Insulin signaling via Akt2 switches plakophilin 1 function from stabilizing cell adhesion to promoting cell proliferation
Insulin signaling via Akt2 switches plakophilin 1 function from stabilizing cell adhesion to promoting cell proliferation
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DOI：
10.1242/jcs.118992
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发表时间：
2013-04-15
影响因子：
4
通讯作者：
Hatzfeld, Mechthild
中科院分区：
文献类型：
--
作者：
Wolf, Annika;Rietscher, Katrin;Hatzfeld, Mechthild
粘附连接蛋白的下调是癌发生过程中的常见事件。桥粒蛋白如何通过调节粘附和增殖之间的平衡来促进肿瘤形成尚不清楚。桥粒蛋白 plakophilin 1 可以通过将桥粒蛋白募集到质膜上来增加细胞间粘附，或通过提高翻译速率来刺激增殖。在这里，我们证明 plakophilin 1 的这些双重功能受到生长因子信号传导的调节。胰岛素刺激诱导 plakophilin 1 磷酸化，这与细胞间粘附减少和 plakophilin 1 在翻译刺激中的活性增加相关。磷酸化由 Akt2 在 plakophilin 1 N 末端结构域内的四个基序处介导。 plakophilin 1 磷酸化模拟突变体显示细胞间粘附减少并在细胞质中积累，在细胞质中它增加了翻译和增殖率并赋予了不依赖贴壁的生长的能力。细胞质积累是由磷酸化 plakophilin 1 的稳定介导的，其半衰期显着增加，而非磷酸化 plakophilin 1 的降解速度更快。我们的数据表明，在激活生长因子信号传导后，plakophilin 1 从桥粒相关的生长抑制功能转变为细胞质增殖促进功能。这支持了这样的观点，即在几种肿瘤中观察到的 plakophilin 1 的失调，以一种背景依赖性方式直接导致过度增殖和癌发生。
Downregulation of adherens junction proteins is a frequent event in carcinogenesis. How desmosomal proteins contribute to tumor formation by regulating the balance between adhesion and proliferation is not well understood. The desmosomal protein plakophilin 1 can increase intercellular adhesion by recruiting desmosomal proteins to the plasma membrane or stimulate proliferation by enhancing translation rates. Here, we show that these dual functions of plakophilin 1 are regulated by growth factor signaling. Insulin stimulation induced the phosphorylation of plakophilin 1, which correlated with reduced intercellular adhesion and an increased activity of plakophilin 1 in the stimulation of translation. Phosphorylation was mediated by Akt2 at four motifs within the plakophilin 1 N-terminal domain. A plakophilin 1 phospho-mimetic mutant revealed reduced intercellular adhesion and accumulated in the cytoplasm, where it increased translation and proliferation rates and conferred the capacity of anchorage-independent growth. The cytoplasmic accumulation was mediated by the stabilization of phosphorylated plakophilin 1, which displayed a considerably increased half-life, whereas non-phosphorylated plakophilin 1 was more rapidly degraded. Our data indicate that upon activation of growth factor signaling, plakophilin 1 switches from a desmosome-associated growth-inhibiting to a cytoplasmic proliferation-promoting function. This supports the view that the deregulation of plakophilin 1, as observed in several tumors, directly contributes to hyperproliferation and carcinogenesis in a context-dependent manner.