A Rap guanine nucleotide exchange factor enriched highly in the basal ganglia
A Rap guanine nucleotide exchange factor enriched highly in the basal ganglia
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DOI：
10.1073/pnas.95.22.13278
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发表时间：
1998-10-27
影响因子：
11.1
通讯作者：
Graybiel, AM
中科院分区：
文献类型：
--
作者：
Kawasaki, H;Sprihtgett, GM;Graybiel, AM
Ras 蛋白是生长、分化和恶性转化的关键调节因子，最近被发现与大脑中的突触功能和区域特异性学习和记忆功能有关。 Rap 蛋白是 Ras 小 G 蛋白超家族的成员，可以通过 Ras/Raf-1/丝裂原激活蛋白 (MAP) 激酶途径抑制 Ras 信号传导，或者通过 B-Raf 激活 MAP 激酶，Rap 和 Ras 蛋白均可通过鸟嘌呤核苷酸交换因子 (GEF) 激活。Ras GEF 较多，但迄今为止仅鉴定出一种 Rap GEF。我们现在报道了大脑富集基因 CalDAG-GEFI 的克隆，该基因对 Rap1A 具有底物特异性，具有钙 (Ca2+) 和二酰甘油 (DAG) 的双重结合域，并且在大脑基底神经节通路及其轴突末端区域中富集表达。 CalDAG-GEFI 的表达可激活 Rap1A 并抑制 293T 细胞中 Erk/MAP 激酶级联的 Ras 依赖性激活。 Ca2+ 离子载体和佛波酯强烈且相加地增强了 Rap1A 的激活，相比之下，CalDAG-GEFII，我们克隆的第二个 CalDAG-GEF 家族成员，发现其与 RasGRP 相同 [Ebinu, J. O., Bottorff, D. A., Chan, E. Y. W., Stang, S. L,, Dunn, R. J. & Stone, J, C, (1998) Science 280, 1082-1088]，表现出不同的大脑表达模式，无法激活 Rap1A，但在 Ca2+ 和 DAG 调节下激活 H-Ras、R-Ras 和 Erk/MAP 激酶级联。我们认为 CalDAG-GEF 蛋白在确定 Ca2+ 和 DAG 动员诱导的 Ras 和 Rap1 信号传导的相对激活方面具有关键的神经元功能。 CalDAG-GEFI 和 CalDAG-GEFII 在造血器官中的表达表明这种控制可能在 Ras/Rap 正常和恶性状态的调节中具有广泛的意义。
Ras proteins, key regulators of growth, differentiation, and malignant transformation, recently have been implicated in synaptic function and region-specific learning and memory functions in the brain. Rap proteins, members of the Ras small G protein superfamily, can inhibit Ras signaling through the Ras/Raf-1/mitogen-activated protein (MAP) kinase pathway or, through B-Raf, can activate MAP kinase, Rap and Ras proteins both can be activated through guanine nucleotide exchange factors (GEFs), Many Ras GEFs, but to date only one Rap GEF, have been identified. We now report the cloning of a brain-enriched gene, CalDAG-GEFI, which has substrate specificity for Rap1A, dual binding domains for calcium (Ca2+) and diacylglycerol (DAG), and enriched expression in brain basal ganglia pathways and their axon-terminal regions. Expression of CalDAG-GEFI activates Rap1A and inhibits Ras-dependent activation of the Erk/MAP kinase cascade in 293T cells. Ca2+ ionophore and phorbol ester strongly and additively enhance this Rap1A activation, By contrast, CalDAG-GEFII, a second CalDAG-GEF family member that we cloned and found identical to RasGRP [Ebinu, J. O., Bottorff, D. A., Chan, E. Y. W., Stang, S. L,, Dunn, R. J. & Stone, J, C, (1998) Science 280, 1082-1088], exhibits a different brain expression pattern and fails to activate Rap1A, but activates H-Ras, R-Ras, and the Erk/MAP kinase cascade under Ca2+ and DAG modulation. We propose that CalDAG-GEF proteins have a critical neuronal function in determining the relative activation of Ras and Rap1 signaling induced by Ca2+ and DAG mobilization. The expression of CalDAG-GEFI and CalDAG-GEFII in hematopoietic organs suggests that such control may have broad significance in Ras/Rap regulation of normal and malignant states.