Bcl-2 Phosphorylation by p38 MAPK: identification of target sites and biologic consequences - PubMed (original) (raw)

. 2006 Jul 28;281(30):21353-21361.

doi: 10.1074/jbc.M511052200. Epub 2006 May 19.

Maria Elena Marcocci [ 2](#full-view-affiliation-2 "Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata", Via Montpellier 1, I-00133 Rome, Italy."), Maria Torcia 3, Maria Lucibello 4, Paolo Rosini 3, Paolo Bonini 3, Yukiro Higashimoto 5, Gianluca Damonte 6, Andrea Armirotti 6, Sarah Amodei 3, Anna Teresa Palamara [ 7](#full-view-affiliation-7 "Department of Public Health Science "G. Sanarelli," University of Rome "La Sapienza," Piazzale A. Moro 5, I-00185 Rome, Italy."), Tommaso Russo [ 8](#full-view-affiliation-8 "CEINGE Biotecnologie Avanzate, Department of Biochemistry and Medical Biotechnologies, University of Naples "Federico II," Via Comunale Margherita 482, I-80131 Naples, Italy."), Enrico Garaci [ 2](#full-view-affiliation-2 "Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata", Via Montpellier 1, I-00133 Rome, Italy."), Federico Cozzolino 9

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

Giovanna De Chiara et al. J Biol Chem. 2006.

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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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