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首页> 外文期刊>Molecular and Cellular Biology >Cloning and characterization of Ras-GRF2, a novel guanine nucleotide exchange factor for Ras.
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Cloning and characterization of Ras-GRF2, a novel guanine nucleotide exchange factor for Ras.

机译：Ras-GRF2（一种新型的Ras鸟嘌呤核苷酸交换因子）的克隆和鉴定。

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Conversion of Ras proteins into an activated GTP-bound state able to bind effector proteins is catalyzed by specific guanine nucleotide exchange factors in response to a large number of extracellular stimuli. Here we report the isolation of mouse cDNAs encoding Ras-GRF2, a multidomain 135-kDa protein containing a COOH-terminal Cdc25-related domain that stimulates release of GDP from Ras but not other GTPases in vitro. Ras-GRF2 bound specifically to immobilized Ras lacking bound nucleotides, suggesting stabilization of the nucleotide-free form of Ras as a mechanism of catalyzing nucleotide exchange. The NH2-terminal region of Ras-GRF2 is predicted to contain features common to various signaling proteins including two pleckstrin homology domains and a Dbl homology region. Ras-GRF2 also contains an IQ motif which was required for its apparent constitutive association with calmodulin in epithelial cells ectopically expressing Ras-GRF2. Transient expression of Ras-GRF2 in kidney epithelial cells stimulated GTP binding by Ras and potentiated calcium ionophore-induced activation of mitogen-activated protein kinase (ERK1) dependent upon the IQ motif. Calcium influx caused Ras-GRF2 subcellular localization to change from cytosolic to peripheral, suggesting a possible mechanism for controlling Ras-GRF2 interactions with Ras at the plasma membrane. Epithelial cells overexpressing Ras-GRF2 are morphologically transformed and grow in a disorganized manner with minimal intercellular contacts. Northern analysis indicated a 9-kb GRF2 transcript in brain and lung, where p135 Ras-GRF2 is known to be expressed, and RNAs of 12 kb and 2.2 kb were detected in several tissues. Thus, Ras-GRF2 proteins with different domain structures may be widely expressed and couple diverse extracellular signals to Ras activation.
机译：响应大量的细胞外刺激，特定鸟嘌呤核苷酸交换因子可催化将Ras蛋白转换为能够结合效应蛋白的活化GTP结合状态。在这里，我们报告了编码Ras-GRF2的小鼠cDNA的分离，Ras-GRF2是一个多域135-kDa蛋白质，包含一个COOH末端Cdc25相关域，可刺激Ras释放GDP，但在体外不刺激其他GTPases。 Ras-GRF2与缺乏结合核苷酸的固定化Ras特异性结合，提示稳定无核苷酸形式的Ras作为催化核苷酸交换的机制。 Ras-GRF2的NH2末端区域预计包含各种信号蛋白共有的特征，包括两个pleckstrin同源结构域和一个Dbl同源区域。 Ras-GRF2还包含一个IQ基序，这是其与异位表达Ras-GRF2的上皮细胞中钙调蛋白的明显组成性结合所必需的。 Ras-GRF2在肾上皮细胞中的瞬时表达通过Ras刺激了GTP结合，并增强了钙离子载体诱导的有丝分裂原激活的蛋白激酶（ERK1）的活化，具体取决于IQ模体。钙流入导致Ras-GRF2亚细胞定位从胞质变为外周，提示控制Ras-GRF2与质膜上Ras相互作用的可能机制。过度表达Ras-GRF2的上皮细胞经过形态学转化，以杂乱无章的方式生长，且细胞间接触最少。 Northern分析表明在脑和肺中有9kb的GRF2转录本，已知在其中表达了p135 Ras-GRF2，并且在几种组织中检测到了12kb和2.2kb的RNA。因此，具有不同结构域结构的Ras-GRF2蛋白可能会广泛表达，并将各种细胞外信号与Ras激活偶联。

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