Role of the TFG N-terminus and coiled-coil domain in the transforming activity of the thyroid TRK-T3 oncogene
Role of the TFG N-terminus and coiled-coil domain in the transforming activity of the thyroid TRK-T3 oncogene
复制标题
DOI：
10.1038/sj.onc.1201596
复制
发表时间：
1998-02-12
期刊：
影响因子：
8
通讯作者：
Pierotti, MA
中科院分区：
文献类型：
--
作者：
Greco, A;Fusetti, L;Pierotti, MA
甲状腺TRK-T3癌基因是由1号染色体上的NTRK1(神经生长因子的受体之一)的酪氨酸激酶(TK)结构域与3号染色体上的新基因TFG序列融合而成的。68 kDa的TRK-T3融合癌蛋白显示出结构性的酪氨酸激酶活性，使其能够转化小鼠NIH3T3细胞。TRK-T3的TFG部分包含一个卷曲的结构域，最可能与受体酪氨酸激酶活性的组成性、配体无关的激活有关。我们之前已经证明，TRK-T3癌蛋白在体内形成三个或四个分子的复合体。通过不同的实验方法，我们在这里证明了TRK-T3的活性取决于低聚物的形成，此外，对不同TRK-T3突变体的分析表明，TFG螺旋卷曲结构域及其N-末端区域都是激活和充分转化TRK-T3癌蛋白活性所必需的，尽管它们很可能在转化过程的不同步骤中发挥作用，但螺旋卷曲结构域的缺失取消了寡聚体的形成，导致结构性激活；N-末端区域的缺失虽然不影响磷酸化和复合体的形成，但放弃了转化，从而表明它们在细胞定位和/或与底物的相互作用中发挥了作用。
The thyroid TRK-T3 oncogene results from the fusion of the tyrosine kinase (TK) domain of NTRK1 (one of the receptors for the Nerve Growth Factor) on chromosome 1 to sequences of a novel gene, TFG, on chromosome 3., The 68 kDa TRK-T3 fusion oncoprotein displays a constitutive tyrosine kinase activity resulting in its capability to transform mouse NIH3T3 cells, The TFG portion of TRK-T3 contains a coiled-coil domain most likely responsible for the constitutive, ligand-independent activation of the receptor tyrosine kinase activity. We have previously shown that TRK-T3 oncoprotein forms, in vivo, complexes of three or four molecules. By mean of different experimental approaches, we show here that TRK-T3 activity depends on oligomers formation, In addition, the analysis of different TRK-T3 mutants indicates that the TFG coiled-coil domain and its N-terminal region are both required for the activation and the fully transforming activity of the TRK-T3 oncoprotein, although, most likely, they play a role in different steps of the transforming process, The deletion of the coiled-coil domain abrogates the oligomers formation leading to a constitutive activation; the deletion of the N-terminal region, although not affecting phosphorylation and complexes formation, abrogates transformation, thus suggesting a role in cellular localization and/or interaction with substrata.