ANGPTL3 stimulates endothelial cell adhesion and migration via integrin αvβ3 and induces blood vessel formation in vivo
ANGPTL3 stimulates endothelial cell adhesion and migration via integrin αvβ3 and induces blood vessel formation in vivo
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DOI：
10.1074/jbc.m109768200
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发表时间：
2002-05-10
影响因子：
4.8
通讯作者：
Gerber, HP
中科院分区：
文献类型：
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作者：
Camenisch, G;Pisabarro, MT;Gerber, HP
分泌因子的血管生成素家族在功能上由C-末端纤维蛋白原（FBN）样结构域限定，其介导与Tie 2受体的结合，从而促进最终调节血管形成的级联事件。通过筛选表达的序列标签数据库的同源性的共识FBN样动机，我们已经确定ANGPTL 3，肝脏特异性，分泌因子组成的N-末端卷曲螺旋结构域和C-末端FBN样结构域。然而，免疫共沉淀实验未能检测到ANGPTL 3与Tie 2受体的结合。生成ANGPTL 3的FBN样结构域的分子模型，并预测与整合素的潜在结合。这一假设通过以下发现得到实验证实：重组ANGPTL 3结合α（v）β（3）并诱导整合素α（v）β（3）依赖性趋触内皮细胞粘附和迁移，并刺激整合素活化的信号转导途径特征，包括Akt磷酸化、促分裂原活化蛋白激酶和粘着斑激酶。当在大鼠角膜测定中测试时，ANGPTL 3强烈诱导血管生成，其幅度与血管内皮生长因子-A所观察到的相当。此外，C-末端FBN样结构域单独足以诱导内皮细胞粘附和体内血管生成。总之，我们的数据表明ANGPTL 3是与整合素α（v）β（3）结合的分泌因子的血管生成素样家族的第一个成员，并表明在血管生成的调节中可能起作用。
The angiopoietin family of secreted factors is functionally defined by the C-terminal fibrinogen (FBN)-like domain, which mediates binding to the Tie2 receptor and thereby facilitates a cascade of events ultimately regulating blood vessel formation. By screening expressed sequence tag data bases for homologies to a consensus FBN-like motive, we have identified ANGPTL3, a liver-specific, secreted factor consisting of an N-terminal coiled-coil domain and the C-terminal FBN-like domain. Co-immunoprecipitation experiments, however, failed to detect binding of ANGPTL3 to the Tie2 receptor. A molecular model of the FBN-like domain of ANGPTL3 was generated and predicted potential binding to integrins. This hypothesis was experimentally confirmed by the finding that recombinant ANGPTL3 bound to alpha(v)beta(3) and induced integrin alpha(v)beta(3)-dependent haptotactic endothelial cell adhesion and migration and stimulated signal transduction pathways characteristic for integrin activation, including phosphorylation of Akt, mitogen-activated protein kinase, and focal adhesion kinase. When tested in the rat corneal assay, ANGPTL3 strongly induced angiogenesis with comparable magnitude as observed for vascular endothelial growth factor-A. Moreover, the C-terminal FBN-like domain alone was sufficient to induce endothelial cell adhesion and in vivo angiogenesis. Taken together, our data demonstrate that ANGPTL3 is the first member of the angiopoietin-like family of secreted factors binding to integrin alpha(v)beta(3) and suggest a possible role in the regulation of angiogenesis.