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 (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.
Malathi
Krishnamurthy
K
Vascular Biology Laboratory, Department of Neurosurgery, St. Luke's Roosevelt Hospital Center, New York, NY 10025, USA.
Li
Xiaogui
X
Krizanova
Olga
O
Ondrias
Karol
K
Sperber
Kirk
K
Ablamunits
Vitaly
V
Jayaraman
Thottala
T
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology*; D020013:Calcium Signaling; D019926:Cyclin B / Q000502:physiology*; D056744:Cyclin B1; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D010766:Phosphorylation; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*
C534699:CCNB1 protein, human; D015220:Calcium Channels; C534701:Ccnb1 protein, rat; D019926:Cyclin B; D056744:Cyclin B1; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D015544:Inositol 1,4,5-Trisphosphate; D016203:CDC2 Protein Kinase; D002118:Calcium