...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Molecular and Cellular Biology >Prostate-Specific Membrane Antigen Regulates Angiogenesis by Modulating Integrin Signal Transduction
【24h】

Prostate-Specific Membrane Antigen Regulates Angiogenesis by Modulating Integrin Signal Transduction

机译：前列腺特异性膜抗原通过调节整合素信号转导来调节血管生成。

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The transmembrane peptidase prostate-specific membrane antigen (PSMA) is universally upregulated in the vasculature of solid tumors, but its functional role in tumor angiogenesis has not been investigated. Here we show that angiogenesis is severely impaired in PSMA-null animals and that this angiogenic defect occurs at the level of endothelial cell invasion through the extracellular matrix barrier. Because proteolytic degradation of the extracellular matrix is a critical component of endothelial invasion in angiogenesis, it is logical to assume that PSMA participates in matrix degradation. However, we demonstrate a novel and more complex role for PSMA in angiogenesis, where it is a principal component of a regulatory loop that is tightly modulating laminin-specific integrin signaling and GTPase-dependent, p21-activated kinase 1 (PAK-1) activity. We show that PSMA inhibition, knockdown, or deficiency decreases endothelial cell invasion in vitro via integrin and PAK, thus abrogating angiogenesis. Interestingly, the neutralization of β1 or the inactivation of PAK increases PSMA activity, suggesting that they negatively regulate PSMA. This negative regulation is mediated by the cytoskeleton as the disruption of interactions between the PSMA cytoplasmic tail and the anchor protein filamin A decreases PSMA activity, integrin function, and PAK activation. Finally, the inhibition of PAK activation enhances the PSMA/filamin A interaction and, thus, boosts PSMA activity. These data imply that PSMA participates in an autoregulatory loop, wherein active PSMA facilitates integrin signaling and PAK activation, leading to both productive invasion and downregulation of integrin β1 signaling via reduced PSMA activity. Therefore, we have identified a novel role for PSMA as a true molecular interface, integrating both extracellular and intracellular signals during angiogenesis.
机译：跨膜肽酶前列腺特异膜抗原（PSMA）在实体瘤的脉管系统中普遍上调，但尚未研究其在肿瘤血管生成中的功能。在这里，我们显示在PSMA无效的动物中血管生成受到严重损害，并且这种血管生成缺陷发生在通过细胞外基质屏障对内皮细胞的侵袭水平上。由于细胞外基质的蛋白水解降解是血管生成中内皮细胞入侵的关键因素，因此可以合理地假设PSMA参与了基质降解。但是，我们证明了PSMA在血管生成中具有新颖和更复杂的作用，其中它是紧密调节层粘连蛋白特异性整合素信号转导和GTPase依赖性，p21活化的激酶1（PAK-1）活性的调节环的主要组成部分。 。我们表明，PSMA抑制，敲低或缺乏减少通过整合素和PAK体外内皮细胞入侵，从而废止血管生成。有趣的是，β 1 的中和作用或PAK的失活会增加PSMA的活性，表明它们对PSMA具有负调节作用。这种负调节作用是由细胞骨架介导的，因为PSMA细胞质尾巴与锚蛋白丝素A之间相互作用的破坏降低了PSMA活性，整联蛋白功能和PAK活化。最后，抑制PAK活化可增强PSMA /丝氨酸A的相互作用，从而增强PSMA活性。这些数据表明，PSMA参与了自调节循环，其中主动PSMA促进了整联蛋白信号传导和PAK激活，从而通过降低PSMA活性导致了整合素β 1 信号的生产性入侵和下调。因此，我们已经确定了PSMA作为真正的分子界面的新作用，在血管生成过程中整合了细胞外和细胞内信号。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号