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首页> 外文期刊>Molecular and Cellular Biology >Insulin-Like Growth Factor (IGF) Binding Protein 2 Functions Coordinately with Receptor Protein Tyrosine Phosphatase β and the IGF-I Receptor To Regulate IGF-I-Stimulated Signaling
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Insulin-Like Growth Factor (IGF) Binding Protein 2 Functions Coordinately with Receptor Protein Tyrosine Phosphatase β and the IGF-I Receptor To Regulate IGF-I-Stimulated Signaling

机译：胰岛素样生长因子（IGF）结合蛋白2与受体蛋白酪氨酸磷酸酶β和IGF-I受体协同调节IGF-I刺激的信号传导。

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Insulin-like growth factor I (IGF-I) is a mitogen for vascular smooth muscle cells (VSMC) and has been implicated in the development and progression of atherosclerosis. IGF binding proteins (IGFBPs) modify IGF-I actions independently of IGF binding, but a receptor-based mechanism by which they function has not been elucidated. We investigated the role of IGFBP-2 and receptor protein tyrosine phosphatase β (RPTPβ) in regulating IGF-I signaling and cellular proliferation. IGFBP-2 bound RPTPβ, which led to its dimerization and inactivation. This enhanced PTEN tyrosine phosphorylation and inhibited PTEN activity. Utilization of substrate trapping and phosphatase-dead mutants showed that RPTPβ bound specifically to PTEN and dephosphorylated it. IGFBP-2 knockdown led to decreased PTEN tyrosine phosphorylation and decreased AKT Ser473 activation. IGFBP-2 enhanced IGF-I-stimulated VSMC migration and proliferation. Analysis of aortas obtained from IGFBP-2?/? mice showed that RPTPβ was activated, and this was associated with inhibition of IGF-I stimulated AKT Ser473 phosphorylation and VSMC proliferation. These changes were rescued following administration of IGFBP-2. These findings present a novel mechanism for coordinate regulation of IGFBP-2 and IGF-I signaling functions that lead to stimulation of VSMC proliferation. The results have important implications for understanding how IGFBPs modulate the cellular response to IGF-I.
机译：胰岛素样生长因子I（IGF-1）是血管平滑肌细胞（VSMC）的促分裂原，与动脉粥样硬化的发生和发展有关。 IGF结合蛋白（IGFBP）独立于IGF结合而修饰IGF-1的作用，但是尚未阐明其作用的基于受体的机制。我们研究了IGFBP-2和受体蛋白酪氨酸磷酸酶β（RPTPβ）在调节IGF-1信号传导和细胞增殖中的作用。 IGFBP-2结合RPTPβ，导致其二聚化和失活。这增强了PTEN酪氨酸磷酸化并抑制了PTEN活性。利用底物捕获和磷酸酶死亡的突变体表明，RPTPβ与PTEN特异性结合并使其磷酸化。 IGFBP-2敲低导致PTEN酪氨酸磷酸化降低和AKT Ser473激活降低。 IGFBP-2增强了IGF-I刺激的VSMC迁移和增殖。从IGFBP-2小鼠的主动脉分析表明RPTPβ被激活，这与抑制IGF-I刺激的AKT Ser473磷酸化和VSMC增殖有关。这些变化在IGFBP-2给药后得以挽救。这些发现提出了一种新的机制，用于协调IGFBP-2和IGF-1信号传导功能，从而刺激VSMC增殖。该结果对于理解IGFBP如何调节对IGF-1的细胞应答具有重要意义。

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