Anchored p90 Ribosomal S6 Kinase 3 Is Required for Cardiac Myocyte Hypertrophy

Abstract

Rationale Cardiac myocyte hypertrophy is the main compensatory response to chronic stress on the heart. p90 Ribosomal S6 Kinase (RSK) family members are effectors for extracellular signal-regulated kinases that induce myocyte growth. Although increased RSK activity has been observed in stressed myocytes, the functions of individual RSK family members have remained poorly defined, despite being potential therapeutic targets for cardiac disease. Objective To demonstrate that type 3 RSK (RSK3) is required for cardiac myocyte hypertrophy. Methods and Results RSK3 contains a unique N-terminal domain that is not conserved in other RSK family members. We show that this domain mediates the regulated binding of RSK3 to the muscle A-kinase anchoring protein (mAKAP) scaffold, defining a novel kinase anchoring event. Disruption of both RSK3 expression using RNA interference and RSK3 anchoring using a competing mAKAP peptide inhibited the hypertrophy of cultured myocytes. In vivo, RSK3 gene deletion in the mouse attenuated the concentric myocyte hypertrophy induced by pressure overload and catecholamine infusion. Conclusions Taken together, these data demonstrate that anchored RSK3 transduces signals that modulate pathologic myocyte growth. Targeting of signaling complexes that contain select kinase isoforms should provide an approach for the specific inhibition of cardiac myocyte hypertrophy and for the development of novel strategies for the prevention and treatment of heart failure.

Ubiquitin-Specific Protease 4 Is an Endogenous Negative Regulator of Pathological Cardiac Hypertrophy

“…3,4 Existing antihypertrophic therapies generally targeting membrane receptors seem to have limited efficacy 5 and lead to systemic and off target effects, 6 possibly because of nonspecific suppression of downstream signaling. 7 Identification of novel molecular regulators with pathway specificity within the intracellular hypertrophic signaling network may allow to characterize novel intervention targets for the treatment of cardiac hypertrophy and heart failure.…”

Interactions between the Regulatory Subunit of Type I Protein Kinase A and p90 Ribosomal S6 Kinase1 Regulate Cardiomyocyte Apoptosis

“…Therefore, it has been suggested that RSK1 plays an important role in the onset of cardiac hypertrophy (Proud, 2004;Rolfe et al, 2005). However, the role of RSK1 in cardiac hypertrophy has been challenged (Fonseca et al, 2011), and a recent study has shown that RSK3 plays an important role in cardiac hypertrophy (Li et al, 2013). Regions of the hypertrophied heart are also exposed to hypoxic conditions resulting from overgrowth of cardiac tissue and insufficient blood supply (Kang and Izumo, 2000;Fortuno et al, 2001), and the chronic hypoxic condition can induce cardiomyocyte apoptosis and the loss of cells.…”

Two widely used RSK inhibitors, BI-D1870 and SL0101, alter mTORC1 signaling in a RSK-independent manner

“…1D). In addition, in several articles SL0101 was used to validate the effects of BI-D1870 [10,23,28,32,34,[37][38][39][40][41][42][43][44][45][46], although unexpected differences were observed between the two inhibitors. For example, SL0101 and BI-D1870 were both observed to inhibit glucose uptake, yet by different mechanisms [23].…”