Controlling the cell cycle: The role of calcium/calmodulin-stimulated protein kinases I and II

Many studies have implicated Ca2+ and calmodulin (CaM) as regulators of the cell cycle. Ca2+/CaM-stimulated proteins, including the family of multifunctional Ca2+/CaM-stimulated protein kinases (CaMK), have also been identified as mediators of cell cycle progression. CaMKII is the best-characterized member of this family, and is regulated by multi-site phosphorylation and targeting. Using pharmacological inhibitors that were believed to be specific for CaMKII, CaMKII has been implicated in every phase of the cell cycle. However, these ‘specific’ inhibitors also produce effects on other CaMKs. These additional effects are usually ignored, and the effects of the inhibitors are normally attributed to CaMKII without further investigation. Using new specific molecular techniques, it has become clear that CaMKI is an important regulator of G1, whereas CaMKII is essential for regulating G2/M and the metaphase-anaphase transition. If the mechanisms controlling these events can be fully elucidated, new targets for controlling proliferative diseases may be identified.