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J. Biol. Chem., Vol. 279, Issue 1, 13-18, January 2, 2004

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Phosphatidylinositide 3-Kinase Priming Couples c-FLIP to T Cell Activation^*

Li-Wen Fang, Tzong-Shyuang Tai¶, Wan-Ni Yu, Fang Liao||, and Ming-Zong Lai¶**

From the Graduate Institute of Life Science, National Defense Medical Center, Taipei 11472, the ^¶Graduate Institute of Immunology, National Taiwan University, Taipei 10002, and the Institute of Molecular Biology and ^||Institute of Biomedical Science, Academia Sinica, Taipei 11529, Taiwan

Cellular FLICE (FADD-like interleukin-1--converting enzyme)-inhibitory protein (c-FLIP) inhibits death receptor-induced apoptosis by binding to FADD (Fas-associated death domain protein) and pro-caspase-8. c-FLIP has also been shown to transmit activation signals and to enhance interleukin (IL)-2 production. However, c-FLIP-mediated T cell activation is difficult to detect in most cells. We found that in DO11.10 T cells, c-FLIP expression led to inhibition of IL-2 production, in contrast to the readily detectable c-FLIP-induced activation in Jurkat cells. A direct comparison revealed that distinct signal pathways were regulated by c-FLIP in Jurkat cells and DO11.10 cells. We investigated whether constitutively activated phosphatidylinositide 3-kinase (PI3K) in Jurkat cells stimulated c-FLIP. Inhibition of PI3K in Jurkat cells abrogated a c-FLIP-mediated increase in IL-2 production. In addition, c-FLIP coordinated with active PI3K for ERK activation. Furthermore, introduction of PTEN back into Jurkat cells eliminated the stimulatory effect of c-FLIP on IL-2 production and ERK activation. Our results suggest that priming with PI3K promotes the coupling of c-FLIP to T cell activation.

Received for publication, April 14, 2003 , and in revised form, October 22, 2003.

^* This work was supported by Grants 89-2316-B001-019 and 90-2320-B001-059 from the National Science Council (Taiwan) and a grant from the Academia Sinica. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Inst. of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan. Tel.: 886-2-2789-9236; Fax: 886-2-2782-6085; E-mail: mblai{at}ccvax.sinica.edu.tw.

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