Suppr超能文献

一种不易断裂的尿激酶型纤溶酶原激活物受体表现出细胞表面清除的失调。

A cleavage-resistant urokinase plasminogen activator receptor exhibits dysregulated cell-surface clearance.

机构信息

Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.

出版信息

J Biol Chem. 2010 Apr 23;285(17):12595-603. doi: 10.1074/jbc.M109.008581. Epub 2010 Feb 22.

Abstract

Urokinase plasminogen activator receptor (u-PAR) binds urokinase plasminogen activator (u-PA) and participates in plasminogen activation in addition to modulating several cellular processes such as adhesion, proliferation, and migration. u-PAR is susceptible to proteolysis by its cognate ligand and several other proteases. To elucidate the biological significance of receptor cleavage by u-PA, we engineered and expressed a two-chain urokinase plasminogen activator (tcu-PA) cleavage-resistant u-PAR (cr-u-PAR). This mutated receptor was similar to wild-type u-PAR in binding u-PA and initiating plasminogen activation. However, cr-u-PAR exhibited accelerated internalization and resurfacing due to direct association with the endocytic receptor alpha(2)-macroglobulin receptor/low density lipoprotein receptor-related protein in the absence of the enzyme x inhibitor complex of tcu-PA and plasminogen activator inhibitor-1 (tcu-PA.PAI-1). cr-u-PAR-expressing cells had enhanced migration compared with wild-type u-PAR-expressing cells, and cr-u-PAR was less sensitive to chymotrypsin cleavage as compared with wt u-PAR. Our studies suggest that these mutations in the linker region result in a rearrangement within the cr-u-PAR structure that makes it resemble its ligand-bound form. This constitutively active variant may mimic highly glycosylated cleavage-resistant u-PAR expressed in certain highly malignant cancer-cells.

摘要

尿激酶型纤溶酶原激活物受体(u-PAR)结合尿激酶型纤溶酶原激活物(u-PA),并参与纤溶酶原的激活,除此之外还调节几种细胞过程,如黏附、增殖和迁移。u-PAR 易受其同源配体和几种其他蛋白酶的蛋白水解。为了阐明 u-PA 对受体切割的生物学意义,我们设计并表达了一种两链尿激酶纤溶酶原激活物(tcu-PA)切割抗性 u-PAR(cr-u-PAR)。这种突变受体在结合 u-PA 和启动纤溶酶原激活方面与野生型 u-PAR 相似。然而,由于与内吞受体 α2-巨球蛋白受体/低密度脂蛋白受体相关蛋白的直接关联,cr-u-PAR 表现出加速的内化和再循环,而没有 tcu-PA 和纤溶酶原激活物抑制剂-1(tcu-PA.PAI-1)的酶 x 抑制剂复合物。与表达野生型 u-PAR 的细胞相比,表达 cr-u-PAR 的细胞具有增强的迁移能力,并且与 wt u-PAR 相比,cr-u-PAR 对糜蛋白酶切割的敏感性较低。我们的研究表明,这些连接区的突变导致 cr-u-PAR 结构内的重排,使其类似于其配体结合形式。这种组成型激活的变体可能模拟某些高度恶性癌细胞中表达的高度糖基化的切割抗性 u-PAR。

相似文献

1
A cleavage-resistant urokinase plasminogen activator receptor exhibits dysregulated cell-surface clearance.
J Biol Chem. 2010 Apr 23;285(17):12595-603. doi: 10.1074/jbc.M109.008581. Epub 2010 Feb 22.
3
In vivo and in vitro expression of the plasminogen activators and urokinase type plasminogen activator receptor (u-PAR) in the pig oviduct.
Anim Reprod Sci. 2012 Dec;136(1-2):90-9. doi: 10.1016/j.anireprosci.2012.09.013. Epub 2012 Oct 5.
10
Two-chain urokinase, receptor, and type 1 inhibitor in cultured human mesangial cells.
Am J Physiol. 1993 Mar;264(3 Pt 2):F532-9. doi: 10.1152/ajprenal.1993.264.3.F532.

本文引用的文献

1
The urokinase receptor promotes cancer metastasis independently of urokinase-type plasminogen activator in mice.
Am J Pathol. 2009 Jul;175(1):190-200. doi: 10.2353/ajpath.2009.081053. Epub 2009 Jun 4.
2
Clathrin and LRP-1-independent constitutive endocytosis and recycling of uPAR.
PLoS One. 2008;3(11):e3730. doi: 10.1371/journal.pone.0003730. Epub 2008 Nov 14.
3
Sucralfate modulates uPAR and EGFR expression in an experimental rat model of cervicitis.
Int J Immunopathol Pharmacol. 2008 Jul-Sep;21(3):651-8. doi: 10.1177/039463200802100319.
4
Intact and cleaved uPAR forms: diagnostic and prognostic value in cancer.
Front Biosci. 2008 May 1;13:6752-62. doi: 10.2741/3186.
5
Crystal structures of two human vitronectin, urokinase and urokinase receptor complexes.
Nat Struct Mol Biol. 2008 Apr;15(4):422-3. doi: 10.1038/nsmb.1404. Epub 2008 Mar 23.
6
Purification of immunoglobulin G.
Curr Protoc Cell Biol. 2001 May;Chapter 16:Unit 16.3. doi: 10.1002/0471143030.cb1603s05.
7
uPAR-induced cell adhesion and migration: vitronectin provides the key.
J Cell Biol. 2007 Jun 4;177(5):927-39. doi: 10.1083/jcb.200612058.
8
Urokinase receptor cleavage: a crucial step in fibroblast-to-myofibroblast differentiation.
Mol Biol Cell. 2007 Jul;18(7):2716-27. doi: 10.1091/mbc.e06-10-0912. Epub 2007 May 16.
10
Structural basis of interaction between urokinase-type plasminogen activator and its receptor.
J Mol Biol. 2006 Oct 20;363(2):482-95. doi: 10.1016/j.jmb.2006.08.063. Epub 2006 Aug 26.

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验