Persistent signaling by dysregulated thrombin receptor trafficking promotes breast carcinoma cell invasion
Persistent signaling by dysregulated thrombin receptor trafficking promotes breast carcinoma cell invasion
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DOI：
10.1128/mcb.24.5.1990-1999.2004
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发表时间：
2004-03-01
影响因子：
5.3
通讯作者：
Trejo, J
中科院分区：
文献类型：
--
作者：
Booden, MA;Eckert, LB;Trejo, J
蛋白酶激活受体1(PAR1)是一种G蛋白偶联的凝血酶受体，其表达增加与乳腺癌细胞的侵袭有关。PAR1被不可逆转地激活、内化并直接分选到溶酶体，这是终止信号的关键过程。我们确定，在转移性乳腺癌细胞中，激活的PAR1转运发生了严重的变化，但在非转移性或正常的乳腺上皮细胞中则没有。因此，蛋白水解性激活的受体不会被分选到溶酶体中并被降解。蛋白水解性激活的PAR1的运输改变导致持续激活肌醇磷脂的水解和细胞外信号调节的激酶信号，即使在凝血酶退出后也是如此，并增强了细胞的侵袭。因此，我们的结果表明，激活的PAR1的运输过程中的一个新的变化导致了持续的信号传递，并且除了其他过程和蛋白质外，还促进了乳腺癌细胞的侵袭。
Increased expression of protease-activated receptor 1 (PAR1), a G protein-coupled receptor for thrombin, has previously been correlated with breast carcinoma cell invasion. PAR1 is irreversibly proteolytically activated, internalized, and sorted directly to lysosomes, a critical process for the termination of signaling. We determined that activated PAR1 trafficking is severely altered in metastatic breast carcinoma cells but not in nonmetastatic or normal breast epithelial cells. Consequently, the proteolytically activated receptor is not sorted to lysosomes and degraded. Altered trafficking of proteolytically activated PAR1 caused sustained activation of phosphoinositide hydrolysis and extracellular signal-regulated kinase signaling, even after thrombin withdrawal, and enhanced cellular invasion. Thus, our results reveal that a novel alteration in trafficking of activated PAR1 causes persistent signaling and, in addition to other processes and proteins, contributes to breast carcinoma cell invasion.