Calcium is a major second messenger in all cells, and is integral in many important signalling pathways. Changes in intracellular Ca2+ regulate many biological processes, including neurotransmitter release, gene expression, and the cell cycle. Though free Ca2+ can activate a number of proteins directly (for example myosin, phospholipase A2, and protein kinase C), it regulates the activity of many enzymes indirectly via a number of low molecular weight Ca2+ binding proteins, the most abundant of which is calmodulin (CaM). There are three main families of restricted Ca2+/CaM stimulated protein kinases: phosphorylase kinase (PhK), elongation factor 2 kinase (eEF2K) and myosin light chain kinase (MLCK). The most basic method of controlling kinase function is via the regulation of Ca2+ dynamics, specifically the frequency, amplitude and duration of oscillations in the intracellular concentration of Ca2+. 
The multifunctional Ca2+/CaMstimulated protein kinase II (CaMKII) can translate the frequency of Ca2+ spikes into corresponding amounts of kinase activity.The multifunctional calcium/calmodulin stimulated protein kinases can be classified into two broad families based on the homology of their domain structures.The four kinases which form one family  – calcium/calmodulin stimulated protein kinase kinase (CaMKK) and calcium/calmodulin stimulated protein kinase I, IV and II (CaMKI, CaMKIV and CaMKII). Calcium/calmodulin stimulated protein kinase kinase (CaMKK) is a multifunctional protein kinase encoded by two genes (CAMKK1 and CAMKK2) that produce CaMKKα and CaMKKβ, respectively. CaMKK, CaMKI and CaMKIV have been shown to form a signalling pathway termed the Ca2+/CaM-dependent kinase cascade, which has been implicated in several cellular processes, including axonal and dendritic outgrowth and elongation, adiposity regulation, glucose homeostasis, hematopoietic stem cell maintenance, cell proliferation, apoptosis, and normal immune cell function.


1.Kaestner L,et al. Adv Exp Med Biol. 2020;1131:625-648.