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Extracellular signal-regulated kinases 1/2 as regulators of cardiac hypertrophy.

Mutlak M, Kehat I - Front Pharmacol (2015)

Bottom Line: Several mouse models were generated in order to directly understand the causal role of ERK1/2 activation in the heart.While there is little doubt that ERK1/2 activation or the lack of it modulates the hypertrophic process or the type of hypertrophy that develops, it appears that not all ERK1/2 activation events are the same.While much has been learned, some questions remain regarding the exact role of ERK1/2 in the heart, the upstream events that result in ERK1/2 activation and the downstream effector in hypertrophy.

View Article: PubMed Central - PubMed

Affiliation: The Rappaport Institute and the Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology , Haifa, Israel.

ABSTRACT
Cardiac hypertrophy results from increased mechanical load on the heart and through the actions of local and systemic neuro-humoral factors, cytokines and growth factors. These mechanical and neuroendocrine effectors act through stretch, G protein-coupled receptors and tyrosine kinases to induce the activation of a myriad of intracellular signaling pathways including the extracellular signal-regulated kinases 1/2 (ERK1/2). Since most stimuli that provoke myocardial hypertrophy also elicit an acute phosphorylation of the threonine-glutamate-tyrosine (TEY) motif within the activation loops of ERK1 and ERK2 kinases, resulting in their activation, ERKs have long been considered promotors of cardiac hypertrophy. Several mouse models were generated in order to directly understand the causal role of ERK1/2 activation in the heart. These models include direct manipulation of ERK1/2 such as overexpression, mutagenesis or knockout models, manipulations of upstream kinases such as MEK1 and manipulations of the phosphatases that dephosphorylate ERK1/2 such as DUSP6. The emerging understanding from these studies, as will be discussed here, is more complex than originally considered. While there is little doubt that ERK1/2 activation or the lack of it modulates the hypertrophic process or the type of hypertrophy that develops, it appears that not all ERK1/2 activation events are the same. While much has been learned, some questions remain regarding the exact role of ERK1/2 in the heart, the upstream events that result in ERK1/2 activation and the downstream effector in hypertrophy.

No MeSH data available.


Related in: MedlinePlus

The quantitative information about a constant extracellular stimulus like pressure overload may be carried by the duration of ERK activation, by amplitude of ERK activation (phosphorylation level), by the frequency with which the activity of ERK shifts between active and inactive states, by the translocation of ERK to a subcellular location such as the nucleus, or through a combination of these factors.
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Figure 2: The quantitative information about a constant extracellular stimulus like pressure overload may be carried by the duration of ERK activation, by amplitude of ERK activation (phosphorylation level), by the frequency with which the activity of ERK shifts between active and inactive states, by the translocation of ERK to a subcellular location such as the nucleus, or through a combination of these factors.

Mentions: The quantitative information about a constant extracellular stimulus like pressure overload may be carried by the number of active ERK molecules, or signal amplitude, or by the frequency with which the activity of ERK shifts between active and inactive states, or signal frequency (Figure 2). It is also not clear whether the cell responds to the absolute number of phosphorylated ERK molecules or to the fraction of phospho-ERK to total ERK molecules in the cytoplasm or nucleus. For example, the interpretation of constant epidermal growth factor receptor signaling in cells was shown to result in discrete pulses of ERK activation and incorporated both frequency and amplitude modulated elements (Albeck et al., 2013). A study in human cancer cells found a very large cell to cell variability in the levels of nuclear ERK2. Despite this variability, the amount of ERK2 entering the nucleus upon EGF stimulation was proportional to the basal level of nuclear ERK2 in each cell, suggesting a fold-change response mechanism (Cohen-Saidon et al., 2009). Therefore the question whether downstream targets of ERK respond to ERK fold or absolute changes in phospho-ERK molecules is still open. It should be noted that overexpression of wild-type ERK in the heart did not result in cardiac hypertrophy both at baseline or following TAC pressure overload and that overexpression of constitutively active mutant of MEK1 in the heart resulted in an increase in both total ERK1/2 and phospho-ERK1/2. Since a detailed estimation of phospho-ERK to total ERK ratios in both nucleus and cytoplasm was not performed in these studies it is difficult to draw direct conclusion from these studies regarding ERK cellular sensing.


