Minimal active domain and mechanism of action of the angiogenesis inhibitor histidine-rich glycoprotein
Minimal active domain and mechanism of action of the angiogenesis inhibitor histidine-rich glycoprotein
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DOI：
10.1158/0008-5472.can-05-2217
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发表时间：
2006-02-15
期刊：
影响因子：
11.2
通讯作者：
Claesson-Welsh, L
中科院分区：
文献类型：
--
作者：
Dixelius, J;Olsson, AK;Claesson-Welsh, L
富组氨酸糖蛋白（HRGP）是一种丰富的肝素结合血浆蛋白，可有效抑制小鼠肿瘤模型的生长和血管形成。我们已经表明，HRGP的抗血管生成作用是依赖于其组氨酸/脯氨酸丰富的结构域，这需要从母蛋白释放发挥其作用。在这里，我们确定了一个35个氨基酸的肽，HRGP 330，来自组氨酸/脯氨酸丰富的结构域赋予体外和体内的抗血管生成特性。HRGP 330的作用机制涉及通过破坏整联蛋白连接激酶（ILK）和粘着斑激酶（FAK）功能来颠覆粘着斑功能，抑制血管内皮生长因子（VEGF）诱导的FAK底物的酪氨酸磷酸化，辅肌动蛋白，并因此导致内皮细胞运动停滞。受干扰的粘着斑功能反映在HRGP以及HRGP 330以涉及α（v）β（3）整联蛋白的方式阻止内皮细胞粘附于玻连蛋白的能力中。总之，HRGP 330，我们定义为最小的抗血管生成域HRGP，发挥其作用，通过信号转导靶向局灶性粘连，从而中断VEGF诱导的内皮细胞运动。
Histidine-rich glycoprotein (HRGP) is an abundant heparin-binding plasma protein that efficiently arrests growth and vascularization of mouse tumor models. We have shown that the antiangiogenic effect of HRGP is dependent on its histidine/proline-rich domain, which needs to be released from the mother protein to exert its effects. Here we identify a 35-amino-acid peptide, HRGP330, derived from the histidine/proline-rich domain as endowed with antiangiogenic properties in vitro and in vivo. The mechanism of action of HRGP330 involves subversion of focal adhesion function by disruption of integrin-linked kinase (ILK) and focal adhesion kinase (FAK) functions, inhibition of vascular endothelial growth factor (VEGF)-induced tyrosine phosphorylation of the FAK substrate a.-actinin, and, as a consequence, an arrest in endothelial cell motility. The disturbed focal adhesion function is reflected in the ability of HRGP as well as of HRGP330 to prevent endothelial cell adhesion to vitronectin in a manner involving alpha(v)beta(3) integrin. In conclusion, HRGP330, which we define as the minimal antiangiogenic domain of HRGP, exerts its effects through signal transduction targeting focal adhesions, thereby interrupting VEGF-induced endothelial cell motility.