Bryson Bryan D, White Forest M
Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, United States of America; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, United States of America.
PLoS One. 2015 May 15;10(5):e0126242. doi: 10.1371/journal.pone.0126242. eCollection 2015.
Lysine acetylation has been primarily investigated in the context of transcriptional regulation, but a role for acetylation in mediating other cellular responses has emerged. Multiple studies have described global lysine acetylation profiles for particular biological states, but none to date have investigated the temporal dynamics regulating cellular response to perturbation. Reasoning that lysine acetylation may be altered in response to growth factors, we implemented quantitative mass spectrometry-based proteomics to investigate the temporal dynamics of lysine acetylation in response to growth factor stimulation in cultured carcinoma cell lines. We found that lysine acetylation changed rapidly in response to activation of several different receptor tyrosine kinases by their respective ligands. To uncover the effects of lysine acetylation dynamics on tyrosine phosphorylation signaling networks, cells were treated with an HDAC inhibitor. This short-term pharmacological inhibition of histone deacetylase activity modulated signaling networks involving phosphorylated tyrosine and thereby altered the response to receptor tyrosine kinase activation. This result highlights the interconnectivity of lysine acetylation and tyrosine phosphorylation signaling networks and suggests that HDAC inhibition may influence cellular responses by affecting both types of post-translational modifications.
赖氨酸乙酰化主要是在转录调控的背景下进行研究的，但乙酰化在介导其他细胞反应中的作用也已显现。多项研究描述了特定生物学状态下的全局赖氨酸乙酰化谱，但迄今为止，尚无研究探讨调节细胞对扰动反应的时间动态。鉴于赖氨酸乙酰化可能会因生长因子而发生改变，我们采用基于定量质谱的蛋白质组学方法，研究培养的癌细胞系中赖氨酸乙酰化对生长因子刺激的时间动态变化。我们发现，几种不同的受体酪氨酸激酶被其各自配体激活后，赖氨酸乙酰化会迅速发生变化。为了揭示赖氨酸乙酰化动态对酪氨酸磷酸化信号网络的影响，我们用组蛋白去乙酰化酶（HDAC）抑制剂处理细胞。这种对组蛋白去乙酰化酶活性的短期药理抑制作用调节了涉及磷酸化酪氨酸的信号网络，从而改变了对受体酪氨酸激酶激活的反应。这一结果突出了赖氨酸乙酰化和酪氨酸磷酸化信号网络的相互联系，并表明HDAC抑制可能通过影响这两种翻译后修饰来影响细胞反应。
