Cell cycle-coupled CK1δ turnover, autoinhibition, and activity

Casein kinase 1{delta} (CK1{delta}) is a ubiquitously expressed kinase involved in diverse cellular processes, including cell cycle regulation. CK1{delta} activity is attenuated by (auto)phosphorylation. However, inhibitory phosphorylation is efficiently opposed by cellular phosphatases as CK1{delta} accumulates in its hypophosphorylated, active state. CK1{delta} is a target of the nuclear ubiquitin ligase APC/C-CDH1, yet the kinase is apparently stable. Thus, the physiological relevance of CK1{delta} (auto)phosphorylation, autoinhibition, and regulated turnover has remained unclear. Here we show that CK1{delta} activity and abundance are coordinated in a cell cycle-dependent manner. During G1, assembled CK1{delta} kinase is stable while free active kinase is degraded. In S phase, unassembled CK1{delta} is no longer degraded, likely to support functions in DNA damage signaling. Upon mitotic entry, the downregulation of phosphatases promotes CK1{delta} (auto)phosphorylation and consequent autoinhibition, thereby preserving a pool of kinase to rapidly reestablish the post-mitotic steady state.