Human Ca2+/calmodulin-dependent protein kinase kinase beta gene encodes multiple isoforms that display distinct kinase activity

Ca+2/calmodulin-dependent protein kinases (CaMKs) are activated upon bindin g of Ca+2/calmodulin. To gain maximal activity, CaMK I and CaMK TV can be f urther phosphorylated by an upstream kinase, CaMK kinase (CaMKK). We previo usly isolated cDNA clones encoding human CaMKK beta isoforms that are heter ogeneous 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 s tudy, we examined the genomic organization and transcription of the human C aMKK beta gene. The human CaMKK beta locus spans more than 40 kilobase pair s and maps to chromosome 12q24.2. It is organized into 18 exons and 17 intr ons that are flanked by typical splice donor and acceptor sequences. Two ma jor species of transcripts, namely the beta1 (5.6 kilobase pairs) and beta2 (2.9 kilobase pairs), are generated through differential usage of polyaden ylation sites located in the last and penultimate exons. Additional forms o f CaMKK beta transcripts were also identified that resulted from alternativ e splicing of the internal exons 14 and/or 16. These isoforms display diffe rential 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 e xpression of CaMKK beta isoforms with distinct activity further suggests th e complexity of the regulation of the CaMKK/CaMK cascade and an important r ole for CaMKK in the action of Ca+2- mediated cellular responses.