Key role of ERK1/2 molecular scaffolds in heart pathology
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Cellular and Molecular Life Sciences
Review
Key role of ERK1/2 molecular scaffolds in heart pathology Guido Tarone · Mauro Sbroggiò · Mara Brancaccio
Received: 28 November 2012 / Revised: 22 February 2013 / Accepted: 6 March 2013 © Springer Basel 2013
Abstract The ability of cardiomyocytes to detect mechanical and humoral stimuli is critical for adaptation of the myocardium in response to new conditions and for sustaining the increased workload during stress. While certain stimuli mediate a beneficial adaptation to stress conditions, others result in maladaptive remodelling, ultimately leading to heart failure. Specific signalling pathways activating either adaptive or maladaptive cardiac remodelling have been identified. Paradoxically, however, in a number of cases, the transduction pathways involved in such opposing responses engage the same signalling proteins. A notable example is the Raf–MEK1/2–ERK1/2 signalling pathway that can control both adaptive and maladaptive remodelling. ERK1/2 signalling requires a signalosome complex where a scaffold protein drives the assembly of these three kinases into a linear pathway to facilitate their sequential phosphorylation, ultimately targeting specific effector molecules. Interestingly, a number of different Raf–MEK1/2–ERK1/2 scaffold proteins have been identified, and their role in determining the adaptive or maladaptive cardiac remodelling is a promising field of investigation for the development of therapeutic strategies capable of selectively potentiating the adaptive response.
G. Tarone (*) · M. Brancaccio Department of Molecular Biotechnology and Health Science, Molecular Biotechnology Center, University of Torino, via Nizza, 52, 10126 Turin, Italy e-mail: [email protected] Present Address: M. Sbroggiò Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
Keywords Scaffold proteins · ERK1/2 pathway · Cardiac remodelling · Intracellular signalling
Introduction Heart failure is a complex disease due to inherited gene mutations or to acquired abnormalities in heart function mainly due to chronic exposure to work overload. This condition is usually detected by the heart, with the subsequent activation of a process called adaptive heart remodelling, a complex and coordinated reaction of the entire organ that includes cardiomyocyte hypertrophy, metabolic changes, and modifications in calcium handling and contractile function. The vascular bed and stromal tissue also undergo important remodelling to support the increased metabolic need and increased mechanical strain of the organ. This initial adaptive response can, however, progress toward contractile dysfunction and heart dilation due to cardiomyocyte death, inflammatory reactions and heart fibrosis. Heart remodelling is triggered by the activation of mechanical signals, cytokine growth factors and neurohumoral stimuli. While some of these stimuli mainly mediate an adaptive heart remodelling response, others result in maladaptive ch
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