The Tumor Suppressor Death-Associated Protein Kinase Targets to TCR-Stimulated NF-κB Activation

Abstract

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-κB activation as a target of DAPK. In contrast, IL-1β- and TNF-α-triggered NF-κB activation was not affected by DAPK. We further found that DAPK selectively modulated the TCR-induced translocation of protein kinase Cθ, Bcl-10, and IκB kinase into membrane rafts. Notably, the effect of DAPK on the raft entry was specific for the NF-κB 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-κB and T cell activation.