Identification of domains of the insulin-like growth factor I receptor that are required for protection from apoptosis
Identification of domains of the insulin-like growth factor I receptor that are required for protection from apoptosis
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DOI：
10.1128/mcb.17.1.427
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发表时间：
1997-01-01
影响因子：
5.3
通讯作者：
Blattler, WA
中科院分区：
文献类型：
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作者：
OConnor, R;KauffmannZeh, A;Blattler, WA
使用一系列的胰岛素样生长因子I（IGF-I）受体突变体，我们试图定义所需的域从受体传递抗凋亡信号，并比较这些域与有丝分裂或转化所需的。在用野生型IGF-I受体转染的FL5.12细胞中，IGF-I提供了对白细胞介素3戒断的保护，但不是促有丝分裂的。缺乏功能性ATP结合位点的IGF-I受体对细胞凋亡没有保护作用。然而，在酪氨酸残基950处或在激酶结构域内的酪氨酸簇（1131、1135和1136）中突变的受体仍然能够抑制细胞凋亡，尽管已知这些突变抑制转化和促有丝分裂功能。在IGF-I受体的C末端，两个突变，一个在酪氨酸1251和一个取代残基组氨酸1293和赖氨酸1294，取消了抗凋亡功能，而突变的四个丝氨酸在1280至1283没有。有趣的是，在C末端截短的受体具有增强的抗凋亡功能。在Rat-1/ c-MycER成纤维细胞中，Y 950 F突变体和酪氨酸簇突变体仍然可以提供对c-Myc诱导的凋亡的保护，而突变体Y1250/1251 F不能。这些研究表明，IGF-I受体的抗凋亡功能所需的结构域与其增殖或转化功能所需的结构域不同，并表明抑制凋亡所需的受体结构域是必要的，但不足以转化。
Using a series of insulin-like growth factor I (IGF-I) receptor mutants, we have attempted to define domains required for transmitting the antiapoptotic signal from the receptor and to compare these domains with those required for mitogenesis or transformation. In FL5.12 cells transfected with wild-type IGF-I receptors, IGF-I affords protection from interleukin 3 withdrawal but is not mitogenic. An IGF-I receptor lacking a functional ATP binding site provided no protection from apoptosis. However, receptors mutated at tyrosine residue 950 or in the tyrosine cluster (1131, 1135, and 1136) within the kinase domain remained capable of suppressing apoptosis, although such mutations are known to inactivate transforming and mitogenic functions. In the C terminus of the IGF-I receptor, two mutations, one at tyrosine 1251 and one which replaced residues histidine 1293 and lysine 1294, abolished the antiapoptotic function, whereas mutation of the four serines at 1280 to 1283 did not. Interestingly, receptors truncated at the C terminus had enhanced antiapoptotic function. In Rat-1/ c-MycER fibroblasts, the Y950F mutant and the tyrosine cluster mutant could still provide protection from c-Myc-induced apoptosis, whereas mutant Y1250/1251F could not. These studies demonstrate that the domains of the IGF-I receptor required for its antiapoptotic function are distinct from those required for its proliferation or transformation functions and suggest that domains of the receptor required for inhibition of apoptosis are necessary but not sufficient for transformation.