Extracellular signal-regulated kinases 1/2 as regulators of cardiac hypertrophy.

Mutlak M, Kehat I - Front Pharmacol (2015)

The quantitative information about a constant extracellular stimulus like pressure overload may be carried by the duration of ERK activation, by amplitude of ERK activation (phosphorylation level), by the frequency with which the activity of ERK shifts between active and inactive states, by the translocation of ERK to a subcellular location such as the nucleus, or through a combination of these factors.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4513555&req=5

Figure 2: The quantitative information about a constant extracellular stimulus like pressure overload may be carried by the duration of ERK activation, by amplitude of ERK activation (phosphorylation level), by the frequency with which the activity of ERK shifts between active and inactive states, by the translocation of ERK to a subcellular location such as the nucleus, or through a combination of these factors.
Mentions: The quantitative information about a constant extracellular stimulus like pressure overload may be carried by the number of active ERK molecules, or signal amplitude, or by the frequency with which the activity of ERK shifts between active and inactive states, or signal frequency (Figure 2). It is also not clear whether the cell responds to the absolute number of phosphorylated ERK molecules or to the fraction of phospho-ERK to total ERK molecules in the cytoplasm or nucleus. For example, the interpretation of constant epidermal growth factor receptor signaling in cells was shown to result in discrete pulses of ERK activation and incorporated both frequency and amplitude modulated elements (Albeck et al., 2013). A study in human cancer cells found a very large cell to cell variability in the levels of nuclear ERK2. Despite this variability, the amount of ERK2 entering the nucleus upon EGF stimulation was proportional to the basal level of nuclear ERK2 in each cell, suggesting a fold-change response mechanism (Cohen-Saidon et al., 2009). Therefore the question whether downstream targets of ERK respond to ERK fold or absolute changes in phospho-ERK molecules is still open. It should be noted that overexpression of wild-type ERK in the heart did not result in cardiac hypertrophy both at baseline or following TAC pressure overload and that overexpression of constitutively active mutant of MEK1 in the heart resulted in an increase in both total ERK1/2 and phospho-ERK1/2. Since a detailed estimation of phospho-ERK to total ERK ratios in both nucleus and cytoplasm was not performed in these studies it is difficult to draw direct conclusion from these studies regarding ERK cellular sensing.

Bottom Line: Several mouse models were generated in order to directly understand the causal role of ERK1/2 activation in the heart.While there is little doubt that ERK1/2 activation or the lack of it modulates the hypertrophic process or the type of hypertrophy that develops, it appears that not all ERK1/2 activation events are the same.While much has been learned, some questions remain regarding the exact role of ERK1/2 in the heart, the upstream events that result in ERK1/2 activation and the downstream effector in hypertrophy.

View Article: PubMed Central - PubMed

Affiliation: The Rappaport Institute and the Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology , Haifa, Israel.

ABSTRACT
Cardiac hypertrophy results from increased mechanical load on the heart and through the actions of local and systemic neuro-humoral factors, cytokines and growth factors. These mechanical and neuroendocrine effectors act through stretch, G protein-coupled receptors and tyrosine kinases to induce the activation of a myriad of intracellular signaling pathways including the extracellular signal-regulated kinases 1/2 (ERK1/2). Since most stimuli that provoke myocardial hypertrophy also elicit an acute phosphorylation of the threonine-glutamate-tyrosine (TEY) motif within the activation loops of ERK1 and ERK2 kinases, resulting in their activation, ERKs have long been considered promotors of cardiac hypertrophy. Several mouse models were generated in order to directly understand the causal role of ERK1/2 activation in the heart. These models include direct manipulation of ERK1/2 such as overexpression, mutagenesis or knockout models, manipulations of upstream kinases such as MEK1 and manipulations of the phosphatases that dephosphorylate ERK1/2 such as DUSP6. The emerging understanding from these studies, as will be discussed here, is more complex than originally considered. While there is little doubt that ERK1/2 activation or the lack of it modulates the hypertrophic process or the type of hypertrophy that develops, it appears that not all ERK1/2 activation events are the same. While much has been learned, some questions remain regarding the exact role of ERK1/2 in the heart, the upstream events that result in ERK1/2 activation and the downstream effector in hypertrophy.

No MeSH data available.


Related in: MedlinePlus