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Journal of Biochemistry Advance Access originally published online on December 15, 2007
Journal of Biochemistry 2008 143(3):349-358; doi:10.1093/jb/mvm236
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© 2007 The Japanese Biochemical Society.

Nuclear Localization Signal and Phosphorylation of Serine350 Specify Intracellular Localization of DRAK2

Hiroshi Kuwahara, Michihiko Nishizaki and Hiroshi Kanazawa*

Department of Biological Sciences, Graduate School of Science, Osaka University, Machikaneyama-cho, Toyonaka City, Osaka 560-0043, Japan

*To whom correspondence should be addressed. Tel: +81 6 6850 5812, Fax: +81 6 6850 5812, E-mail: kanazawa{at}bio.sci.osaka-u.ac.jp

Received September 4, 2007; Accepted November 13, 2007


  Abstract

DAP kinase-related apoptosis-inducing kinase 2 (DRAK2) is a serine/threonine kinase of the death-associated protein kinase family. DRAK2 mediates apoptosis induced by extracellular stimuli, including UV irradiation and interleukin-2, and also regulates T-cell receptor sensitivity in developing thymocytes. During these events, the subcellular localization of DRAK2 changes between the nucleus and cytoplasm. We found that DRAK2 has a putative nuclear-localization signal (NLS) sequence. Mutations in this sequence interfered with DRAK2 localization to the nucleus. Furthermore, green fluorescence protein fused to the putative NLS accumulated in the nucleus, indicating that the putative sequence functions as an NLS. We also found that the function of the NLS was regulated by phosphorylation. Phorbol myristate acetate (PMA) induced the accumulation of DRAK2 in the cytoplasm of NIH3T3 cells, whereas in the absence of PMA, DRAK2 was localized to the nucleus. Ectopic expression of PKC-{gamma} induced cytoplasmic localization of DRAK2 and PKC-{gamma} phosphorylated Ser350 flanking the NLS. DRAK2, but not the Ser350Asp mutant, accumulated in the nuclei of ACL-15 cells in response to UV-irradiation. These results suggest that phosphorylation of Ser350 plays an essential role in regulating translocation of DRAK2 to the nucleus from the cytoplasm, possibly by affecting the activity of the NLS.

Key Words: nuclear localization signal, phosphorylation, protein kinase C (PKC), serine/threonine kinase

Abbreviations: DRAK2, DAP kinase-related apoptosis-inducing kinase 2; DAPK, death-associated protein kinase; NLS, nuclear localization signal; PMA, phorbol myristate acetate; PKC, protein kinase C; TCR, T-cell receptor


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