A novel protease-activated receptor-1 interactor, Bicaudal D1, regulates G protein signaling and internalization.
A novel protease-activated receptor-1 interactor, Bicaudal D1, regulates G protein signaling and internalization.
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Bicaudal D1 是一种新型蛋白酶激活受体 1 相互作用因子，可调节 G 蛋白信号传导和内化。
DOI：
10.1074/jbc.m110.105403
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Kuliopulos,Athan
中科院分区：
文献类型：
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作者：
Swift,Steven;Xu,Jian;Trivedi,Vishal;Austin,KarynM;Tressel,SarahL;Zhang,Lei;Covic,Lidija;Kuliopulos,Athan
蛋白酶激活受体-1（PAR 1）是一种G蛋白偶联受体，在癌症、血管生成、炎症和血栓形成中起关键作用。PAR 1的胞外结构域的蛋白水解切割产生以不寻常的分子内模式激活PAR 1的拴系配体。从不可逆切割的PAR 1发出的信号通过G蛋白解偶联和内化而终止;然而，PAR 1信号关闭的机制仍然不清楚。利用酵母双杂交技术，我们鉴定出BicD 1（BicD 1）是与PAR 1C端胞质结构域直接相互作用的基因。BICD最初被鉴定为与mRNA和高尔基体-内质网转运相关的重要发育基因。我们发现了BicD 1在PAR 1下游G蛋白信号传导、细胞增殖和内吞作用的调节中的新功能。BicD 1及其C-末端CC 3结构域通过与PAR 1的胞质第8螺旋的卷曲螺旋相互作用抑制PAR 1向Gq-磷脂酶C-β的信号传导。出乎意料的是，BicD 1也被发现是PAR 1驱动的乳腺癌细胞增殖的有效抑制剂。BicD 1的生长抑制作用需要与PAR 1的第8螺旋相互作用的能力。BicD 1表达的沉默损害了PAR 1的内吞作用，并且BicD 1与PAR 1和微管蛋白共定位，表明BicD 1是参与PAR 1从质膜转运到内体囊泡的重要衔接蛋白。总之，这些发现提供了PAR 1信号终止和通过非G蛋白效应子BicD 1内化之间的联系。
Protease-activated receptor-1 (PAR1) is a G protein-coupled receptor that plays critical roles in cancer, angiogenesis, inflammation, and thrombosis. Proteolytic cleavage of the extracellular domain of PAR1 generates a tethered ligand that activates PAR1 in an unusual intramolecular mode. The signal emanating from the irreversibly cleaved PAR1 is terminated by G protein uncoupling and internalization; however, the mechanisms of PAR1 signal shut off still remain unclear. Using a yeast two-hybrid screen, we identified Bicaudal D1 (BicD1) as a direct interactor with the C-terminal cytoplasmic domain of PAR1.BICDwas originally identified as an essential developmental gene associated with mRNA and Golgi-endoplasmic reticulum transport. We discovered a novel function of BicD1 in the modulation of G protein signaling, cell proliferation, and endocytosis downstream of PAR1. BicD1 and its C-terminal CC3 domain inhibited PAR1 signaling to Gq-phospholipase C-β through coiled-coil interactions with the cytoplasmic 8th helix of PAR1. Unexpectedly, BicD1 was also found to be a potent suppressor of PAR1-driven proliferation of breast carcinoma cells. The growth-suppressing effects of BicD1 required the ability to interact with the 8th helix of PAR1. Silencing of BicD1 expression impaired endocytosis of PAR1, and BicD1 co-localized with PAR1 and tubulin, implicating BicD1 as an important adapter protein involved in the transport of PAR1 from the plasma membrane to endosomal vesicles. Together, these findings provide a link between PAR1 signal termination and internalization through the non-G protein effector, BicD1.