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

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.

Lithium and exercise ameliorate insulin-deficient hyperglycemia by independently attenuating pancreatic α-cell mass and hepatic gluconeogenesis

“…4a,b). Moreover, CaMKK2 levels, which are known to be involved in AMPK activation and muscle regeneration [21], tended to be lower after STZ treatment (Fig. 4a,c).…”

SARS-CoV-2 accessory proteins ORF3a and ORF7a modulate autophagic flux and Ca2+homeostasis in yeast

“…Several viroporins from other viruses have been shown to manipulate Ca 2+ homeostasis for the benefit of their own multiplication (Nieva et al, 2012). Specificallly, it is well known for some viroporins that their Ca 2+ release function is aimed at the stimulation of autophagy via activation of Ca 2+ /calmodulin and the AMP-activated protein kinase AMPK (Crawford et al, 2012; Crawford and Estes, 2013; Tokumitsu and Sakagami, 2022). An exciting hypothesis could be that SARS-CoV-2 ORF3a might have evolved as a dual function autophagy modulator, (i) stimulating autophagy indirectly via Ca 2+ release from vacuoles/lysosomes and (ii) inhibiting directly the processing of autophagosomes at vacuoles/lysosomes by interfering with SNARE complex binding.…”

The role of CaMKK2 in Golgi-associated vesicle trafficking

“…CaMKK2 has a significant kinase activity at steady state, but its activity is significantly increased by an elevation in intracellular Ca 2+ and binding of calcium–calmodulin (CaM) [ 6–8 ]. The interaction of CaMKK2 with CaM releases the binding of the autoinhibitory region and leads to the activation of the enzymatic activity [ 9 , 10 ]. Its autonomous activity is dependent on the autophosphorylation of Thr482 in the C-terminal regulatory domain, while the calmodulin-dependent activity is dependent on the phosphorylation of serine residues in the N-terminal regulatory domain [ 11 ].…”