Research Papers:

The trans-membrane domain of Bcl-2α, but not its hydrophobic cleft, is a critical determinant for efficient IP3 receptor inhibition

Hristina Ivanova, Abigael Ritane, Larry Wagner, Tomas Luyten, George Shapovalov, Kirsten Welkenhuyzen, Bruno Seitaj, Giovanni Monaco, Humbert De Smedt, Natalia Prevarskaya, David I. Yule, Jan B. Parys and Geert Bultynck _

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Oncotarget. 2016; 7:55704-55720. https://doi.org/10.18632/oncotarget.11005

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Hristina Ivanova1, Abigael Ritaine2, Larry Wagner3, Tomas Luyten1, George Shapovalov2, Kirsten Welkenhuyzen1, Bruno Seitaj1, Giovanni Monaco1, Humbert De Smedt1, Natalia Prevarskaya2, David I. Yule3, Jan B. Parys1, Geert Bultynck1

1Katholieke Universiteit Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine and Leuven Cancer Institute (LKI), BE-3000 Leuven, Belgium

2Inserm U-1003, Equipe Labellisée par la Ligue Nationale Contre le Cancer et LABEX (Laboratoire d'excellence), Université Lille1, 59655 Villeneuve d'Ascq, France

3University of Rochester Medical Center School of Medicine and Dentistry, Rochester, NY 14642, USA

Correspondence to:

Geert Bultynck, email: [email protected]

Keywords: calcium signaling, anti-apoptotic Bcl-2, trans-membrane domain, hydrophobic cleft, IP3 receptor

Received: March 03, 2016     Accepted: July 18, 2016     Published: August 2, 2016


The anti-apoptotic Bcl-2 protein is emerging as an efficient inhibitor of IP3R function, contributing to its oncogenic properties. Yet, the underlying molecular mechanisms remain not fully understood. Using mutations or pharmacological inhibition to antagonize Bcl-2’s hydrophobic cleft, we excluded this functional domain as responsible for Bcl-2-mediated IP3Rs inhibition. In contrast, the deletion of the C-terminus, containing the trans-membrane domain, which is only present in Bcl-2α, but not in Bcl-2β, led to impaired inhibition of IP3R-mediated Ca2+ release and staurosporine-induced apoptosis. Strikingly, the trans-membrane domain was sufficient for IP3R binding and inhibition. We therefore propose a novel model, in which the Bcl-2’s C-terminus serves as a functional anchor, which beyond mere ER-membrane targeting, underlies efficient IP3R inhibition by (i) positioning the BH4 domain in the close proximity of its binding site on IP3R, thus facilitating their interaction; (ii) inhibiting IP3R-channel openings through a direct interaction with the C-terminal region of the channel downstream of the channel-pore. Finally, since the hydrophobic cleft of Bcl-2 was not involved in IP3R suppression, our findings indicate that ABT-199 does not interfere with IP3R regulation by Bcl-2 and its mechanism of action as a cell-death therapeutic in cancer cells likely does not involve Ca2+ signaling.

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