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J. Biol. Chem., Vol. 276, Issue 33, 31113-31123, August 17, 2001

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Human Ca²⁺/Calmodulin-dependent Protein Kinase Kinase  Gene Encodes Multiple Isoforms That Display Distinct Kinase Activity^*

Li-Sung Hsu^§, Gen-Der Chen^§¶, Liang-Shong Lee, Chin-Wen Chi^¶**, Jan-Fang Cheng, and Jeou-Yuan Chen^§¶§§

From the  Graduate Institute of Life Sciences, National Defense Medical Center, ^§ Institute of Biomedical Sciences, Academia Sinica,  Neurological Institute and ^** Medical Research and Education Department, Veterans General Hospital-Taipei, and ^¶ National Yang-Ming University, Taipei, Taiwan, Republic of China, and  Genome Sciences Department, Lawrence Berkeley National Laboratory, Berkeley, California 94720

Ca⁺²/calmodulin-dependent protein kinases (CaMKs) are activated upon binding of Ca⁺²/calmodulin. To gain maximal activity, CaMK I and CaMK IV can be further phosphorylated by an upstream kinase, CaMK kinase (CaMKK). We previously isolated cDNA clones encoding human CaMKK  isoforms that are heterogeneous in their 3'-sequences (Hsu, L.-S., Tsou, A.-P., Chi, C.-W., Lee, C.-H., and Chen, J.-Y. (1998) J. Biomed. Sci. 5, 141-149). In the present study, we examined the genomic organization and transcription of the human CaMKK  gene. The human CaMKK  locus spans more than 40 kilobase pairs and maps to chromosome 12q24.2. It is organized into 18 exons and 17 introns that are flanked by typical splice donor and acceptor sequences. Two major species of transcripts, namely the 1 (5.6 kilobase pairs) and 2 (2.9 kilobase pairs), are generated through differential usage of polyadenylation sites located in the last and penultimate exons. Additional forms of CaMKK  transcripts were also identified that resulted from alternative splicing of the internal exons 14 and/or 16. These isoforms display differential expression patterns in human tissues and tumor-derived cell lines. They also exhibit a distinct ability to undergo autophosphorylation and to phosphorylate the downstream kinases CaMK I and CaMK IV. The differential expression of CaMKK  isoforms with distinct activity further suggests the complexity of the regulation of the CaMKK/CaMK cascade and an important role for CaMKK in the action of Ca⁺²-mediated cellular responses.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EMBL Data Bank with accession number(s) AF287630, AF287631, AF321575-AF321578, and AF321389-AF321402.

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