Thrombin and Lysophosphatidic Acid Receptors Utilize Distinct rhoGEFs in Prostate Cancer Cells*
Thrombin and Lysophosphatidic Acid Receptors Utilize Distinct rhoGEFs in Prostate Cancer Cells*
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DOI：
10.1074/jbc.c400105200
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发表时间：
2004-07
影响因子：
4.8
通讯作者：
Qin Wang;Min Liu;T. Kozasa;J. Rothstein;P. Sternweis;R. Neubig
中科院分区：
文献类型：
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作者：
Qin Wang;Min Liu;T. Kozasa;J. Rothstein;P. Sternweis;R. Neubig
凝血酶和溶血磷脂酸(LPA)受体在血管生物学、发育和癌症中发挥重要作用。这些受体通过G12/13家族异源三聚体G蛋白激活Rho，已知G12/13家族异三聚体G蛋白可以直接激活三个不同的Rho鸟嘌呤核苷酸交换因子(RhoGen)，其中包含G蛋白信号转导(RGS)结构域的调节因子(RGS-RhoGEF)。然而，目前尚不清楚这些RGS-ROGEF中的哪一个(LARG(白血病相关的ROGEF)、p115ROGEF或PDZROGEF)在G蛋白偶联受体刺激的Rho信号转导中发挥作用。使用能够抑制RGS-RhoGf特异性表达的寡核苷酸小干扰RNA，我们发现在HEK293T和PC-3前列腺癌细胞系中，凝血酶受体对Rho的刺激主要是由LARG介导的。相反，在PC-3细胞中，LPA刺激的Rho反应依赖于PDZro-gef的表达。抑制p115~(Rh)的作用不明显。因此，不同的RhoGEF(LARG和PDZROGEF)通过凝血酶和LPA受体介导Rho下游信号。
Thrombin and lysophosphatidic acid (LPA) receptors play important roles in vascular biology, development, and cancer. These receptors activate rho via G12/13 family heterotrimeric G proteins, which are known to directly activate three distinct rho guanine nucleotide exchange factors (rhoGEFs) that contain a regulator of G protein signaling (RGS) domain (RGS-rhoGEFs). However, it is not known which, if any, of these RGS-rhoGEFs (LARG (leukemia-associated rhoGEF), p115rhoGEF, or PDZrhoGEF) plays a role in G protein-coupled receptor-stimulated rho signaling. Using oligonucleotide small interfering RNAs that suppress specific RGS-rhoGEF expression, we show that thrombin receptor stimulation of rho is primarily mediated by LARG in HEK293T and PC-3 prostate cancer cell lines. In contrast, the LPA-stimulated rho response in PC-3 cells is dependent on PDZrhoGEF expression. Suppression of p115rhoGEF had no effect. Thus different rhoGEFs (LARG and PDZrhoGEF) mediate downstream rho signaling by the thrombin and LPA receptors.