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Cdc2/Cyclin B1 Interacts with and Modulates Inositol 1,4,5-Trisphosphate Receptor (Type 1) Functions¹

Xiaogui Li^2,*, Krishnamurthy Malathi^2,*, Olga Krizanova, Karol Ondrias, Kirk Sperber, Vitaly Ablamunits^* and Thottala Jayaraman^3,*,

^* Vascular Biology Laboratory, Department of Neurosurgery, St. Luke’s Roosevelt Hospital Center, New York, NY 10025; Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032; Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Bratislava, Slovak Republic; and Department of Immunobiology, Mount Sinai Medical Center, New York, NY 10029

The resistance of inositol 1,4,5-trisphosphate receptor (IP₃R)-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 IP₃-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 Arg³⁹¹, Arg⁴⁴¹, and Arg⁸⁷¹; 2) IP₃R1 phosphorylation at Thr⁷⁹⁹ by the cdc2/CyB complex increases IP₃ binding; and 3) cdc2/CyB phosphorylation increases IP₃-gated Ca²⁺ release. Taken together, these results demonstrate that cdc2/CyB phosphorylation positively regulates IP₃-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 inhibitor(s) may constitute a new therapy for the treatment of several human immune disorders.

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

X Li, K. Malathi, O. Krizanova, K. Ondrias, K. Sperber, V. Ablamunits, and T. Jayaraman
The JI 2005 175: 8440. [Full Text]  

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