Calcium/calmodulin-dependent protein kinase kinase 2: roles in signaling and pathophysiology

Abstract

Many cellular Ca(2+)-dependent signaling cascades utilize calmodulin (CaM) as the intracellular Ca(2+) receptor. Ca(2+)/CaM binds and activates a plethora of enzymes, including CaM kinases (CaMKs). CaMKK2 is one of the most versatile of the CaMKs and will phosphorylate and activate CaMKI, CaMKIV, and AMP-activated protein kinase. Cell expression of CaMKK2 is limited, yet CaMKK2 is involved in regulating many important physiological and pathophysiological processes, including energy balance, adiposity, glucose homeostasis, hematopoiesis, inflammation, and cancer. Here, we explore known functions of CaMKK2 and discuss its potential as a target for therapeutic intervention.

FIGURE 1.

Schematic representation of the structure-activity relationships of CaMKK2. A, CaMKK2 consists of unique N- and C-terminal domains (blue and green, respectively) and a central Ser/Thr-directed kinase domain (red) that is followed by a regulatory domain composed of overlapping autoinhibitory and CaM-binding regions (Autoreg/CaM, gray). A region of 23 amino acids (residues 129–151) located at the N terminus of the catalytic domain has been identified as an important regulatory element. CDK5 and GSK3 phosphorylate Ser-129, Ser-133, and Ser-137. PKA phosphorylates Ser-100, Ser-495, and Ser-511. Thr-482 has been identified as an auto/transphosphorylation site. B, although CaMKK2 has autonomous activity for some substrates, binding to Ca²⁺/CaM relieves autoinhibition, resulting in a fully active kinase. Mutation of Ser-129, Ser-133, and Ser-137 increases autonomous activity with little change in Ca²⁺/CaM-dependent activity. Of note, mutation of Ser-129, Ser-133, and Ser-137 also decreases the stability of CaMKK2. This implies that the autonomously active CaMKK2 generated by dephosphorylation of these Ser residues would display a shorter half-life and be more rapidly degraded. Mutation of PKA residues does not affect CaMKK2 autonomous activity. Phosphorylation of Ser and Thr residues is depicted as blue and red clouds, respectively.

FIGURE 2.

CaMKK2 functions as a molecular hub to regulate critical cell functions. CaMKK2 can be activated by signaling through G_q-coupled receptors, IP₃-mediated release of Ca²⁺ via activation of the IP₃ receptor, or Ca²⁺ entry into cells via plasma membrane ion channels (i.e. voltage-dependent calcium channel (VDCC)). Calcium signals from integrin and other immunoreceptor tyrosine-based activation motif (ITAM)-coupled immune receptors can activate IP₃-mediated release of Ca²⁺, activate CaMKK2, and cross-regulate heterologous receptors, such as the Toll-like receptors (TLR). Signaling pathways modulating GSK3/CDK5 activities can modulate the stability and autonomous activity of CaMKK2. Signals regulating the intracellular level of cAMP can activate EPAC/PKA-dependent pathways and, in turn, regulate CaMKK2 activity. CaMKI, CaMKIV, and AMPK couple CaMKK2 to multiple downstream cascades, which conspire to regulate critical cell functions. FcR, Fc receptor; PDE, phosphodiesterase.