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首页> 外文期刊>Molecular and Cellular Biology >Leukemia-Associated Rho Guanine Nucleotide Exchange Factor Promotes Gαq-Coupled Activation of RhoA
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Leukemia-Associated Rho Guanine Nucleotide Exchange Factor Promotes Gαq-Coupled Activation of RhoA

机译：白血病相关的Rho鸟嘌呤核苷酸交换因子促进Gαq耦合的RhoA激活。

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Leukemia-associated Rho guanine-nucleotide exchange factor (LARG) belongs to the subfamily of Dbl homology RhoGEF proteins (including p115 RhoGEF and PDZ-RhoGEF) that possess amino-terminal regulator of G protein signaling (RGS) boxes also found within GTPase-accelerating proteins (GAPs) for heterotrimeric G protein α subunits. p115 RhoGEF stimulates the intrinsic GTP hydrolysis activity of Gα12/13 subunits and acts as an effector for G13-coupled receptors by linking receptor activation to RhoA activation. The presence of RGS box and Dbl homology domains within LARG suggests this protein may also function as a GAP toward specific Gα subunits and couple Gα activation to RhoA-mediating signaling pathways. Unlike the RGS box of p115 RhoGEF, the RGS box of LARG interacts not only with Gα12 and Gα13 but also with Gαq. In cellular coimmunoprecipitation studies, the LARG RGS box formed stable complexes with the transition state mimetic forms of Gαq, Gα12, and Gα13. Expression of the LARG RGS box diminished the transforming activity of oncogenic G protein-coupled receptors (Mas, G2A, and m1-muscarinic cholinergic) coupled to Gαq and Gα13. Activated Gαq, as well as Gα12 and Gα13, cooperated with LARG and caused synergistic activation of RhoA, suggesting that all three Gα subunits stimulate LARG-mediated activation of RhoA. Our findings suggest that the RhoA exchange factor LARG, unlike the related p115 RhoGEF and PDZ-RhoGEF proteins, can serve as an effector for Gq-coupled receptors, mediating their functional linkage to RhoA-dependent signaling pathways.
机译：白血病相关的Rho鸟嘌呤核苷酸交换因子（LARG）属于Dbl同源性RhoGEF蛋白（包括p115 RhoGEF和PDZ-RhoGEF）的亚家族，这些蛋白具有也在GTPase加速中发现的G蛋白信号转导（RGS）盒的氨基末端调节剂。三聚体G蛋白α亚基的蛋白（GAP）。 p115 RhoGEF刺激Gα12/ 13亚基固有的GTP水解活性，并通过将受体激活与RhoA激活联系起来，充当G13偶联受体的效应子。 LARG内RGS box和Dbl同源结构域的存在表明该蛋白还可能对特定的Gα亚基起GAP的作用，并将Gα激活与RhoA介导的信号通路耦合。与p115 RhoGEF的RGS盒不同，LARG的RGS盒不仅与Gα12和Gα13相互作用，而且与Gαq相互作用。在细胞免疫共沉淀研究中，LARG RGS盒与过渡态模拟形式Gαq，Gα12和Gα13形成了稳定的复合物。 LARG RGS盒的表达减弱了与Gαq和Gα13偶联的致癌G蛋白偶联受体（Mas，G2A和m1-毒蕈碱胆碱能）的转化活性。活化的Gαq以及Gα12和Gα13与LARG协同作用，引起RhoA的协同活化，表明所有三个Gα亚基均刺激LARG介导的RhoA活化。我们的发现表明，与相关的p115 RhoGEF和PDZ-RhoGEF蛋白不同，RhoA交换因子LARG可以作为Gq偶联受体的效应子，介导它们与RhoA依赖性信号通路的功能性连接。

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