CaMKK2: bridging the gap between Ca2+ signaling and energy-sensing

Abstract

Calcium (Ca2+) ions are ubiquitous and indispensable signaling messengers that regulate virtually every cell function. The unique ability of Ca2+ to regulate so many different processes yet cause stimulus specific changes in cell function requires sensing and decoding of Ca2+ signals. Ca2+-sensing proteins, such as calmodulin, decode Ca2+ signals by binding and modifying the function of a diverse range of effector proteins. These effectors include the Ca2+-calmodulin dependent protein kinase kinase-2 (CaMKK2) enzyme, which is the core component of a signaling cascade that plays a key role in important physiological and pathophysiological processes, including brain function and cancer. In addition to its role as a Ca2+ signal decoder, CaMKK2 also serves as an important junction point that connects Ca2+ signaling with energy metabolism. By activating the metabolic regulator AMP-activated protein kinase (AMPK), CaMKK2 integrates Ca2+ signals with cellular energy status, enabling the synchronization of cellular activities regulated by Ca2+ with energy availability. Here, we review the structure, regulation, and function of CaMKK2 and discuss its potential as a treatment target for neurological disorders, metabolic disease, and cancer.

Keywords: AMPK; CaMKK2; calcium signaling; calmodulin; energy-sensing.

Figure 1. CaMKK2 signaling pathway

CaMKK2 is activated by voltage and ligand-gated Ca²⁺ channels (Ca_V1.2 and NMDA receptor) as well as hormone receptors (GSHR) that increase intracellular Ca²⁺ and cause accumulation of the Ca²⁺-calmodulin complex. CaMKK2 decodes Ca²⁺ signals generated by these cell surface activators by triggering the downstream activation of the CaMK1, CaMK4, AMPK, and Akt/PKB signaling pathways. Through these downstream pathways, CaMKK2 regulates a variety of cellular processes that support brain function and whole-body energy homeostasis.

Figure 2. Domain structure of CaMKK2 protein isoforms

The domain structure of the seven known protein isoforms of human CaMKK2 displaying the location of the kinase domain (cyan), RP-insert (blue), the partially overlapping autoinhibitory (AIS; green and black stripes) and calmodulin-binding sequences (CaMBS; green), as well as the regulatory S3-node (orange). The N-terminal regions of each CaMKK2 isoform are highly-conserved but they differ in their C-terminal sequences. Of note, isoform-3 has an alternative C-terminal sequence of unknown function (yellow and black stripes). Isoform-7 also has an alternative C-terminal sequence (red and black stripes) that is unique from the other isoforms that contains a putative nuclear localisation sequence (NLS).

Figure 3. CaMKK2 is a signaling hub for multiple signal transduction pathways

The domain structure of human CaMKK2 showing the positions of the regulatory phosphorylation sites. Autophosphorylation of Thr85 and Thr486 enhance CaMKK2 activity. In the S3-node, phosphorylation of Ser137 by CDK5 primes CaMKK2 for subsequent phosphorylation on Ser133 and Ser129 by GSK3, which decreases CaMKK2 activity. Phosphorylation of Ser100, Ser495 and Ser511 by PKA blocks CaMKK2 activation by Ca²⁺-calmodulin, and promotes the binding of 14-3-3 adaptor proteins, which keep CaMKK2 in an inactive state.