Endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through α2β1 integrin
Endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through α2β1 integrin
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DOI：
10.1083/jcb.200401150
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发表时间：
2004-07-05
影响因子：
7.8
通讯作者：
Iozzo, RV
中科院分区：
文献类型：
--
作者：
Bix, G;Fu, J;Iozzo, RV
Endorepellin 是硫酸乙酰肝素蛋白聚糖的 COOH 末端结构域，可抑制血管生成的多个方面。我们为一种新的生物轴提供了证据，该轴将基底膜蛋白核心的可溶性片段与胶原蛋白 1、α2β1 整联蛋白的主要细胞表面受体连接起来，并对导致内皮素抗血管生成活性的细胞内信号传导事件进行了初步研究。内皮素和 α2β1 整合素之间的相互作用触发独特的信号通路，导致第二信使 cAMP 增加；激活两种近端激酶：蛋白激酶 A 和粘着斑激酶； p38 丝裂原激活蛋白激酶和热休克蛋白 27 瞬时激活，随后后两种蛋白快速下调；并最终分解肌动蛋白应力纤维和粘着斑。最终结果是严重阻碍内皮细胞迁移和血管生成。由于基底膜聚糖存在于内皮细胞和平滑肌细胞基底膜中，因此血管生成初始阶段的蛋白水解活性可以从血管壁释放抗血管生成片段，包括内皮素。
Endorepellin, the COOH-terminal domain of the heparan sulfate proteoglycan perlecan, inhibits several aspects of angiogenesis. We provide evidence for a novel biological axis that links a soluble fragment of perlecan protein core to the major cell surface receptor for collagen 1, alpha2beta1 integrin, and provide an initial investigation of the intracellular signaling events that lead to endorepellin antiangiogenic activity. The interaction between endorepellin and alpha2beta1 integrin triggers a unique signaling pathway that causes an increase in the second messenger cAMP; activation of two proximal kinases, protein kinase A and focal adhesion kinase; transient activation of p38 mitogen-activated protein kinase and heat shock protein 27, followed by a rapid down-regulation of the latter two proteins; and ultimately disassembly of actin stress fibers and focal adhesions. The end result is a profound block of endothelial cell migration and angiogenesis. Because perlecan is present in both endothelial and smooth muscle cell basement membranes, proteolytic activity during the initial stages of angiogenesis could liberate antiangiogenic fragments from blood vessels' walls, including endorepellin.