synergistic activation of NFAT in cells expressing p85 mutants that contained th...Continue Reading

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Citations

Aug 24, 1999·European Journal of Immunology·J BrockdorffT Mustelin
Sep 5, 2002·Journal of Cellular Biochemistry·Claudia GentiliAna Russo De Boland
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Dec 3, 2004·Molecular Biology of the Cell·Peggy LafusteFrançois-Jérôme Authier
Mar 4, 2005·Molecular and Cellular Biology·Souad RahmouniTomas Mustelin
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Mar 4, 2014·Biochemical and Biophysical Research Communications·Fugui YanHuahao Shen
Mar 9, 2002·Seminars in Immunology·Maria-Cristina Seminario, Ronald L Wange
Jun 1, 2002·International Immunology·Heather BoneNeil A Williams
Dec 10, 2003·The Journal of Immunology : Official Journal of the American Association of Immunologists·Huong HuynhTomas Mustelin
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