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B Activation1
,¶
,
* Institute of Immunology and
Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan;
Institute of Molecular Biology and
Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan; and
¶ Department of Medical Nutrition, I-Shou University, Kaoshiung, Taiwan, Republic of China
Death-associated protein kinase (DAPK) is a unique multidomain kinase acting both as a tumor suppressor and an apoptosis inducer. The molecular mechanism underlying the effector function of DAPK is not fully understood, while the role of DAPK in T lymphocyte activation is mostly unknown. DAPK was activated after TCR stimulation. Through the expression of a dominant-negative and a constitutively active form of DAPK in T cells, we found that DAPK negatively regulated T cell activation. DAPK markedly affected T cell proliferation and IL-2 production. We identified TCR-induced NF-
B activation as a target of DAPK. In contrast, IL-1β- and TNF-
-triggered NF-B activation was not affected by DAPK. We further found that DAPK selectively modulated the TCR-induced translocation of protein kinase C
, Bcl-10, and IB kinase into membrane rafts. Notably, the effect of DAPK on the raft entry was specific for the NF-B pathway, as other raft-associated molecules, such as linker for activation of T cells, were not affected. Our results clearly demonstrate that DAPK is a novel regulator targeted to TCR-activated NF-B and T cell activation.
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.
1 This work was supported by Grant AS-95-TP-B01 from Academia Sinica (Taipei, Taiwan) and Grant NHRI-EX96-9527NI from NHRI (Miadi, Taiwan).
2 Address correspondence and reprint requests to Dr. Ming-Zong Lai, Institute of Molecular Biology, Academia Sinica, Nankang, Taipei 11529, Taiwan. E-mail address: mblai{at}imb.sinica.edu.tw
3 Abbreviations used in this paper: DAPK, death-associated protein kinase; MLC, myosin II regulatory L chain; c-IAP, cellular inhibitor of apoptosis; IKK, IB kinase; PKC, protein kinase C; siRNA, small interfering RNA; MALT1, mucosa-associated lymphoid-tissue lymphoma translocation gene 1; LAT, linker for activation of T cells; Hsp, heat shock protein; YFP, yellow fluorescent protein; DRAK, DAPK-related associated kinase; DN, dominant negative; NLC, normal littermate control; CHX, cycloheximide.
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