Department of Neurosurgery, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Mol Cancer Res. 2011 Sep;9(9):1199-208. doi: 10.1158/1541-7786.MCR-11-0229. Epub 2011 Jul 20.
Delta epidermal growth factor receptor (ΔEGFR), an in-frame deletion mutant of the extracellular ligand-binding domain, which occurs in about 30% of glioblastoma, is a potent oncogene that promotes tumor growth and progression. The signaling of ΔEGFR is ligand-independent and low intensity, allowing it to evade the normal mechanisms of internalization and degradation by the endocytic machinery and hence is persistent. The basis of the oncogenic potential of ΔEGFR remains incompletely understood, including whether dimerization plays an important role in its signal and whether its oncogenic potential is dependent on its relatively low intensity, when compared with the acutely activated wild-type receptor. To examine these two important questions, we have generated a chimeric ΔEGFR that allows forced dimerization via domains derived from variants of the FKBP12 protein that are brought together by FK506 derivatives. Forced dimerization of chimeric ΔEGFR significantly increased the intensity of its signal, as measured by receptor phosphorylation levels, suggesting that the naturally occurring ΔEGFR does not form strong or stable dimers as part of its low level signal. Interestingly, the increased activity of dimerized, chimeric ΔEGFR did not promote receptor internalization, implying that reduced rate of endocytic downregulation of ΔEGFR is an inherent characteristic. Significantly, forced dimerization enhanced the oncogenic signal of the receptor, implying that the ΔEGFR is a potent oncogene despite, not because of its low intensity.
德尔塔表皮生长因子受体（ΔEGFR）是细胞外配体结合域的一种框架内缺失突变体，约发生于 30%的胶质母细胞瘤中，是一种促进肿瘤生长和进展的强效致癌基因。ΔEGFR 的信号是配体非依赖性和低强度的，使其能够逃避内吞机制的正常内化和降解机制，因此持续存在。ΔEGFR 的致癌潜力的基础仍不完全清楚，包括二聚化是否在其信号中发挥重要作用，以及与急性激活的野生型受体相比，其致癌潜力是否依赖于其相对较低的强度。为了研究这两个重要问题，我们生成了一种嵌合 ΔEGFR，通过 FK506 衍生物将 FKBP12 蛋白变体衍生的结构域结合在一起，从而实现强制二聚化。嵌合 ΔEGFR 的强制二聚化显著增加了其信号的强度，如受体磷酸化水平所示，这表明自然发生的 ΔEGFR 不会形成强或稳定的二聚体作为其低水平信号的一部分。有趣的是，二聚化嵌合 ΔEGFR 的活性增加并没有促进受体内化，这意味着 ΔEGFR 的内吞下调率降低是其固有的特征。重要的是，强制二聚化增强了受体的致癌信号，这意味着 ΔEGFR 是一种强效致癌基因，尽管不是因为其低强度。
