Insulin receptor substrates form high-molecular-mass complexes that modulate their availability to insulin/insulin-like growth factor-I receptor tyrosine kinases
Insulin receptor substrates form high-molecular-mass complexes that modulate their availability to insulin/insulin-like growth factor-I receptor tyrosine kinases
复制标题
DOI：
10.1016/j.bbrc.2010.12.045
复制
发表时间：
2011-01-21
影响因子：
3.1
通讯作者：
Takahashi, Shin-Ichiro
中科院分区：
文献类型：
--
作者：
Fukushima, Toshiaki;Arai, Toshiya;Takahashi, Shin-Ichiro
胰岛素受体底物（IRS）被激活的胰岛素/胰岛素样生长因子（IGF）-I受体酪氨酸激酶磷酸化。磷酸化酪氨酰IRS被具有src同源区2（SH 2）结构域的信号分子识别，其介导各种胰岛素/IGF生物活性。然而，我们已经表明，IRS也与其他蛋白质的磷酸酪氨酸独立的机制。在这里，我们证明了IRSs与各种蛋白质形成高分子量复合物（我们将这些复合物命名为IRSomes），并阐明了它们可能的作用。细胞裂解物的蓝色天然聚丙烯酰胺凝胶电泳显示IRSome形成。某些蛋白质以IRS亚型、细胞类型或刺激特异性方式与IRS相关。体外酪氨酸磷酸化测定的结果表明，当IRS-1包含在用TNF-α处理的3 T3-L1脂肪细胞制备的IRSomes中时，胰岛素受体对IRS-1的酪氨酸磷酸化减少。此外，当IRS-2包含在用二丁酰cAMP处理的FRTL-5甲状腺细胞制备的IRSomes中时，IGF-I受体对IRS-2的酪氨酸磷酸化增加。这些结果表明，细胞因子/细胞因子诱导的IRSomes形成调节IRS对受体酪氨酸激酶的可用性。(C)2010年爱思唯尔公司All rights reserved.
Insulin receptor substrates (IRSs) are phosphorylated by activated insulin/insulin-like growth factor (IGF)-I receptor tyrosine kinases. Phosphotyrosyl IRSs are recognized by signaling molecules possessing src homology region 2 (SH2) domains, which mediate various insulin/IGF bioactivities. However, we have shown that IRSs are also associated with other proteins by a phosphotyrosine-independent mechanism. Here, we demonstrated that IRSs form high-molecular-mass complexes (we named these complexes IRSomes) with various proteins and we elucidated their possible roles. Blue native-polyacrylamide gel electrophoresis of cell lysates revealed IRSome formation. Some proteins associated with IRSs in IRS-isoform-, cell-type-, or stimulus-specific manners. Results of the in vitro tyrosine phosphorylation assay indicated that tyrosine phosphorylation of IRS-1 by insulin receptor was decreased when IRS-1 was contained in IRSomes prepared from 3T3-L1 adipocytes treated with TNF-alpha. Also, tyrosine phosphorylation of IRS-2 by IGF-I receptor was increased when IRS-2 was contained in IRSomes prepared from FRTL-5 thyrocytes treated with dibutyryl cAMP. These results demonstrated that cytokine/hormone-induced formation of IRSomes modulates availability of IRSs to receptor tyrosine kinases. (C) 2010 Elsevier Inc. All rights reserved.