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-Stirnulated Signaling
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-Stirnulated Signaling
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DOI：
10.1128/mcb.01011-12
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发表时间：
2012-10-01
影响因子：
5.3
通讯作者：
Clemmons, David R.
中科院分区：
文献类型：
--
作者：
Shen, Xinchun;Xi, Gang;Clemmons, David R.
胰岛素样生长因子I（IGF-I）是血管平滑肌细胞（VSMC）的有丝分裂原，与动脉粥样硬化的发生和进展有关。IGF结合蛋白（IGFBPs）独立于IGF结合改变IGF-I的作用，但它们发挥作用的基于受体的机制尚未阐明。我们研究了IGFBP-2和受体蛋白酪氨酸磷酸酶β（RPTP β）在调节IGF-I信号传导和细胞增殖中的作用。IGFBP-2结合RPTP β，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。底物捕获突变体和磷酸酶失活突变体的应用表明，RPTP β特异性结合PTEN并使其去磷酸化，IGFBP-2敲低导致PTEN酪氨酸磷酸化和Ala Ser 473活化减少。IGFBP-2增强IGF-I刺激的VSMC迁移和增殖。从IGFBP-2（-/-）小鼠获得的血管分析显示RPTP β被激活，这与IGF-I刺激的AKT Ser 473磷酸化和VSMC增殖的抑制有关。这些变化在IGFBP-2给药后得到挽救。这些发现为协调调节IGFBP-2和IGF-I信号功能导致刺激VSMC增殖提供了一种新的机制。这些结果对于了解IGFBPs如何调节细胞对IGF-I的反应具有重要意义。
Insulin-lilce 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 beta (RPTP beta) in regulating IGF-I signaling and cellular proliferation. IGFBP-2 bound RPTP beta, 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 RPTP beta bound specifically to PTEN and dephosphorylated it. IGFBP-2 knockdown led to decreased PTEN tyrosine phosphorylation and decreased Ala Ser473 activation. IGFBP-2 enhanced IGF-I-stimulated VSMC migration and proliferation. Analysis of aortas obtained from IGFBP-2(-/-) mice showed that RPTP beta 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 fmdings 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.