Cdc2/cyclin B1 interacts with and modulates inositol 1,4,5-trisphosphate receptor (type 1) functions

The resistance of inositol 1,4,5-trisphosphate receptor (IP ₃R)-deficient cells to multiple forms of apoptosis demonstrates the importance of IP₃-gated calcium (Ca²⁺) release to cellular apoptosis. However, the specific upstream biochemical events leading to IP ₃-gated Ca²⁺ release during apoptosis induction are not known. We have shown previously that the cyclin-dependent kinase 1/cyclin B (cdk1/CyB or cdc2/CyB) complex phosphorylates IP₃R1 in vitro and in vivo at Ser⁴²¹ and Thr⁷⁹⁹. In this study, we show that: 1) the cdc2/CyB complex directly interacts with IP₃R1 through Arg ³⁹¹, Arg⁴⁴¹, and Arg⁸⁷¹; 2) IP₃R1 phosphorylation at Thr⁷⁹⁹ by the cdc2/CyB complex increases IP ₃ binding; and 3) cdc2/CyB phosphorylation increases IP ₃-gated Ca²⁺ release. Taken together, these results demonstrate that cdc2/CyB phosphorylation positively regulates IP ₃-gated Ca²⁺ signaling. In addition, identification of a CyB docking site(s) on IP₃R1 demonstrates, for the first time, a direct interaction between a cell cycle component and an intracellular calcium release channel. Blocking this phosphorylation event with a specific peptide in inhibitor(s) may constitute a new therapy for the treatment of several human immune disorders.