Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK1 signaling cascade and, upon calcium influx, activates CREB-dependent gene transcription, regulates calcium-mediated granulocyte function and respiratory burst and promotes basal dendritic growth of hippocampal neurons. In neutrophil cells, required for cytokine-induced proliferative responses and activation of the respiratory burst. Activates the transcription factor CREB1 in hippocampal neuron nuclei. May play a role in apoptosis of erythroleukemia cells. In vitro, phosphorylates transcription factor CREM isoform Beta (By similarity). Isoform 1 but not isoform 2 activates CREB1. ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein] ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-threonyl-[protein] Activated by Ca(2+)/calmodulin. Binding of calmodulin results in conformational change that relieves intrasteric autoinhibition and allows phosphorylation of Thr-180 within the activation loop by CaMKK1 or CaMKK2. Phosphorylation of Thr-180 results in several fold increase in total activity. Unlike CaMK4, may be unable to exhibit autonomous activity after Ca(2+)/calmodulin activation (By similarity). Predominantly cytoplasmic. Nuclear upon activation. Expressed ubiquitously with high levels in brain and low levels in kidney. Isoform 2 is highly expressed in brain compared to other tissues. In hematopoietic cell lines predominant expression was detected in T and EC cells. In EML cell line differentiation, expression increases 4 to 8 hours after treatment with all-trans retinoic acid (ATRA) and then declines after 24 hours of ATRA induction. Down-regulated upon cholesterol-rich diet. The autoinhibitory domain overlaps with the calmodulin binding region and interacts in the inactive folded state with the catalytic domain as a pseudosubstrate. Inactive. Does not activate CREB1. Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CaMK subfamily.