The AP-1 Complex Regulates Intracellular Localization of Insulin Receptor Substrate 1, Which Is Required for Insulin-Like Growth Factor I-Dependent Cell Proliferation
The AP-1 Complex Regulates Intracellular Localization of Insulin Receptor Substrate 1, Which Is Required for Insulin-Like Growth Factor I-Dependent Cell Proliferation
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DOI：
10.1128/mcb.01394-12
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发表时间：
2013-03
影响因子：
5.3
通讯作者：
Yosuke Yoneyama;M. Matsuo;Kazumi Take;Tomohiro Kabuta;K. Chida;F. Hakuno;Shin-ichiro Takahashi
中科院分区：
文献类型：
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作者：
Yosuke Yoneyama;M. Matsuo;Kazumi Take;Tomohiro Kabuta;K. Chida;F. Hakuno;Shin-ichiro Takahashi
胰岛素/胰岛素样生长因子I （IGF-I）受体的激活和随后胰岛素受体底物（IRSs）的酪氨酸磷酸化是多种胰岛素/IGF生物活性（包括有丝分裂发生）的关键初始事件。据报道，IRS-1与细胞膜间室相关，这种定位被认为对胰岛素/IGF信号转导很重要。然而，IRS-1定位的分子机制尚不清楚。在L6成肌细胞中，IRS-1与无处不在表达的AP-1复合物的μ1A结合，该复合物将货物蛋白包装到源自细胞膜的网格蛋白包被的囊泡中。野生型IRS-1主要定位于囊泡结构，而缺乏3个YXXΦ基序负责结合μ1A的IRS-1突变体则错误定位于甘露糖-6-磷酸受体阳性结构，这表明在这些突变体中，ap -1向外周囊泡的转运受到抑制。此外，IRS-1中AP-1结合位点的缺失会损害igf -i诱导的细胞增殖，并伴随着IRS-1酪氨酸磷酸化及其与磷酸肌苷（PI） 3激酶的关联减少。这些数据证明了ap -1依赖的IRS-1定位在介导igf - i刺激的信号传导和最大的有丝分裂反应中的重要性。
ABSTRACT The activation of the insulin/insulin-like growth factor I (IGF-I) receptor and the subsequent tyrosine phosphorylation of insulin receptor substrates (IRSs) are key initial events in a variety of insulin/IGF bioactivities, including mitogenesis. It has been reported that IRS-1 associates with intracellular membrane compartments, and this localization is believed to be important for insulin/IGF signal transduction. However, the molecular mechanisms underlying IRS-1 localization remain unclear. Here we show that in L6 myoblasts, IRS-1 associates with μ1A of the ubiquitously expressed AP-1 complex, which packages cargo proteins into clathrin-coated vesicles derived from intracellular membranes. While wild-type IRS-1 was predominantly localized to vesicular structures, IRS-1 mutants lacking three YXXΦ motifs responsible for binding to μ1A were mislocalized to the mannose-6-phosphate receptor-positive structures, suggesting that AP-1-dependent transport to peripheral vesicles is inhibited in these mutants. Furthermore, deletion of AP-1 binding sites in IRS-1 impaired IGF-I-induced cell proliferation, accompanied by reduced tyrosine phosphorylation of IRS-1 and its association with phosphoinositide (PI) 3-kinase. These data demonstrate the importance of AP-1-dependent localization of IRS-1 in mediating IGF-I-stimulated signaling and maximum mitogenic response.