Institute of Biochemistry II and Cluster of Excellence Macromolecular Complexes, Goethe University School of Medicine, Frankfurt (Main), Germany.
Sci Signal. 2009 Dec 22;2(102):ra84. doi: 10.1126/scisignal.2000576.
Binding of epidermal growth factor (EGF) to its receptor leads to receptor dimerization, assembly of protein complexes, and activation of signaling networks that control key cellular responses. Despite their fundamental role in cell biology, little is known about protein complexes associated with the EGF receptor (EGFR) before growth factor stimulation. We used a modified membrane yeast two-hybrid system together with bioinformatics to identify 87 candidate proteins interacting with the ligand-unoccupied EGFR. Among them was histone deacetylase 6 (HDAC6), a cytoplasmic lysine deacetylase, which we found negatively regulated EGFR endocytosis and degradation by controlling the acetylation status of alpha-tubulin and, subsequently, receptor trafficking along microtubules. A negative feedback loop consisting of EGFR-mediated phosphorylation of HDAC6 Tyr(570) resulted in reduced deacetylase activity and increased acetylation of alpha-tubulin. This study illustrates the complexity of the EGFR-associated interactome and identifies protein acetylation as a previously unknown regulator of receptor endocytosis and degradation.
表皮生长因子（EGF）与其受体结合导致受体二聚化、蛋白复合物组装以及激活信号网络，从而控制关键的细胞反应。尽管它们在细胞生物学中具有基本作用，但在生长因子刺激之前，人们对与表皮生长因子受体（EGFR）相关的蛋白复合物知之甚少。我们使用改良的膜酵母双杂交系统和生物信息学方法来鉴定 87 种与配体非占据的 EGFR 相互作用的候选蛋白。其中包括组蛋白去乙酰化酶 6（HDAC6），一种细胞质赖氨酸去乙酰化酶，我们发现它通过控制微管上的受体运输来负调控 EGFR 的内吞作用和降解，从而控制微管上的受体运输。由 EGFR 介导的 HDAC6 Tyr（570）磷酸化组成的负反馈回路导致去乙酰化酶活性降低和α-微管蛋白乙酰化增加。这项研究说明了 EGFR 相关相互作用组的复杂性，并确定了蛋白乙酰化是受体内吞作用和降解的一个以前未知的调节剂。
