Insulin receptor substrate-1 is the predominant signaling molecule activated by insulin-like growth factor-I, insulin, and interleukin-4 in estrogen receptor-positive human breast cancer cells
Insulin receptor substrate-1 is the predominant signaling molecule activated by insulin-like growth factor-I, insulin, and interleukin-4 in estrogen receptor-positive human breast cancer cells
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DOI：
10.1074/jbc.273.16.9994
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发表时间：
1998-04-17
影响因子：
4.8
通讯作者：
Yee, D
中科院分区：
文献类型：
--
作者：
Jackson, JG;White, MF;Yee, D
由于胰岛素样生长因子-I(IGF-I)、胰岛素和白介素4(IL-4)在乳腺癌细胞中具有已知的生物学效应，并通过胰岛素受体底物(IRS)接头蛋白传递信号，因此我们检测了IRS-1和IRS-2在乳腺肿瘤和细胞系中的表达和功能。IRS-1和IRS-2在细胞系和原发乳腺肿瘤标本中均有表达。与IRS-2相比，IGF-I、胰岛素和IL-4处理MCF-7和ZR-75，以及IGF-I处理T47-D乳腺癌细胞，导致IRS-1的酪氨酸磷酸化程度大大增加。此外，IGF-I比胰岛素或IL-4更能刺激IRS-1的酪氨酸磷酸化。胰岛素样生长因子-I还增强了磷脂酰肌醇-S-激酶的P85调节亚基与胰岛素受体-1的结合，并刺激了与IL-4和胰岛素相比的酶活性增加。同样，在IGF-I刺激的细胞中，丝裂原激活的蛋白激酶活性更高。为了确定这些通路激活的功能意义，我们用Wortmannin抑制了磷脂酰肌醇3-激酶的激活，用PD098059抑制了丝裂原激活的蛋白激酶的激活。这两种化合物都抑制了IGF刺激的生长，这表明两种途径都参与了对IGF-I的有丝分裂反应。我们得出结论，IGF-I、胰岛素和IL-4激活的主要信号分子是IRS-1，而不是IRS-2。此外，与胰岛素或IL-4相比，IGF-I对IRS-1酪氨酸磷酸化的增强与有丝分裂下游信号通路的更大激活有关，从而促进细胞生长。
Because insulin-like growth factor-I (IGF-I), insulin, and interleukin-4 (IL-4) have known biological effects in breast cancer cells and signal through insulin receptor substrate (IRS) adaptor proteins, we examined the expression and function of IRS-1 and IRS-2 in breast tumors and cell lines. IRS-1 and IRS-2 were expressed by cell lines and primary breast tumor specimens. IGF-I, insulin, and IL-4 treatment of MCF-7 and ZR-75, and IGF-I treatment of T47-D breast cancer cells, resulted in much greater tyrosine phosphorylation of IRS-1 compared with IRS-2. Furthermore, IGF-I stimulated greater tyrosine phosphorylation of IRS-1 than either insulin or IL-4. IGF-I treatment also enhanced association of the p85 regulatory subunit of phosphatidylinositol S-kinase with IRS-1 and stimulated increased enzymatic activity compared with IL-4 and insulin in all three cell lines. Similarly, mitogen-activated protein kinase activity was greater in IGF-I-stimulated cells. To determine the functional significance of the activation of these pathways, we inhibited activation of phosphatidylinositol 3-kinase with wortmannin and mitogen-activated protein kinase with PD098059. Both compounds inhibited IGF-stimulated growth, suggesting that both pathways contributed to the mitogenic response to IGF-I. We conclude that IRS-1, and not IRS-2, is the predominant signaling molecule activated by IGF-I, insulin, and IL-4. Furthermore, enhanced tyrosine phosphorylation of IRS-1 by IGF-I, compared with either insulin or IL-4, is associated with greater activation of mitogenic downstream signaling pathways resulting in enhanced cell growth.