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

• CaMKK and 14-3-3 co-immunoprecipitated from co-transfected heterologous cells as well as from rat brain homogenate, and site-directed mutagenesis studies identified phospho-Ser74 in CaMKK as the primary 14-3-3 binding site [5].
• It is likely that the lower efficiency of transcriptional activation by transfected CaM-kinase IV in previous studies was due to the fact that the CaM-kinase IV was not activated by CaM-kinase IV kinase [6].
• In this paper we examine the kinetics and site-specificity of CREB phosphorylation in vitro by CaM-kinase IV after its phosphorylation and activation by a newly discovered brain CaM-kinase IV kinase [6].
• The phosphorylation and inhibition of CaMKK by PKA is likely to be involved in modulating the balance between cAMP- and Ca2+-dependent signal transduction pathways [7].
• Six phosphorylation sites on CaM-kinase kinase alpha, Ser(24) for autophosphorylation, and Ser(52), Ser(74), Thr(108), Ser(458), and Ser(475) for phosphorylation by PKA, were identified by amino acid sequence analysis of the phosphopeptides purified from the tryptic digest of the phosphorylated enzymes [8].

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].

References