Both isoforms of CaMKK, CAMKK1 (CaMKK-alpha) and CAMKK2 (CaMKK-beta) are fully activated upon autophosphorylation, which, under physiological conditions, takes places after binding to the Ca2+/calmodulin complex (CALM1:4xCa2+) (Okuno et al. 1997, Yamamori et al. 2004). While several autophosphorylation sites in both CAMKK1 and CAMKK2 have been reported, it is not clear whether these sites are calmodulin-dependent and physiologically relevant (Tokumitsu et al. 2011, Scott et al. 2015). CAMKK1 is negatively regulated by phosphorylation of S74 and T108 by PKA. Constitutive phosphorylation of CAMKK2 by GSK3B and CDK5 may be required to prevent calmodulin-independent phosphorylation (Green et al. 2011). Once activated, CaMKK phosphorylates CaMKIV in a Ca2+/Calmodulin dependent manner (Yamamori et al. 2004). Because of uncertain localization of CaMKKs (Nakamura et al. 1996, Sakagami et al. 2000, Nakamura et al. 2001, Kitani et al. 2003), CaMKK autophosphorylation may occur in the nucleus, or in the cytosol, or in both cellular compartments.