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首页> 外文期刊>Molecular biology of the cell >The association between integrin-associated protein and SHPS-1 regulates insulin-like growth factor-I receptor signaling in vascular smooth muscle cells
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The association between integrin-associated protein and SHPS-1 regulates insulin-like growth factor-I receptor signaling in vascular smooth muscle cells

机译：整合素相关蛋白和SHPS-1之间的关联调节血管平滑肌细胞中的胰岛素样生长因子-I受体信号传导

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Growth factor signaling is usually analyzed in isolation without considering the effect of ligand occupancy of transmembrane proteins other than the growth factor receptors themselves. In smooth muscle cells, the transmembrane protein Src homology 2 domain containing protein tyrosine phosphatase substrate-1 (SHPS-1) has been shown to be an important regulator of insulin-like growth factor-I (IGF-I) signaling. SHPS-1 is phosphorylated in response to IGF-I, leading to recruitment of Src homology 2 domain tyrosine phosphatase (SHP-2). Subsequently, SHP-2 is transferred to IGF-I receptor and regulates the duration of IGF-I receptor phosphorylation. Whether ligand occupancy of SHPS-1 influences SHPS-I phosphorylation or SHP-2 recruitment, thereby altering growth factor signaling, is unknown. Previous studies have shown that integrin associated protein (IAP) associates with SHPS-I. We undertook these studies to determine whether this interaction controlled SHPS-1 phosphorylation and/or SHP-2 recruitment and thereby regulated IGF-I signaling. Disruption of IAP-SHPS-1 binding, by using an IAP monoclonal antibody or cells expressing mutant forms of IAP that did not bind to SHPS-1, inhibited IGF-I-stimulated SHPS-1 phosphorylation and SHP-2 recruitment. This was associated with a lack of SHP-2 transfer to lGF-I receptor and sustained receptor phosphorylation. This resulted in an inability of lGF-I to stimulate sustained mitogen-activated protein kinase activation, cell proliferation, and cell migration. The effect was specific for IGF-I because disruption of the TAP-SHPS-1 interaction had no effect on platelet-derived growth factor-stimulated SHPS-1 phosphorylation or cell migration. In summary, our results show that 1) ligand occupancy of SHPS-1 is a key determinant of its ability to be phosphorylated after IGF-l stimulation, and 2) the interaction between IAP and SHPS-1 is an important regulator of IGF-I signaling because disruption of the results in impaired SHP-2 recruitment and subsequent inhibition of IGF-I-stimulated cell proliferation and migration. [References: 38]
机译：通常单独分析生长因子信号传导，而不考虑除生长因子受体本身以外的跨膜蛋白的配体占据效应。在平滑肌细胞中，跨膜蛋白Src同源2域包含蛋白酪氨酸磷酸酶底物1（SHPS-1）已被证明是胰岛素样生长因子I（IGF-1）信号的重要调节剂。 SHPS-1响应IGF-I磷酸化，导致募集Src同源性2域酪氨酸磷酸酶（SHP-2）。随后，将SHP-2转移至IGF-1受体并调节IGF-1受体磷酸化的持续时间。尚不清楚SHPS-1的配体占用是否影响SHPS-1磷酸化或SHP-2募集，从而改变生长因子信号传导。先前的研究表明，整联蛋白相关蛋白（IAP）与SHPS-1相关。我们进行了这些研究，以确定这种相互作用是否控制SHPS-1磷酸化和/或SHP-2募集，从而调节IGF-1信号传导。通过使用IAP单克隆抗体或表达不与SHPS-1结合的IAP突变形式的细胞破坏IAP-SHPS-1结合，可以抑制IGF-I刺激的SHPS-1磷酸化和SHP-2募集。这与缺乏SHP-2转移至IGF-1受体和持续的受体磷酸化有关。这导致lGF-1不能刺激持续的丝裂原活化的蛋白激酶活化，细胞增殖和细胞迁移。该作用对IGF-1具有特异性，因为TAP-SHPS-1相互作用的破坏对血小板衍生的生长因子刺激的SHPS-1磷酸化或细胞迁移没有影响。总之，我们的结果表明，1）SHPS-1的配体占有率是其在IGF-1刺激后被磷酸化的能力的关键决定因素; 2）IAP和SHPS-1之间的相互作用是IGF-1的重要调节剂信号转导，因为破坏结果会削弱SHP-2募集并随后抑制IGF-I刺激的细胞增殖和迁移。 [参考：38]

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