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Gene Review

CAMKK1  -  calcium/calmodulin-dependent protein...

Homo sapiens

Synonyms: CAMKKA, CaM-KK 1, CaM-KK alpha, CaM-kinase IV kinase, CaM-kinase kinase 1, ...
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Disease relevance of CAMKK1

  • The human CaMKK, which was expressed as a Flag-tagged protein in human non-small cell lung cancer H- 1299 cells followed by immunoprecipitation with anti-Flag antibody, was shown to phosphorylate recombinant human CaMK I in a calcium/CaM-dependent fashion [1].

High impact information on CAMKK1

  • CaMKK and CaMKIV localize both to the nucleus and to the cytoplasm, whereas CaMKI is only cytosolic [2].
  • Activation of PKB by CaMKK appears to be important in protection of neurons from programmed cell death during development [2].
  • Inhibition of CaMKK with STO-609 or downregulation of CaMKKbeta using RNA interference decreased thrombin-induced AMPK activation significantly, indicating that CaMKKbeta was the responsible AMPK kinase [3].
  • Eleven of the 64 SNPs mapped to genes encoding pivotal components of the growth hormone/insulin-like growth factor (GH-IGF) pathway, including CAMKK1 E375G (OR=1.37, P=5.4x10(-5)), AKAP9 M463I (OR=1.32, P=1.0x10(-4)) and GHR P495T (OR=12.98, P=0.0019) [4].
  • It directly inhibited CaMKK activity, and it also blocked dephosphorylation of Thr108, an inhibitory PKA phosphorylation site [5].

Biological context of CAMKK1


Anatomical context of CAMKK1

  • CaM-KIdelta exhibits Ca(2+)/CaM-dependent activity that is enhanced (approximately 30-fold) in vitro by phosphorylation of its Thr180 by CaM-K kinase (CaM-KK)alpha, consistent with detection of CaM-KIdelta-activating activity in HeLa cells [9].
  • Here, we examined the expression of multifunctional Ca2+-calmodulin-dependent protein kinases (CaMK) in human skeletal muscle and show that CaMKII and CaMKK, but not CaMKI or CaMKIV, are expressed [10].
  • In intact PC12 cells, activation of PKA with forskolin resulted in a rapid inhibition of both CaMKK and CaMKI activity [7].

Associations of CAMKK1 with chemical compounds

  • A CaMKK inhibitor (KN-93) and phosphatidylinositol 3-kinase inhibitors (wortmannin and LY294002) do not inhibit IL-1beta-induced NF-kappaB activation [11].
  • Furthermore, a dominant negative mutant of Akt abolishes IKKbeta inhibition by CaMKKc and ionomycin, suggesting that Akt acts as a mediator of CaMKK signaling to inhibit IL-1beta-induced IKK activity at an upstream target site [11].
  • First, in response to an increase in intracellular Ca(2+), CaMKIV binds Ca(2+)/CaM and becomes phosphorylated on T200 by CaMKK [12].
  • Moreover, adenosine effect was Ca2+ and CaMKK independent, although probably associated with upstream LKB1 [13].

Regulatory relationships of CAMKK1

  • Phosphorylation of CREB by CaM-kinase IV activated by CaM-kinase IV kinase [6].
  • Taken together, these results indicate a novel regulatory mechanism for IL-1beta signaling and suggest that CaMKK-dependent Akt activation inhibits IL-1beta-induced NF-kappaB activation through interference with the coupling of IRAK1 to MyD88 [11].

Other interactions of CAMKK1

  • Together these studies demonstrate the critical role of specific amino acids in the autoinhibition of CaMKI and also in its activation by CaM and phosphorylation by CaMKK [14].
  • Although CaM-kinase II weakly phosphorylated CaM under the same conditions, CaM-kinase I, CaM-kinase kinase alpha, and cAMP-dependent protein kinase did not phosphorylate CaM [15].
  • The nucleotide-induced phosphorylation of AMPK was affected by changes in the concentration of intracellular Ca2+ and by Ca2+/calmodulin-dependent kinase kinase (CaMKK), although most likely it was not dependent on LKB1 kinase [13].

