Human tumstatin land human endostatin exhibit distinct antiangiogenic activities mediated by αvβ3 and α5β1 integrins
Human tumstatin land human endostatin exhibit distinct antiangiogenic activities mediated by αvβ3 and α5β1 integrins
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DOI：
10.1073/pnas.0730882100
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发表时间：
2003-04-15
影响因子：
11.1
通讯作者：
Kalluri, R
中科院分区：
文献类型：
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作者：
Sudhakar, A;Sugimoto, H;Kalluri, R
Tumstatin和Endostatin是两种血管生成的抑制剂，分别来自被称为IV型胶原的Alpha3链和XVIII型胶原的Alpha1链的前体人胶原分子。虽然这两种抑制物都是胶原蛋白的非胶原性(Nc1)结构域片段，但它们只有14%的氨基酸同源性。在目前的研究中，我们评估了这两个胶原硬化抑制剂诱导的功能受体、作用机制和细胞内信号转导。人转抑素通过抑制内皮细胞增殖和促进细胞凋亡而阻止血管生成，但不影响迁移，而人内皮抑素则通过抑制内皮细胞迁移而不影响增殖。我们证明了人转抑素以玻璃体连接蛋白/纤维连接蛋白/RGD环肽非依赖的方式与α5β1整合素结合，而人内皮抑素与纤维连接蛋白/RGD环肽竞争结合α5β1整合素。人转抑素的活性是由α-β3整合素介导的，而人内皮抑素的活性是由α-5β-1整合素介导的。此外，尽管人转抑素与α-β3整合素结合可抑制粘着斑激酶/磷脂酰肌醇3-激酶/Akt/mTOR/4E-BP1途径介导的Cap依赖的翻译(蛋白质合成)，但人内皮抑素与α5β1整合素结合可抑制粘着斑激酶/c-Raf/MEK1/2/p38/ERK1丝裂原激活的蛋白激酶途径，而对磷脂酰肌醇3-激酶/Akt/mTOR/4E-BP1和帽依赖性翻译无影响。总而言之，人类转抑素和内皮抑素的这些不同的特性提供了对它们不同的抗血管生成作用的第一次洞察，并主张将它们结合起来用于靶向肿瘤血管生成。
Tumstatin and endostatin are two inhibitors of angiogenesis derived from precursor human collagen molecules known as alpha3 chain of type IV collagen and alpha1 chain of type XVIII collagen, respectively. Although both these inhibitors are noncollagenous (NC1) domain fragments of collagens, they only share a 14% amino acid homology. In the present study we evaluated the functional receptors, mechanism of action, and intracellular signaling induced by these two collagen-clerived inhibitors. Human turnstatin prevents angiogenesis via inhibition of endothelial cell proliferation and promotion of apoptosis with no effect on migration, whereas human endostatin prevents endothelial cell migration with no effect on proliferation. We demonstrate that human turnstatin binds to alphavbeta3 integrin in a vitronectin/fibronectin/RGD cyclic peptide independent manner, whereas human endostatin competes with fibronectin/RGD cyclic peptide to bind alpha5beta1 integrin. The activity of human turnstatin is mediated by alphavbeta3 integrin, whereas the activity of human endostatin is mediated by alpha5beta1 integrin. Additionally, although human turnstatin binding to alphavbeta3 integrin leads to the inhibition of Cap-dependent translation (protein synthesis) mediated by focal adhesion kinase/phosphatidylinositol 3-kinase/Akt/mTOR/4E-BP1 pathway, human endostatin binding to alpha5beta1 integrin leads to the inhibition of focal adhesion kinase/c-Raf/MEK1/2/p38/ERK1 mitogen-activated protein kinase pathway, with no effect on phosphatidylinositol 3-kinase/Akt/mTOR/4E-BP1 and Cap-dependent translation. Collectively, such distinct properties of human turnstatin and human endostatin provide the first insight into their diverse antiangiogenic actions and argue for combining them for targeting tumor angiogenesis.