Molecular and Cellular Endocrinology 252 (2006) 224–230 The p38 MAPK signaling pathway: A major regulator of skeletal muscle development Aviad Keren, Yael Tamir, Eyal Bengal * Department of Biochemistry, Rappaport Institute for Research in the Medical Sciences, Faculty of Medicine, Technion-Israel Institute of Technology, P.O. Box 9649, Haifa 31096, Israel Abstract Skeletal muscle development is regulated by extracellular growth factors that transmit largely unknown signals into the cell affecting the muscle- transcription program. One intracellular signaling pathway activated during the differentiation of myogenic cell lines is p38 mitogen-activated protein kinase (MAPK). As a result of modifying the activity of p38 in myoblasts, the pathway proved essential for the expression of muscle-specific genes. P38 affects the activities of transcription factors from the MyoD and MEF2 families and participates in the remodeling of chromatin at specific muscle-regulatory regions. P38 cooperates with the myogenic transcription factors in the activation of a subset of late-transcribed genes, hence contributing to the temporal expression of genes during differentiation. Recent developmental studies with mouse and Xenopus embryos, substantiated and further extended the essential role of p38 in myogenesis. Evidence exists supporting the crucial role for p38 signaling in activating MEF2 transcription factors during somite development in mice. In Xenopus, p38 signaling was shown to be needed for the early expression of Myf5 and for the expression of several muscle structural genes. The emerging data indicate that p38 participates in several stages of the myogenic program. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Signaling; p38 MAPK; Skeletal muscle; Myogenesis 1. Introduction Identification of the p38 mitogen-activated protein kinase (MAPK) signaling pathway was originally based on its acti- vation by environmental stresses and by pro-inflammatory cytokines. Over time, it became clear that the p38 pathway functions in a large number of cellular processes unrelated to stress responses and including cell growth, cell differentiation, cell cycle arrest and apoptosis. This is not surprising since in the course of the years many extracellular stimuli including growth factors and hormones have been shown to activate the p38 pathway. The activation of p38 in response to a wide range of extracellular stimuli can be seen in part by the diverse range of MAPK kinase kinases (MAP3K) that participate in p38 acti- Abbreviations: MAPK, mitogen-activated protein kinase; MAP3K, MAPK kinase kinase; MKK6, 3, MAP kinase kinase 6, 3; MEF2, myocyte enhancer factor 2; BMP, bone morphogenic protein; MRF, myogenic regulatory factor; XMyf5, Xenopus Myf5; XMyoD, Xenopus MyoD; ERK, extracellular regulated kinase; RMS, rhabdomyosarcoma; PI3-K, phosphoinositide 3-kinase; mTOR, mammalian target of rapamycin * Corresponding author. Tel.: +972 4 8295 287; fax: +972 4 8553 299. E-mail address: bengal@tx.technion.ac.il (E. Bengal). vation (TAK1, ASK1, DLK, MEKK4), contributing to the com- plexity of this signaling pathway. The MAP3Ks phosphorylate and activate the MAPK kinases (MAP2Ks) MKK6 and MKK3 which in turn phosphorylate the p38 MAPKs. In vertebrates, there are four isoforms of p38: p38, ,  and . The isoforms can be categorized by a Thr-Gly-Tyr (TGY) dual phosphoryla- tion motif. Once activated, p38s phosphorylate serine/threonine residues of their substrates. The list of downstream substrates of p38 keeps growing and includes other protein kinases and many transcription factors suggesting its possible role in regu- lating gene expression at the transcriptional level. Several of the downstream targets of p38 that are lineage-specific or playing an essential role in development have led to the identification of the central role of the p38 pathway in developmental and differenti- ation processes. The drosophila p38 gene has been suggested to play a role in decapentaplegic (dpp)-regulated wing morphogen- esis (Adachi-Yamada et al., 1999). p38 was also demonstrated to affect the asymmetric development of the drosophila egg by con- trolling the localization of Oskar and Gurken which are essential for the posterior and dorsal specification, respectively (Suzanne et al., 1999). In mice, p38 activity was recently demonstrated to be required for the development of the 8–16 cell stage embryo (Natale et al., 2004). Essential roles for p38 signaling in several 0303-7207/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mce.2006.03.017