Regulation of Rac1 activation by the low density lipoprotein receptor-related protein.
Regulation of Rac1 activation by the low density lipoprotein receptor-related protein.
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DOI：
10.1083/jcb.200207070
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发表时间：
2002-12-23
期刊：
影响因子：
--
通讯作者：
Gonias SL
中科院分区：
文献类型：
--
作者：
Ma Z;Thomas KS;Webb DJ;Moravec R;Salicioni AM;Mars WM;Gonias SL
低密度脂蛋白受体相关蛋白（LRP-1）结合并介导多种配体的内吞作用，将尿激酶型纤溶酶原激活物受体（uPAR）和其他膜蛋白转运到内体中，并结合参与细胞信号传导的细胞内衔接蛋白。在本文中，我们表明在小鼠胚胎成纤维细胞（MEF）和L929细胞中，LRP-1是Rac 1激活的主要调节因子，并且这种活性取决于uPAR。与表达LRP-1的MEFs相比，LRP-1缺陷的MEFs表现出增加的Rac 1活化，并且这种特性通过表达VLDL受体（与LRP-1相同的基因家族的成员，具有重叠的配体结合特异性）而逆转。用受体相关蛋白（RAP）中和LRP-1的活性增加了MEFs和L929细胞中Rac 1的活化和细胞迁移。同样的参数不受RAP在uPAR−/− MEFs，从uPAR基因敲除胚胎制备，并在uPAR缺陷的LM-TK−细胞。与uPAR−/− MEFs相比，未处理的uPAR+/+ MEFs表现出显著增加的Rac 1激活。除了Rac 1，LRP-1抑制MEF中细胞外信号调节激酶（ERK）的激活;然而，Rac 1（而不是ERK）是LRP-1对MEF迁移的影响的原因。因此，LRP-1调节同一细胞中的两种信号蛋白（Rac 1和ERK），这两种蛋白都可能影响细胞迁移。在uPAR阴性细胞中，LRP-1中和不影响Rac 1激活，LRP-1可能调节细胞迁移的其他机制未被揭示。
The low density lipoprotein receptor–related protein (LRP-1) binds and mediates the endocytosis of multiple ligands, transports the urokinase-type plasminogen activator receptor (uPAR) and other membrane proteins into endosomes, and binds intracellular adaptor proteins involved in cell signaling. In this paper, we show that in murine embryonic fibroblasts (MEFs) and L929 cells, LRP-1 functions as a major regulator of Rac1 activation, and that this activity depends on uPAR. LRP-1–deficient MEFs demonstrated increased Rac1 activation compared with LRP-1–expressing MEFs, and this property was reversed by expressing the VLDL receptor, a member of the same gene family as LRP-1, with overlapping ligand-binding specificity. Neutralizing the activity of LRP-1 with receptor-associated protein (RAP) increased Rac1 activation and cell migration in MEFs and L929 cells. The same parameters were unaffected by RAP in uPAR−/− MEFs, prepared from uPAR gene knockout embryos, and in uPAR-deficient LM-TK− cells. Untreated uPAR+/+ MEFs demonstrated substantially increased Rac1 activation compared with uPAR−/− MEFs. In addition to Rac1, LRP-1 suppressed activation of extracellular signal–regulated kinase (ERK) in MEFs; however, it was Rac1 (and not ERK) that was responsible for the effects of LRP-1 on MEF migration. Thus, LRP-1 regulates two signaling proteins in the same cell (Rac1 and ERK), both of which may impact on cell migration. In uPAR-negative cells, LRP-1 neutralization does not affect Rac1 activation, and other mechanisms by which LRP-1 may regulate cell migration are not unmasked.
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DOI：
10.1083/jcb.200110161
发表时间：
2002-02-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Chew TL;Wolf WA;Gallagher PJ;Matsumura F;Chisholm RL
通讯作者：
Chisholm RL
DOI：
10.1083/jcb.146.1.149
发表时间：
1999-07-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Nguyen DH;Catling AD;Webb DJ;Sankovic M;Walker LA;Somlyo AV;Weber MJ;Gonias SL
通讯作者：
Gonias SL
影响因子：
4.8
作者：
Barnes, H;Larsen, B;van der Geer, P
通讯作者：
van der Geer, P
影响因子：
4.8
作者：
Hamik, A;Setiadi, H;Morrissey, JH
通讯作者：
Morrissey, JH
影响因子：
5.3
作者：
Kinoshita, A;Whelan, CM;Hyman, BT
通讯作者：
Hyman, BT