Syndecan-1 regulates alphavbeta3 and alphavbeta5 integrin activation during angiogenesis and is blocked by synstatin, a novel peptide inhibitor.
Syndecan-1 regulates alphavbeta3 and alphavbeta5 integrin activation during angiogenesis and is blocked by synstatin, a novel peptide inhibitor.
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DOI：
10.1084/jem.20081278
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发表时间：
2009-03-16
期刊：
影响因子：
--
通讯作者：
Rapraeger AC
中科院分区：
文献类型：
--
作者：
Beauvais DM;Ell BJ;McWhorter AR;Rapraeger AC
多配体蛋白聚糖-1（Sdc 1）是一种基质受体，通过其细胞外结构域与αvβ3和αvβ5整联蛋白结合，可能调节表达这些整联蛋白的细胞的粘附、扩散和侵袭。使用在人乳腺癌细胞中表达的Sdc 1缺失突变体，我们确定了Sdc 1核心蛋白内的活性位点，并衍生出一种称为合成抑素（Synstatin）的肽抑制剂，该抑制剂破坏了Sdc 1与这些整合素的相互作用。因为αvβ3和αvβ5整合素在血管生成中是关键的，在这个过程中Sdc 1的作用还不确定，我们在体外使用人血管内皮细胞来证明Sdc 1调节机制也是这些细胞上整合素活化所必需的。我们发现，Sdc 1表达在血管内皮细胞的微血管生长过程中，从主动脉外植体在体外和小鼠乳腺肿瘤在体内。此外，我们表明，在体外或在体内血管生成的小鼠模型中全身递送时，Sodium阻断血管生成，并在原位小鼠肿瘤模型中损害乳腺肿瘤生长。因此，Sdc 1是血管生成和肿瘤发生过程中这两种重要整联蛋白的关键调节因子，并被新的S肽抑制。
Syndecan-1 (Sdc1) is a matrix receptor shown to associate via its extracellular domain with the αvβ3 and αvβ5 integrins, potentially regulating cell adhesion, spreading, and invasion of cells expressing these integrins. Using Sdc1 deletion mutants expressed in human mammary carcinoma cells, we identified the active site within the Sdc1 core protein and derived a peptide inhibitor called synstatin (SSTN) that disrupts Sdc1's interaction with these integrins. Because the αvβ3 and αvβ5 integrins are critical in angiogenesis, a process in which a role for Sdc1 has been uncertain, we used human vascular endothelial cells in vitro to show that the Sdc1 regulatory mechanism is also required for integrin activation on these cells. We found Sdc1 expressed in the vascular endothelium during microvessel outgrowth from aortic explants in vitro and in mouse mammary tumors in vivo. Moreover, we show that SSTN blocks angiogenesis in vitro or when delivered systemically in a mouse model of angiogenesis in vivo, and impairs mammary tumor growth in an orthotopic mouse tumor model. Thus, Sdc1 is a critical regulator of these two important integrins during angiogenesis and tumorigenesis, and is inhibited by the novel SSTN peptide.
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影响因子：
3.3
作者：
Boettiger, D;Huber, F;Blystone, S
通讯作者：
Blystone, S
影响因子：
64.5
作者：
BROOKS, PC;MONTGOMERY, AMP;CHERESH, DA
通讯作者：
CHERESH, DA
影响因子：
56.9
作者：
BROOKS, PC;CLARK, RAF;CHERESH, DA
通讯作者：
CHERESH, DA
用环状RGD肽抑制α-NU整联蛋白会损害体内实体瘤的血管生成，生长和转移。
影响因子：
8.8
作者：
Buerkle, M A;Pahernik, S A;Sutter, A;Jonczyk, A;Messmer, K;Dellian, M
通讯作者：
Dellian, M
DOI：
10.1083/jcb.200404171
发表时间：
2004-10-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Beauvais DM;Burbach BJ;Rapraeger AC
通讯作者：
Rapraeger AC