Regulation of Mammalian Target of Rapamycin Complex 1 by Bcl-2 and Bcl-XL Proteins

Background: mTORC1 is a protein kinase that plays a central role in cell growth and metabolism. Results: mTORC1 signaling activity is affected by expression levels of two apoptotic proteins, Bcl-2 and Bcl-X L . Conclusion: Bcl-2 and Bcl-X L control mTORC1 activity by affecting the binding of mTORC1 with its inhibitor FKBP38. Significance: The novel cross-talk between Bcl-2/X L and mTORC1 signaling is likely to play an important role in cancer development. Mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cell growth and metabolism. Its activity is controlled by various types of signals, including growth factors, nutrients, and stresses. In this study, we show that changes in expression levels of two antiapoptotic proteins, Bcl-2 and Bcl-X L , also affect mTORC1 signaling activity. In cells overexpressing Bcl-X L , mTORC1 activity is increased and becomes less sensitive to growth factor or nutrient conditions. In contrast, reduction in expression levels of the two antiapoptotic proteins inhibits mTORC1 signaling activity. Our results suggest that the effect of Bcl-2 and Bcl-X L on mTORC1 is mediated by FKBP38, an inhibitor of mTORC1. The two proteins compete with mTORC1 for FKBP38 binding and hence alter mTORC1 activity. This study reveals a novel cross-talk between Bcl-2/X L and mTORC1 signaling, which is likely to contribute to cancer development.