Abstract
MAPK (mitogen-activated protein kinase) signaling pathways regulate a variety of biological processes through multiple cellular mechanisms. In most of these processes, such as apoptosis, MAPKs have a dual role since they can act as activators or inhibitors, depending on the cell type and the stimulus. In this review, we present the main pro- and anti-apoptotic mechanisms regulated by MAPKs, as well as the crosstalk observed between some MAPKs. We also describe the basic signaling properties of MAPKs (ultrasensitivity, hysteresis, digital response), and the presence of different positive feedback loops in apoptosis. We provide a simple guide to predict MAPKs’ behavior, based on the intensity and duration of the stimulus. Finally, we consider the role of MAPKs in osmostress-induced apoptosis by using Xenopus oocytes as a cell model. As we will see, apoptosis is plagued with multiple positive feedback loops. We hope this review will help to understand how MAPK signaling pathways engage irreversible cellular decisions.
Highlights
Over three decades have passed since Sturgill and Ray detected and characterized a new serine/threonine kinase, which was termed MAP kinase (MAPK) as it catalyzes the phosphorylation of microtubule-associated protein 2 (MAP-2) in insulin-treated 3T3-L1 adipocytes [1,2]
14 MAPK members divided into 7 subgroups have been identified, including four conventional MAPK subgroups that work in a typical three-tiered module, such as extracellular-regulated kinase (ERK1/2), C-Jun N-terminal kinase (JNK), p38 MAPK, and ERK5, and three atypical MAPK subgroups that do not follow the classical three-tiered, dual-phosphorylation signaling structure, such as ERK3/4, ERK7/8, and nemo-like kinase (NLK)
MAPK signal crosstalk between JNK and p38 MAPK is an additional regulatory mechanism in stress responses
Summary
Over three decades have passed since Sturgill and Ray detected and characterized a new serine/threonine kinase, which was termed MAP kinase (MAPK) as it catalyzes the phosphorylation of microtubule-associated protein 2 (MAP-2) in insulin-treated 3T3-L1 adipocytes [1,2]. As most family members are involved in processing signals stimulated by growth factors, the super kinase family was termed “mitogen-activated” protein kinase (MAPK) [4]. Dephosphorylation can be achieved by serine/threonine phosphatases [6,7], tyrosine phosphatases (reviewed in [8]), or dual-specificity phosphatases (DUSPs) that dephosphorylate both the Thr and Tyr residues within the activation loop (reviewed in [9]). Over the past 30 years, extensive research has shown that MAPKs play a pivotal role in converting extracellular stimuli into a wide range of cellular responses, including cell growth, migration, proliferation, differentiation, and apoptosis. JNK and p38 MAPK are activated most notably following cell exposure to stress evoked by a variety of physical, chemical, and biological stress stimuli, whereas ERK1/2 cascades mostly process cell growth factor-stimulated signaling [5,11]. We hope this review will help to better understand the complex world of MAPKs
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