DAP-kinase Participates in TNF-– and Fas-induced Apoptosis and Its Function Requires the Death Domain

Correspondence to: Adi Kimchi, Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel., lvkimchi{at}weizmann.weizmann.ac.il (E-mail), 972-8-9342428 (phone), 972-8-9344108 (fax)

Death-associated protein (DAP)–kinase is a calcium/calmodulin regulated serine/threonine kinase that carries ankyrin repeats, a death domain, and is localized to the cytoskeleton. Here, we report that this kinase is involved in tumor necrosis factor (TNF)- and Fas-induced apoptosis. Expression of DAP-kinase antisense RNA protected cells from killing by anti–Fas/APO-1 agonistic antibodies. Deletion of the death domain abrogated the apoptotic functions of the kinase, thus, documenting for the first time the importance of this protein domain. Overexpression of a fragment encompassing the death domain of DAP-kinase acted as a specific dominant negative mutant that protected cells from TNF-, Fas, and FADD/MORT1–induced cell death. DAP-kinase apoptotic function was blocked by bcl-2 as well as by crmA and p35 inhibitors of caspases, but not by the dominant negative mutants of FADD/MORT1 or of caspase 8. Thus, it functions downstream to the receptor complex and upstream to other caspases. The multidomain structure of this serine/threonine kinase, combined with its involvement in cell death induced by several different triggers, place DAP-kinase at one of the central molecular pathways leading to apoptosis.

Key Words: DAP-kinase, tumor necrosis factor-, Fas, death domain, apoptosis

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