Anchored p90 ribosomal S6 kinase 3 is required for cardiac myocyte hypertrophy.
Anchored p90 ribosomal S6 kinase 3 is required for cardiac myocyte hypertrophy.
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DOI：
10.1161/circresaha.112.276162
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发表时间：
2013-01-04
影响因子：
20.1
通讯作者：
Kapiloff MS
中科院分区：
文献类型：
--
作者：
Li J;Kritzer MD;Michel JJ;Le A;Thakur H;Gayanilo M;Passariello CL;Negro A;Danial JB;Oskouei B;Sanders M;Hare JM;Hanauer A;Dodge-Kafka K;Kapiloff MS
心肌细胞肥大是心脏对慢性应激的主要代偿反应。 p90 核糖体 S6 激酶 (RSK) 家族成员是诱导心肌细胞生长的细胞外信号调节激酶的效应子。尽管在应激的心肌细胞中观察到 RSK 活性增加，但单个 RSK 家族成员的功能仍然不明确，尽管它们是心脏病的潜在治疗靶点。证明 3 型 RSK (RSK3) 是心肌细胞肥大所必需的。 RSK3 包含一个独特的 N 端结构域，该结构域在其他 RSK 家族成员中并不保守。我们发现该结构域介导 RSK3 与肌肉 A 激酶锚定蛋白 (mAKAP) 支架的受调节结合，从而定义了一种新的激酶锚定事件。使用 RNA 干扰破坏 RSK3 表达以及使用竞争性 mAKAP 肽锚定 RSK3 抑制培养的肌细胞的肥大。在体内，小鼠中RSK3基因缺失减弱了压力超负荷和儿茶酚胺输注引起的同心肌细胞肥大。总而言之，这些数据表明锚定的 RSK3 转导调节病理性肌细胞生长的信号。靶向含有特定激酶亚型的信号复合物应该为特异性抑制心肌细胞肥大和开发预防和治疗心力衰竭的新策略提供一种方法。
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. To demonstrate that type 3 RSK (RSK3) is required for cardiac myocyte hypertrophy. 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. 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.