Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival.
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 NH(2)-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
Melissa R
MR
Turku Centre for Biotechnology, University of Turku and Abo Akademi University, Turku, Finland.
Li
Song-Ping
SP
Westermarck
Jukka
J
D000818:Animals; D002470:Cell Survival / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*
D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases