CaMKIV (CAMK4) becomes fully activated after a three-step mechanism. In the first step, upon a transient increase in intracellular calcium, calcium-bound calmodulin (Ca2+/CaM) binds to its autoregulatory domain, which relieves intersteric inhibition (Chatila et al. 1996, Tokumitsu et al. 2004). In the second step, an activating protein kinase, calcium/calmodulin-dependent protein kinase kinase (CaMKK), binds to the Ca2+/CaM:CaMKIV complex and phosphorylates CaMKIV on a threonine residue in the activation loop (Chatila et al. 1996, Anderson et al. 1998, Tokumitsu et al. 2004). In the third step, CaMKK-phosphorylated CAMK4 autophosphorylates on two serine residues at the N-terminus (Chatila et al. 1996). After full activation by the three-step mechanism mentioned above, the activity of CaMKIV becomes autonomous and no longer requires bound Ca2+/CaM. This activity is required for CaMKIV-mediated transcriptional regulation. The CaMKIV-associated PP2A then dephosphorylates CaMKIV, thereby terminating autonomous activity and CaMKIV-mediated gene transcription.