Effect of dimerization on signal transduction and biological function of oncogenic Ros, insulin, and insulin-like growth factor I receptors.
Effect of dimerization on signal transduction and biological function of oncogenic Ros, insulin, and insulin-like growth factor I receptors.
复制标题
二聚化对致癌 Ros、胰岛素和胰岛素样生长因子 I 受体信号转导和生物功能的影响。
DOI：
10.1074/jbc.272.1.146
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
Wang,LH
中科院分区：
文献类型：
--
作者：
Chan,JL;Lai,M;Wang,LH
禽肉瘤病毒UR2编码一种致癌的Gag-ROS融合蛋白-酪氨酸激酶(PTK)。我们之前已经获得了两种逆转录病毒，T6和NM1，分别编码致癌的Gag-胰岛素受体和Gag-胰岛素样生长因子I受体(IGFR)融合蛋白。Gag-IGFR融合蛋白二聚化，而Gag-ROS不。为了确定影响二聚化的序列以及二聚化对信号和生物功能的影响，我们构建了在三个融合受体之间交换胞外和跨膜序列的重组体。GAG序列中多个半胱氨酸的存在似乎排除了二聚化，因为3‘半胱氨酸残基的缺失允许二聚化。大多数嵌合受体无论其在细胞表面的构型如何，都能保持较高的PTK活性并诱导转化。UT，UR2/T6嵌合体，保持有丝分裂活性，但转化能力显著降低，而UN7，UR2/NM1重组，也在IGFR中含有Y950F和F951S突变，这两种活性都显著降低。所有的融合受体都能磷酸化胰岛素受体底物1并激活PI3-激酶。UT蛋白可诱导Shc的磷酸化，而UN7蛋白则不能，但两者都不能激活丝裂原激活的蛋白激酶。我们的结果表明，过表达的致癌GAG-融合受体不需要二聚化来实现其信号和转化功能，并且受体PTK的胞外和跨膜序列可以影响其特定的底物相互作用。
The avian sarcoma virus UR2 codes for an oncogenic Gag-Ros fusion protein-tyrosine kinase (PTK). We have previously derived two retroviruses, T6 and NM1, coding for oncogenic Gag-insulin receptor and Gag-insulin-like growth factor I receptor (IGFR) fusion proteins, respectively. The Gag-IGFR fusion protein dimerizes, whereas Gag-Ros does not. To identify sequences affecting dimerization and the effect of dimerization on signaling and biological functions, we generated recombinants exchanging the extracellular and transmembrane sequences among the three fusion receptors. The presence of multiple cysteines in the Gag sequence appears to preclude dimerization, since deletion of the 3′ cysteine residue allows for dimerization. Most of the chimeric receptors retain high PTK activity and induce transformation regardless of their configuration on the cell surface. UT, a UR2/T6 chimera, retained mitogenic activity but has a markedly reduced transforming ability, while UN7, a UR2/NM1 recombinant, which also harbors Y950F and F951S mutations in IGFR, exhibits dramatic reductions in both activities. All of the fusion receptors can phosphorylate insulin receptor substrate 1 and activatePI 3-kinase. UT protein induces Shc phosphorylation, whereas UN7 protein does not, but both are unable to activate mitogen-activated protein kinase. Our results show that overexpressed oncogenic Gag-fusion receptors do not require dimerization for their signaling and transforming functions and that the extracellular and transmembrane sequences of a receptor PTK can affect its specific substrate interactions.