Department of Basic Neurosciences, University Medical Center, Geneva, Switzerland.
PLoS One. 2013 Aug 15;8(8):e71770. doi: 10.1371/journal.pone.0071770. eCollection 2013.
Initiation of human myoblast differentiation requires a negative shift (hyperpolarization) of the resting potential of myoblasts that depends on the activation of Kir2.1 potassium channels. These channels are regulated by a tyrosine phosphorylation. Using human primary myoblast culture, we investigated a possible role of various receptor tyrosine kinases in the induction of the differentiation process. We found that Epidermal Growth Factor Receptor (EGFR) is a key regulator of myoblast differentiation. EGFR activity is down-regulated during early human myoblast differentiation, and this event is required for normal differentiation to take place. Furthermore, EGFR silencing in proliferation conditions was able to trigger the differentiation program. This occurs through an increase of Kir2.1 channel activity that, via a rise of store-operated Ca(2+) entry, leads to the expression of myogenic transcription factors and muscle specific proteins (Myogenin, Myocyte Enhancer Factor 2 (MEF2), Myosin Heavy Chain (MyHC)). Finally, blocking myoblast cell cycle in proliferation conditions using a cdk4 inhibitor greatly decreased myoblast proliferation but was not able, on its own, to promote myoblast differentiation. Taken together, these results show that EGFR down-regulation is an early event that is required for the induction of myoblast differentiation.
人类成肌细胞分化的启动需要成肌细胞静息电位的负向偏移（超极化），这取决于 Kir2.1 钾通道的激活。这些通道受酪氨酸磷酸化调控。我们利用人原代成肌细胞培养物，研究了各种受体酪氨酸激酶在诱导分化过程中的可能作用。我们发现表皮生长因子受体（EGFR）是成肌细胞分化的关键调节因子。EGFR 活性在人类成肌细胞早期分化过程中下调，这一事件对于正常分化的发生是必需的。此外，在增殖条件下沉默 EGFR 能够触发分化程序。这是通过增加 Kir2.1 通道活性来实现的，该活性通过增加储存操作的 Ca2+内流，导致肌生成转录因子和肌肉特异性蛋白（肌细胞生成素、肌增强因子 2（MEF2）、肌球蛋白重链（MyHC））的表达。最后，在增殖条件下使用 cdk4 抑制剂阻断成肌细胞细胞周期，可大大减少成肌细胞增殖，但不能单独促进成肌细胞分化。总之，这些结果表明，EGFR 下调是诱导成肌细胞分化所必需的早期事件。
