Localization and retention of p90 ribosomal S6 kinase 1 in the nucleus: implications for its function.
Localization and retention of p90 ribosomal S6 kinase 1 in the nucleus: implications for its function.
复制标题
p90 核糖体 S6 激酶 1 在细胞核中的定位和保留：对其功能的影响。
DOI：
10.1091/mbc.e11-07-0658
复制
发表时间：
2012-02
影响因子：
3.3
通讯作者：
Patel TB
中科院分区：
文献类型：
--
作者：
Gao X;Chaturvedi D;Patel TB
核糖体S6激酶1 （RSK1）在细胞存活和增殖中起着至关重要的作用，它包含一个允许其进入细胞核的两部分核定位序列。RSK1通过与AKAP95的间接相互作用保留在细胞核中。干扰其核进入或保留会减少DNA合成。核糖体S6激酶1 （RSK1）属于一个具有两个激酶结构域的蛋白家族。在细胞质中被细胞外信号调节激酶（ERK1/2）激活后，它介导许多生长因子和其他激动剂的细胞增殖、细胞生长和促进生存的作用。RSK1的这些不同的生物作用涉及细胞质和核事件的调节。然而，允许RSK1核积累的机制仍然未知。在这里，我们发现RSK1在S221上的磷酸化对于其从细胞质中蛋白激酶A （PKA）的Iα型调节亚基解离是重要的，并且RSK1包含一个二部核定位序列，这是其进入核所必需的。一旦进入细胞核，活性RSK1通过与PKA催化亚基和AKAP95的相互作用保留在细胞核中。不影响其活性但破坏其进入细胞核的RSK1突变或不进入细胞核的AKAP95形式的表达抑制活性RSK1刺激DNA合成的能力。我们的发现确定了活跃的RSK1在细胞核中积累的新机制，并为AKAP95如何协调细胞周期进程提供了新的见解。
Ribosomal S6 kinase 1 (RSK1), which plays a critical role in cell survival and proliferation, contains a bipartite nuclear localization sequence that permits its entry into the nucleus. RSK1 is retained in the nucleus via its indirect interactions with AKAP95. Interference with its nuclear entry or retention decreases DNA synthesis. Ribosomal S6 kinase 1 (RSK1) belongs to a family of proteins with two kinase domains. Following activation in the cytoplasm by extracellular signal-regulated kinases (ERK1/2), it mediates the cell-proliferative, cell-growth, and survival-promoting actions of a number of growth factors and other agonists. These diverse biological actions of RSK1 involve regulation of both cytoplasmic and nuclear events. However, the mechanisms that permit nuclear accumulation of RSK1 remain unknown. Here, we show that phosphorylation of RSK1 on S221 is important for its dissociation from the type Iα regulatory subunit of protein kinase A (PKA) in the cytoplasm and that RSK1 contains a bipartite nuclear localization sequence that is necessary for its nuclear entry. Once inside, the active RSK1 is retained in the nucleus via its interactions with PKA catalytic subunit and AKAP95. Mutations of RSK1 that do not affect its activity but disrupt its entry into the nucleus or expression of AKAP95 forms that do not enter the nucleus inhibit the ability of active RSK1 to stimulate DNA synthesis. Our findings identify novel mechanisms by which active RSK1 accumulates in the nucleus and also provide new insights into how AKAP95 orchestrates cell cycle progression.