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Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival

Melissa R. Junttila^*, Song-Ping Li and Jukka Westermarck^*,,1

^* Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland;

Institute of Biomedicine, Department of Molecular Medicine, University of Helsinki, and National Public Health Institute (KTL), Biomedicum, Helsinki, Finland; and

Institute of Medical Technology, University of Tampere and University Hospital of Tampere, Tampere, Finland

¹Correspondence: Institute of Medical Technology, University of Tampere, Biokatu 6–8, 33250 Tampere, Finland. E-mail: ltjuwe{at}uta.fi

Mitogen-activated protein kinase (MAPK) pathways constitute a large modular network that regulates a variety of physiological processes, such as cell growth, differentiation, and apoptotic cell death. The function of the ERK pathway has been depicted as survival-promoting, in essence by opposing the proapoptotic activity of the stress-activated c-Jun NH₂-terminal kinase (JNK)/p38 MAPK pathways. However, recently published work suggests that extracellular regulated kinase (ERK) pathway activity is suppressed by JNK/p38 kinases during apoptosis induction. In this review, we will summarize the current knowledge about JNK/p38-mediated mechanisms that negatively regulate the ERK pathway. In particular, we will focus on phosphatases (PP2A, MKPs) as inhibitors of ERK pathway activity in regulating apoptosis. A model proposed in this review places the negative regulation of the ERK pathway in a central position for the cellular decision-making process that determines whether cells will live or die in response to apoptosis-promoting signals. In addition, we will discuss the potential functional relevance of negative regulation of ERK pathway activity, for physiological and pathological conditions (e.g., cellular transformation).—Junttila, M.R., Li, S.-P., Westermarck, J. Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival.

Key Words: protein phosphatase • MKK • p38 • ERK • transformation • cancer