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Molecular and Cellular Biology, October 2004, p. 8611-8626, Vol. 24, No. 19
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.19.8611-8626.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Death-Associated Protein Kinase Phosphorylates ZIP Kinase, Forming a Unique Kinase Hierarchy To Activate Its Cell Death Functions

Gidi Shani, Lea Marash, Devrim Gozuacik, Shani Bialik, Lior Teitelbaum, Galit Shohat, and Adi Kimchi*

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel

Received 19 January 2004/ Returned for modification 25 March 2004/ Accepted 2 June 2004

The death-associated protein (DAP) kinase family includes three protein kinases, DAP kinase, DAP kinase-related protein 1, and ZIP kinase, which display 80% amino acid identity within their catalytic domains and are functionally linked to common subcellular changes occurring during cell death, such as the process of membrane blebbing. Here we show physical and functional cross talk between DAP kinase and ZIP kinase. The two kinases display strong synergistic effects on cell death when coexpressed and physically bind each other via their catalytic domains. Furthermore, DAP kinase phosphorylates ZIP kinase at six specific sites within its extracatalytic C-terminal domain. ZIP kinase localizes to both the nucleus and the cytoplasm and fractionates as monomeric and trimeric forms. Significantly, modification of the DAP kinase phosphorylation sites influences both the localization and oligomerization status of ZIP kinase. A mutant ZIP kinase construct, in which the six serine/threonine residues were mutated to aspartic acid to mimic the phosphorylated state, was found predominantly in the cytoplasm as a trimer and possessed greater cell death-inducing potency. This suggests that DAP kinase and ZIP kinase function in a biochemical pathway in which DAP kinase activates the cellular function of ZIP kinase through phosphorylation, leading to amplification of death-promoting signals.

* Corresponding author. Mailing address: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel. Phone: 972 8 9342428. Fax: 972 8 9315938. E-mail: Adi.Kimchi{at}weizmann.ac.il.

Molecular and Cellular Biology, October 2004, p. 8611-8626, Vol. 24, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.19.8611-8626.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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