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

Giovanna De Chiara, Maria Elena Marcocci, Maria Torcia, Maria Lucibello, Paolo Rosini, Paolo Bonini, Yukiro Higashimoto, Gianluca Damonte, Andrea Armirotti, Sarah Amodei, Anna Teresa Palamara, Tommaso Russo, Enrico Garaci, Federico Cozzolino

Research output: Contribution to journalArticlepeer-review

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 Thr56 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 p38α knock-out mice (p38α-/- MEF), whereas they occur within 12 h of serum withdrawal in p38α+/+ 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.

Original languageEnglish
Pages (from-to)21353-21361
Number of pages9
JournalJournal of Biological Chemistry
Volume281
Issue number30
DOIs
Publication statusPublished - Jul 28 2006

ASJC Scopus subject areas

  • Biochemistry

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