Faria T N, Blakesley V A, Kato H, Stannard B, LeRoith D, Roberts C T
Section on Molecular and Cellular Physiology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892.
J Biol Chem. 1994 May 13;269(19):13922-8.
The insulin and insulin-like growth factor I receptors (IR and IGF-IR, respectively) are heterotetrameric tyrosine kinases consisting of two extracellular ligand-binding alpha subunits and two transmembrane catalytic beta subunits. A number of lines of evidence have suggested that the IR and IGF-IR differ with respect to their ability to elicit mitogenic versus metabolic events upon activation by cognate ligands. To ascertain the contribution of the poorly conserved carboxyl-terminal domains to the differential functioning of the IR and IGF-IR, we have constructed receptor chimeras in which the carboxyl-terminal domain of one receptor was fused to the remainder of the heterologous receptor. The responses of a number of parameters after ligand stimulation were examined in stably transfected NIH-3T3 cells expressing the chimeric receptors or the analogous wild-type receptor sequence. Replacement of the IR carboxyl terminus with that of the IGF-IR severely affected insulin-stimulated responses, whereas substitution of the carboxyl terminus of the IGF-IR with that of the IR had a minimal effect. These data suggest that the carboxyl-terminal domains of the IR and IGF-IR are not interchangeable and that the mitogenic activity of the IR can be influenced by sequences present in the carboxyl-terminal domain. The analogous functions of the IGF-IR, on the other hand, do not appear to be greatly affected by the presence of the IR carboxyl-terminal domain.
胰岛素和胰岛素样生长因子I受体（分别为IR和IGF-IR）是由两个细胞外配体结合α亚基和两个跨膜催化β亚基组成的异源四聚体酪氨酸激酶。许多证据表明，IR和IGF-IR在被同源配体激活后引发有丝分裂与代谢事件的能力方面存在差异。为了确定保守性较差的羧基末端结构域对IR和IGF-IR不同功能的贡献，我们构建了受体嵌合体，其中一个受体的羧基末端结构域与异源受体的其余部分融合。在表达嵌合受体或类似野生型受体序列的稳定转染NIH-3T3细胞中，检测了配体刺激后多个参数的反应。用IGF-IR的羧基末端替换IR的羧基末端严重影响胰岛素刺激的反应，而用IR的羧基末端替换IGF-IR的羧基末端影响最小。这些数据表明，IR和IGF-IR的羧基末端结构域不可互换，并且IR的有丝分裂活性可受羧基末端结构域中存在的序列影响。另一方面，IGF-IR的类似功能似乎不受IR羧基末端结构域存在的很大影响。
