Alternative titles; symbols
HGNC Approved Gene Symbol: CAMKK1
Cytogenetic location: 17p13.2 Genomic coordinates (GRCh38): 17:3,860,315-3,893,053 (from NCBI)
CAMKK1 catalyzes the phosphorylation and activation of Ca(2+)/calmodulin kinase (CaMK) as an upstream component of the CaMK cascade that has been implicated in neuronal gene transcription, synaptic plasticity, and long-term memory consolidation (Blaeser et al., 2006).
By screening a rat brain cDNA library using partial amino acid sequence of a 68-kD purified rat brain CaMK kinase, followed by 5-prime RACE, Tokumitsu et al. (1995) cloned rat Camkk1. The deduced 505-amino acid protein has a calculated molecular mass of 56 kD. Camkk1 shares 30 to 40% amino acid identity over the catalytic domains of serine/threonine kinases such as the CaM-kinase family (see CAMK2A; 114078). Camkk1 contains a 22-amino acid proline-, arginine-, and glycine-rich insert between the ATP-binding motif and DGF kinase motif that is similar to the insert in yeast Ste11. Northern blot analysis of rat tissues detected high expression in forebrain, lower expression in cerebellum, and detectable signal in thymus and spleen.
Using Western blot analysis or gel overlay, Tokumitsu et al. (1995) showed that Camkk1 binds calmodulin (CALM1; 114180) and activated Camk4 (114080) with a 6-fold increase in total activity and a 100-fold increase in Camk4 Ca(2+)-independent activity. Camkk1 catalyzed a 10-fold increase in the total activity of Camk1 (604998) and had no effect on Camk2 (see CAMK2A; 114078). Cotransfection of COS-7 cells with Camkk1 and Camk4 resulted in a 14-fold increase in CRE-binding protein (CREB1; 123810)-dependent transcription compared with Camk4 alone, suggesting that Camkk1 enhances Camk4-mediated transcriptional regulation.
Using pharmacologic inhibitors to block potential pathways involved in cytomegalovirus (CMV)-mediated activation of glycolysis, McArdle et al. (2011) found that inhibition of CAMKK, but not CAMK2 or protein kinase A (PKA; see 176911), blocked CMV-mediated glycolysis activation. CMV infection also induced CAMKK1 mRNA and protein expression. Inhibition of CAMKK had a negligible impact on CMV immediate-early protein accumulation, but it severely attenuated production of CMV viral progeny, reduced expression of 1 early CMV gene, and blocked viral DNA replication. CAMKK inhibition had no impact on herpes simplex virus (HSV)-1-induced glycolytic activation and a limited impact on HSV-1 replication. McArdle et al. (2011) concluded that CAMKK has a role that is CMV specific and that it is an important factor in both CMV replication and glycolytic activation.
The International Radiation Hybrid Mapping Consortium mapped the CAMKK1 gene to chromosome 17 (SHGC-32989).
Blaeser et al. (2006) generated mice with targeted disruption of Camkk1 and carried out a variety of behavioral and learning and memory tests. Mutant mice exhibited normal long-term spatial memory, cued fear memory, basal synaptic transmission, and long-term potentiation. However, mutant mice displayed deficient long-term contextual fear memory, as measured in the post-shock freezing response. Mutant mice displayed decreased stress-induced anxiety-like behavior; however, other measures of anxiety such as the elevated plus maze and open field tests showed no difference from wildtype. Blaeser et al. (2006) concluded that Camkk1 plays a selective role in contextual fear memory. They showed that mice lacking Camkk1 displayed decreased phosphorylation and activation of Camk4 and Creb in specific brain areas involved in contextual fear memory formation.
Blaeser, F., Sanders, M. J., Truong, N., Ko, S., Wu, L. J., Wozniak, D. F., Fanselow, M. S., Zhuo, M., Chatila, T. A. Long-term memory deficits in pavlovian fear conditioning in Ca(2+)/calmodulin kinase kinase alpha-deficient mice. Molec. Cell. Biol. 26: 9105-9115, 2006. [PubMed: 17015467] [Full Text: https://doi.org/10.1128/MCB.01452-06]
McArdle, J., Schafer, X. L., Munger, J. Inhibition of calmodulin-dependent kinase kinase blocks human cytomegalovirus-induced glycolytic activation and severely attenuates production of viral progeny. J. Virol. 85: 705-714, 2011. Note: Erratum: J. Virol. 87: 7197 only, 2013. [PubMed: 21084482] [Full Text: https://doi.org/10.1128/JVI.01557-10]
Tokumitsu, H., Enslen, H., Soderling, T. R. Characterization of a Ca(2+)/calmodulin-dependent protein kinase cascade: molecular cloning and expression of calcium/calmodulin-dependent protein kinase kinase. J. Biol. Chem. 270: 19320-19324, 1995. [PubMed: 7642608] [Full Text: https://doi.org/10.1074/jbc.270.33.19320]