Serine/threonine protein phosphatases PP1 and PP2A are key players in apoptosis Alphonse Garcia a, *, Xavier Cayla b , Julien Guergnon a , Frédéric Dessauge a , Véronique Hospital a , Maria Paz Rebollo c , Aarne Fleischer d , Angelita Rebollo d a Laboratoire de Signalisation Immunoparasitaire, URA CNRS 2581, Département de Parasitologie, Institut Pasteur, 25, rue du Dr Roux, 75015 Paris, France b Equipe hypophyse, UMR 6073 INRA-CNRS, Université de Tours, Physiologie de la Reproduction et des Comportements, 37380 Nouzilly, France c Hospital General de Leon, Altos de Nava s/n, 24071 Leon, Spain d Laboratoire d’Immunologie Cellulaire et Tissulaire, INSERM U543, Bâtiment CERVI, Hôpital Pitié-Salpêtrière, 83, bd de l’Hôpital, 75013 Paris, France Received 15 May 2003; accepted 9 September 2003 Abstract The reversible phosphorylation of proteins controlled by protein kinases and protein phosphatases is a major mechanism that regulates a wide variety of cellular processes. In contrast to C. elegans, recent studies in mammalian cells have highlighted a major role of serine/threonine protein phosphorylation in apoptosis. To illustrate the importance of dephosphorylation processes in apoptosis, this review will focus on recent studies suggesting that the interaction of the serine/threonine protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) with certain regulators of the Bcl-2 family is critically involved in the control of apoptosis. © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. Keywords: Apoptosis; PP1; PP2A; Bcl-2; Bad 1. Introduction Apoptosis is a genetically programmed form of cell death, which plays a pivotal role in morphogenesis and develop- ment of multicellular organisms as well as for the removal of damaged cells or potentially dangerous tumour cells. De- regulation of the apoptosis machinery can result in the devel- opment of many human diseases and it has been experimen- tally demonstrated in AIDS, Alzheimer, autoimmunity (lupus, type-I diabetes, rheumatoid arthritis), cancer, heart failure, inflammation and osteoporosis [1–3]. In eukaryotic cells, the activity of at least 30% of proteins can be regulated by phosphorylation. Reversible protein phosphorylation catalysed by protein kinases and protein phosphatases regulates numerous cellular processes includ- ing apoptosis (for general review see [4]). Protein phospho- rylation can also regulate the activity of both protein kinases and protein phosphatases generating, therefore, sophisticated intracellular regulatory networks (reviewed in [5,6]). Inter- estingly, kinases and phosphatases may even interact with the same protein but at different docking sites [7]. Phosphorylation/dephosphorylation of distinct survival signalling pathways regulated by cytokines have been inten- sively investigated in mammalian cells. These studies mainly concern multipotential hematopoietic growth factors such as interleukin-3 (IL-3) or interleukin-2 (IL-2), which in turn activate major apoptotic pathways such as Ras-pathways, proteins of the Bcl-2 family, caspases or even transcription factors including NF-jB and AP1 [8–10]. In this review we focus on the significance and complexity of phosphorylation and dephosphorylation of the Bcl-2 fam- ily proteins. Based on multiple interactions between Bcl-2 and PP1/PP2A phosphatases, we proposed a hypothetical model that may explain how cross talks between both PP1 and PP2A could control cell survival (Fig. 1). * Corresponding author. Tel.: +33-1-40-61-38-21; fax: +33-1-45-68-86-39. E-mail address: agarcia@pasteur.fr (A. Garcia). Biochimie 85 (2003) 721–726 www.elsevier.com/locate/biochi © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. doi:10.1016/j.biochi.2003.09.004