Suppression of signalling through transcription factor NF-AT by interactions between calcineurin and Bcl-2

• DOI: 10.1038/386728a0
• Publication Date: 2003-08-12T02:26:52Z
• Authors: Futoshi Shibasaki; Eisaku Kondo; Tadaatsu Akagi; Frank McKeon
• Keywords: Cell Nucleus; B-Lymphocytes; 0303 health sciences; Binding Sites; NFATC Transcription Factors; Calcineurin; Molecular Sequence Data; Nuclear Proteins; Biological Transport; Intracellular Membranes; Cell Line; DNA-Binding Proteins; 03 medical and health sciences; Cricetinae; Proto-Oncogene Proteins; Consensus Sequence; Phosphoprotein Phosphatases; Animals; Humans; Calmodulin-Binding Proteins; Amino Acid Sequence; Protein Binding

It is not known how the protein Bcl-2 inhibits cell death induced by calcium signalling and growth-factor withdrawal. Here we report that Bcl-2 forms a tight complex with calcineurin, resulting in the targeting of calcineurin to Bcl-2 sites on cytoplasmic membranes, and show that this interaction is dependent on the BH4 domain of Bcl-2. Calcineurin bound to Bcl-2 is an active phosphatase but is unable to promote the nuclear translocation of NF-AT, a transcription-factor required for induction of interleukin-2 expression, suggesting a mechanism by which Bcl-2 suppresses NF-AT activity. We also show that Bax, a pro-apoptotic member of the Bcl-2 family, interferes with interactions between calcineurin and Bcl-2. We propose that the ability of Bcl-2 to block NF-AT signalling is due to the sequestering of active calcineurin to the same domain of Bcl-2 which associates with Rad-1 (ref. 5), and that calcineurin may act in Bcl-2-regulated functions.