Article

Bcl-2 Phosphorylation by p38 MAPK: Identification of target sites and biologic consequences

University of Florence, Florens, Tuscany, Italy
Journal of Biological Chemistry (Impact Factor: 4.6). 08/2006; 281(30):21353-61. DOI: 10.1074/jbc.M511052200
Source: PubMed

ABSTRACT The antiapoptotic role of Bcl-2 can be regulated by its phosphorylation in serine and threonine residues located in a nonstructured loop that links BH3 and BH4 domains. p38 MAPK has been identified as one of the kinases able to mediate such phosphorylation, through direct interaction with Bcl-2 protein in the mitochondrial compartment. In this study, we identify, by using mass spectrometry techniques and specific anti-phosphopeptide antibodies, Ser(87) and Thr(56) as the Bcl-2 residues phosphorylated by p38 MAPK and show that phosphorylation of these residues is always associated with a decrease in the antiapoptotic potential of Bcl-2 protein. Furthermore, we obtained evidence that p38 MAPK-induced Bcl-2 phosphorylation plays a key role in the early events following serum deprivation in embryonic fibroblasts. Both cytochrome c release and caspase activation triggered by p38 MAPK activation and Bcl-2 phosphorylation are absent in embryonic fibroblasts from p38alpha knock-out mice (p38alpha(-/-) MEF), whereas they occur within 12 h of serum withdrawal in p38alpha(+/+) MEF; moreover, they can be prevented by p38 MAPK inhibitors and are not associated with the synthesis of the proapoptotic proteins Bax and Fas. Thus, Bcl-2 phosphorylation by activated p38 MAPK is a key event in the early induction of apoptosis under conditions of cellular stress.

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    • "However, the antiapoptotic effects of Bcl2 were negated by its phosphorylation by p38 MAPK (Fig. 5c). Phosphorylation of Bcl2 by p38 to pBcl2ser87 resulted in decrease of the anti-apoptotic potential, and pBcl2 is an important player in the initiation of the apoptotic signaling cascade (De Chiara et al. 2006) including release of cytochrome c and caspase activation. Thus, the present study also points out an important role of p38 in pro-apoptotic signaling through phosphorylation of Bcl2. "
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