IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis
IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis
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DOI：
10.1038/nature07027
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发表时间：
2008-07-17
期刊：
影响因子：
64.8
通讯作者：
Komuro, Issei
中科院分区：
文献类型：
--
作者：
Zhu, Weidong;Shiojima, Ichiro;Komuro, Issei
胰岛素样生长因子结合蛋白(IGFBPs)结合并调节胰岛素样生长因子(IGF)的作用(1)。虽然IGFBPs的一些作用已被报道为独立于IGFs，但IGFBPs的IGF非依赖性作用的确切机制在很大程度上尚不清楚(1，2)。在这里，我们报告了一个以前未知的IGFBP-4作为心源性生长因子的功能。IGFBP-4在体外促进心肌细胞分化，而敲除IGFbp4在体外和体内都抑制心肌生成。IGFBP-4的心脏效应独立于其IGF结合活性，但通过抑制典型的Wnt信号而介导。IGFBP-4与Wnt受体Frizzled8(Frz8)和Wnt共同受体低密度脂蛋白受体相关蛋白6(LRP6)物理上相互作用，并抑制Wnt3a与Frz8和LRP6的结合。虽然IGFBP-4不依赖IGFBP-4，但IGFS通过IGFBP-4的隔离作用减弱了IGFBP-4的生心作用。因此，IGFBP-4是心脏发生所需的典型Wnt信号的抑制剂，并在IGF信号和Wnt信号之间提供了分子联系。
Insulin- like growth- factor- binding proteins ( IGFBPs) bind to and modulate the actions of insulin- like growth factors ( IGFs)(1). Although some of the actions of IGFBPs have been reported to be independent of IGFs, the precise mechanisms of IGF- independent actions of IGFBPs are largely unknown(1,2). Here we report a previously unknown function for IGFBP- 4 as a cardiogenic growth factor. IGFBP- 4 enhanced cardiomyocyte differentiation in vitro, and knockdown of Igfbp4 attenuated cardiomyogenesis both in vitro and in vivo. The cardiogenic effect of IGFBP- 4 was independent of its IGF- binding activity but was mediated by the inhibitory effect on canonical Wnt signalling. IGFBP- 4 physically interacted with a Wnt receptor, Frizzled 8 ( Frz8), and a Wnt co- receptor, low-density lipoprotein receptor- related protein 6 ( LRP6), and inhibited the binding of Wnt3A to Frz8 and LRP6. Although IGF- independent, the cardiogenic effect of IGFBP- 4 was attenuated by IGFs through IGFBP- 4 sequestration. IGFBP- 4 is therefore an inhibitor of the canonical Wnt signalling required for cardiogenesis and provides a molecular link between IGF signalling and Wnt signalling.