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J. Biol. Chem., Vol. 281, Issue 29, 20427-20439, July 21, 2006

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Molecular Identification and Characterization of a Family of Kinases with Homology to Ca²⁺/Calmodulin-dependent Protein Kinases I/IV^*

Shogo Ohmae¹, Sayaka Takemoto-Kimura¹, Michiko Okamura¹, Aki Adachi-Morishima¹, Mio Nonaka, Toshimitsu Fuse^¶, Satoshi Kida^||, Masahiro Tanji, Tomoyuki Furuyashiki, Yoshiki Arakawa, Shuh Narumiya, Hiroyuki Okuno, and Haruhiko Bito^¶**2

From the Department of Pharmacology, Kyoto University Faculty of Medicine, Yoshida-Konoecho, Sakyo-ku, Kyoto 606-8315, the Department of Neurochemistry and the ^¶Center for Integrated Brain Medical Science, The University of Tokyo Graduate School of Medicine, Hongo, Bunkyo-ku, Tokyo 113-0033, the ^||Department of Bioscience, Tokyo University of Agriculture, Setagaya-ku, Tokyo 156-8502, and the ^**Solution-Oriented Research in Science and Technology (SORST)-Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan

Despite the critical importance of Ca²⁺/calmodulin (CaM)-dependent protein kinase (CaMK) II signaling in neuroplasticity, only a limited amount of work has so far been available regarding the presence and significance of another predominant CaMK subfamily, the CaMKI/CaMKIV family, in the central nervous system. We here searched for kinases with a core catalytic structure similar to CaMKI and CaMKIV. We isolated full-length cDNAs encoding three mouse CaMKI/CaMKIV-related kinases, CLICK-I (CL1)/doublecortin and CaM kinase-Like (DCAMKL)1, CLICK-II (CL2)/DCAMKL2, and CLICK-I,II-related (CLr)/DCAMKL3, the kinase domains of which had an intermediate homology not only to CaMKI/CaMKIV but also to CaMKII. Furthermore, CL1, CL2, and CLr were highly expressed in the central nervous system, in a neuron-specific fashion. CL1 and CL1 were shorter isoforms of DCAMKL1, which lacked the doublecortin-like domain (Dx). In contrast, CL2 and CL2 contained a full N-terminal Dx, whereas CLr only possessed a partial and dysfunctional Dx. Interestingly, despite a large similarity in the kinase domain, CL1/CL2/CLr had an impact on CRE-dependent gene expression distinct from that of the related CaMKI/CaMKIV and CaMKII. Although these were previously shown to activate Ca²⁺/cAMP-response element-binding protein (CREB)-dependent transcription, we here show that CL1 and CL2 were unable to significantly phosphorylate CREB Ser-133 and rather inhibited CRE-dependent gene expression by a dominant mechanism that bypassed CREB and was mediated by phosphorylated TORC2.

Received for publication, December 12, 2005

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY968047 [GenBank] , AY968048 [GenBank] , AY968049 [GenBank] , AY968050 [GenBank] , AY968051 [GenBank] , and DQ286388 [GenBank] .

^* This work was supported in part by grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to H. B., H. O., M. O., and S. T.-K.), from Japan Science and Technology Agency (to H. B.), and from Human Frontier Science Program (to H. B. and H. O.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 81-3-5841-3559; Fax: 81-3-3814-8154; E-mail: hbito{at}m.u-tokyo.ac.jp.

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