MAPK/MSK1 signaling in cardiac myocyte stress responses.

Antigone Lazou, Aristotle University of Thessaloniki, Greece

Cardiac myocytes, the contractile cells of the heart, withdraw from the cell cycle in the perinatal period and become terminally differentiated. In response to a variety of extrinsic and intrinsic pathophysiological stimuli that impose increased stress to the heart, cardiac myocytes undergo hypertrophic growth or cell death (by necrosis and/or apoptosis or autophagy) in a process commonly referred to as cardiac remodeling, which is associated with cardiac pathologies. The principal signaling cascades that have been associated with cardiac myocyte responses are the MAPKs and the Akt pathway. The extracellular signal regulated kinase (ERK1/2) cascade is particularly implicated in the transcriptional changes associated with the hypertrophic response, although evidence also suggests that they may have a role in cell survival. The situation is less clear for p38-MAPK and c-Jun-N-terminal kinases; studies are inconsistent on whether they are associated with hypertrophy, cytoprotection or cell death. MSK1 (mitogen and stress activated kinase 1), a target of both ERK1/2 and p38 MAPK pathways, is considered to be a major convergence point integrating the effects of different extracellular signals. MSK1 is activated via a complex series of phosphorylation and autophosphorylation reactions and has been shown to modulate gene expression at multiple levels by phosphorylating various substrates including transcription factors and chromatin-associated proteins. In cardiac myocytes, activation of MSK1 by α1-adrenergic agonists leads to the phosphorylation of CREB and upregulation of c-jun, thus contributing to the development of the hypertrophic phenotype. Furthermore, under the setting of oxidative stress, MSK1 is cardioprotective by modulating mechanisms of apoptosis and autophagy. These studies highlight the complex role of MSK1 in integrating the effects of diverse extracellular signals in the heart.