Analytical, diagnostic and therapeutic context of CAMKK1

  • Northern blot analysis revealed that human CaMKK is ubiquitously expressed, with brain showing the highest level of expression [1].


  1. Cloning, expression and chromosomal localization of human Ca2+/calmodulin-dependent protein kinase kinase. Hsu, L.S., Tsou, A.P., Chi, C.W., Lee, C.H., Chen, J.Y. J. Biomed. Sci. (1998) [Pubmed]
  2. The Ca-calmodulin-dependent protein kinase cascade. Soderling, T.R. Trends Biochem. Sci. (1999) [Pubmed]
  3. Thrombin activates AMP-activated protein kinase in endothelial cells via a pathway involving Ca2+/calmodulin-dependent protein kinase kinase beta. Stahmann, N., Woods, A., Carling, D., Heller, R. Mol. Cell. Biol. (2006) [Pubmed]
  4. Variants in the GH-IGF axis confer susceptibility to lung cancer. Rudd, M.F., Webb, E.L., Matakidou, A., Sellick, G.S., Williams, R.D., Bridle, H., Eisen, T., Houlston, R.S. Genome Res. (2006) [Pubmed]
  5. Inhibition of calcium/calmodulin-dependent protein kinase kinase by protein 14-3-3. Davare, M.A., Saneyoshi, T., Guire, E.S., Nygaard, S.C., Soderling, T.R. J. Biol. Chem. (2004) [Pubmed]
  6. Phosphorylation of CREB by CaM-kinase IV activated by CaM-kinase IV kinase. Enslen, H., Tokumitsu, H., Soderling, T.R. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  7. Inhibition of the Ca2+/calmodulin-dependent protein kinase I cascade by cAMP-dependent protein kinase. Matsushita, M., Nairn, A.C. J. Biol. Chem. (1999) [Pubmed]
  8. Regulation of Ca(2+)/calmodulin-dependent protein kinase kinase alpha by cAMP-dependent protein kinase: I. Biochemical analysis. Okuno, S., Kitani, T., Fujisawa, H. J. Biochem. (2001) [Pubmed]
  9. Identification and characterization of novel components of a Ca2+/calmodulin-dependent protein kinase cascade in HeLa cells. Ishikawa, Y., Tokumitsu, H., Inuzuka, H., Murata-Hori, M., Hosoya, H., Kobayashi, R. FEBS Lett. (2003) [Pubmed]
  10. Ca2+-calmodulin-dependent protein kinase expression and signalling in skeletal muscle during exercise. Rose, A.J., Kiens, B., Richter, E.A. J. Physiol. (Lond.) (2006) [Pubmed]
  11. Inhibition of interleukin-1beta -induced NF-kappa B activation by calcium/calmodulin-dependent protein kinase kinase occurs through Akt activation associated with interleukin-1 receptor-associated kinase phosphorylation and uncoupling of MyD88. Chen, B.C., Wu, W.T., Ho, F.M., Lin, W.W. J. Biol. Chem. (2002) [Pubmed]
  12. Regulation and function of the calcium/calmodulin-dependent protein kinase IV/protein serine/threonine phosphatase 2A signaling complex. Anderson, K.A., Noeldner, P.K., Reece, K., Wadzinski, B.E., Means, A.R. J. Biol. Chem. (2004) [Pubmed]
  13. Extracellular nucleotides and adenosine independently activate AMP-activated protein kinase in endothelial cells: involvement of P2 receptors and adenosine transporters. da Silva, C.G., Jarzyna, R., Specht, A., Kaczmarek, E. Circ. Res. (2006) [Pubmed]
  14. Characterization of the mechanism of regulation of Ca2+/ calmodulin-dependent protein kinase I by calmodulin and by Ca2+/calmodulin-dependent protein kinase kinase. Matsushita, M., Nairn, A.C. J. Biol. Chem. (1998) [Pubmed]
  15. Phosphorylation of calmodulin by Ca2+/calmodulin-dependent protein kinase IV. Ishida, A., Kameshita, I., Okuno, S., Kitani, T., Fujisawa, H. Arch. Biochem. Biophys. (2002) [Pubmed]
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