Lorenzi M V, Horii Y, Yamanaka R, Sakaguchi K, Miki T
Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):8956-61. doi: 10.1073/pnas.93.17.8956.
A constitutively active form of fibroblast growth factor 2 (FGFR2) was identified in rat osteosarcoma (ROS) cells by an expression cloning strategy. Unlike other tyrosine kinase receptors activated by N-terminal truncation in tumors, this receptor, FGFR2-ROS, contains an altered C terminus generated from chromosomal rearrangement with a novel gene, designated FGFR activating gene 1 (FRAG1). While the removal of the C terminus slightly activates FGFR2, the presence of the FRAG1 sequence drastically stimulates the transforming activity and autophosphorylation of the receptor. FGFR2-ROS is expressed as a unusually large protein and is highly phosphorylated in NIH 3T3 transfectants. FRAG1 is ubiquitously expressed and encodes a predicted protein of 28 kDa lacking significant structural similarity to known proteins. Epitope-tagged FRAG1 protein showed a perinuclear localization by immunofluorescence staining. The highly activated state of FGFR2-ROS appears to be attributed to constitutive dimer formation and higher phosphorylation level as well as possibly altered subcellular localization. These results indicate a unique mechanism of receptor activation by a C terminus alteration through a chromosomal fusion with FRAG1.
通过表达克隆策略在大鼠骨肉瘤（ROS）细胞中鉴定出一种组成型活性形式的成纤维细胞生长因子2（FGFR2）。与肿瘤中通过N端截短激活的其他酪氨酸激酶受体不同，这种受体FGFR2-ROS包含一个由与一个新基因（称为FGFR激活基因1，FRAG1）的染色体重排产生的改变的C末端。虽然去除C末端会轻微激活FGFR2，但FRAG1序列的存在会极大地刺激受体的转化活性和自磷酸化。FGFR2-ROS表达为一种异常大的蛋白质，并且在NIH 3T3转染子中高度磷酸化。FRAG1在全身广泛表达，编码一种预测的28 kDa蛋白质，与已知蛋白质缺乏明显的结构相似性。表位标记的FRAG1蛋白通过免疫荧光染色显示出核周定位。FGFR2-ROS的高度激活状态似乎归因于组成型二聚体形成、更高的磷酸化水平以及可能改变的亚细胞定位。这些结果表明通过与FRAG1的染色体重组导致C末端改变从而激活受体的独特机制。
