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Review
. 2022 Sep 20;23(19):11025.
doi: 10.3390/ijms231911025.

Molecular Mechanisms Underlying Ca2+/Calmodulin-Dependent Protein Kinase Kinase Signal Transduction

Hiroshi Tokumitsu  1 , Hiroyuki Sakagami  2
Affiliations
Review

Molecular Mechanisms Underlying Ca2+/Calmodulin-Dependent Protein Kinase Kinase Signal Transduction

Hiroshi Tokumitsu et al. Int J Mol Sci. .

Abstract

Ca2+/calmodulin-dependent protein kinase kinase (CaMKK) is the activating kinase for multiple downstream kinases, including CaM-kinase I (CaMKI), CaM-kinase IV (CaMKIV), protein kinase B (PKB/Akt), and 5'AMP-kinase (AMPK), through the phosphorylation of their activation-loop Thr residues in response to increasing the intracellular Ca2+ concentration, as CaMKK itself is a Ca2+/CaM-dependent enzyme. The CaMKK-mediated kinase cascade plays important roles in a number of Ca2+-dependent pathways, such as neuronal morphogenesis and plasticity, transcriptional activation, autophagy, and metabolic regulation, as well as in pathophysiological pathways, including cancer progression, metabolic syndrome, and mental disorders. This review focuses on the molecular mechanism underlying CaMKK-mediated signal transduction in normal and pathophysiological conditions. We summarize the current knowledge of the structural, functional, and physiological properties of the regulatory kinase, CaMKK, and the development and application of its pharmacological inhibitors.

Keywords: Ca2+ signaling; CaM-kinase cascade; CaMKK; phosphorylation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
CaMKKα/1; activation mechanism, immunohistochemical localization in the rat brain, and Ca2+/CaM-binding. (A) Sagittal section of the adult rat brain immunostained with a monoclonal antibody against CaMKKα/1 (reproduced from Ref. [61], with permission from John Wiley and Sons). CA1 and CA3, CA1 and CA3 subregions of Ammon’s horn of the hippocampus; Cb, cerebellar cortex; CP, caudate putamen; Cx, cerebral cortex; DG, dentate gyrus; MO, medulla oblongata; OB, olfactory bulb; Pn, pontine nuclei; SNr, substantia nigra pars reticulata; Th, thalamus; and Tu, olfactory tubercle. Scale bar = 2.5 mm. (B) Proposed model of CaMKKα/1 activation mechanism. At low intracellular Ca2+ concentration, CaMKKα/1 is in an inactive conformation, where the catalytic domain (residues 126−434) is tightly associated with the regulatory domain (residues 438−463, C). With increasing intracellular Ca2+ concentration, Ca2+/ CaM binds to regulatory domain of CaMKKα/1 (E) to suppress autoinhibition, thereby activating the kinase [64]. An activated CaMKK recognizes and phosphorylates downstream kinases including CaMKI, IV, and AMPK by using an Arg/Pro rich insert domain (RP-domain, D) [39,65]. Amino acid sequence alignments of the regulatory domain including the autoinhibitory and Ca2+/CaM binding segments (C) and RP-domain (D) in various CaMKKs (rat, human α/1 and β/2 isoforms, and C. elegans). Trp(W)444 and Phe(F)459 in rat CaMKKα/1 (C) are conserved anchoring residues (indicated by light blue boxes) to the N- and C-terminal hydrophobic pockets of Ca2+/CaM, respectively [66]. Ile(I)441 (indicated by a pink box, C) is important for rat CaMKKα/1 autoinhibition [64]. (E) Ribbon diagram of the NMR structure of Ca2+/CaM-CaMKKα/1 regulatory domain peptide (residues 438−463, C) complex was obtained from the Protein Data Bank (PDB) entry 1ckk [66] and was visualized using the UCF Chimera [67]. Modified from Ref. [68].
Figure 2
Figure 2
CaMKKβ/2 activation mechanism and immunohistochemical localization in the rat brain. (A) Sagittal section of the adult rat brain immunostained with a monoclonal antibody against CaMKKβ/2 (reproduced from Ref. [61], with permission from John Wiley and Sons). CA1 and CA3, CA1 and CA3 subregions of Ammon’s horn of the hippocampus; Cb, cerebellar cortex; CP, caudate putamen; Cx, cerebral cortex; DG, dentate gyrus; MO, medulla oblongata; OB, olfactory bulb; Pn, pontine nuclei; SNr, substantia nigra pars reticulata; Th, thalamus; and Tu, olfactory tubercle. Scale bar = 2.5 mm. (B) Proposed model of activation mechanism of CaMKKβ/2. CaMKKβ/2 is constitutively active, exhibiting Ca2+/CaM-independent activity (60–70% of total activity), attributable to the N-terminal regulatory segment (residues 129–151, C) [22,31]. CaMKKβ/2 exhibits increased autonomous activity, caused, at least in part, by intramolecular autophosphorylation at Thr482, resulting in partial disruption of the autoinhibitory mechanism [76]. Phosphorylation at multiple sites in CaMKKβ/2 by CDK5 and GSK3 [77], activated AMPK [78] or PKA [79], likely disrupting the N-terminal regulatory function to generate autonomous activity, thereby holding the inactive kinase in the absence of Ca2+/CaM, in agreement with the finding that CaMKKβ/2-AMPK pathway activation requires Ca2+/CaM signaling [33,34,35]. (C) Amino acid sequence alignment of the N-terminal regulatory segment in rat and human CaMKKβ/2. CDK5/GSK3 phosphorylate human CaMKKβ/2 at Ser129, Ser133, and Ser137 [77]. Activated AMPK and PKA phosphorylate Thr144 in rat CaMKKβ/2 [78,79]. Modified from Ref. [68].
Figure 3
Figure 3
CaMKK-mediated cellular signaling. Increasing intracellular Ca2+ concentration triggers the Ca2+/CaM-dependent activation of CaMKK, resulting in the activation of the downstream protein kinases including CaM-kinase I (CaMKI), CaM-kinase IV (CaMKIV), AMPK (5′AMP-kinase), and protein kinase B (PKB/Akt) through the phosphorylation of their activation-loop Thr residues. The CaMKK-mediated phosphorylation cascade is involved in a wide variety of physiological functions including transcriptional activation, neuronal development and plasticity, metabolic regulation, and cell survival. CaMKK is regulated by multiple cellular signaling cascades, such as intracellular Ca2+, cAMP/PKA signaling, 14-3-3-binding, feedback phosphorylation by activated AMPK, and cyclin-dependent protein kinase 5 (CDK5)/glycogen synthase kinase 3 (GSK3)-mediated phosphorylation. Modified from Ref. [68]. Cream yellow boxes indicate physiological functions of CaMKK-mediated signaling pathways. CREB; cAMP-response element binding protein, βPIX; Pax-interacting exchange factor β, GEF-H1; guanine nucleotide exchange factor H1, ACC; acetyl-CoA carboxylase, ULK1; Unc51-like-kinase 1, and BAD; BCL2 associated agonist of cell death.
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