Nuclear-cytoplasmic shuttling of C-ABL tyrosine kinase
Nuclear-cytoplasmic shuttling of C-ABL tyrosine kinase
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DOI：
10.1073/pnas.95.13.7457
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发表时间：
1998-06-23
影响因子：
11.1
通讯作者：
Hope, TJ
中科院分区：
文献类型：
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作者：
Taagepera, S;McDonald, D;Hope, TJ
广泛表达的非受体酪氨酸激酶c-Abl包含三个核定位信号，然而，它被发现在细胞核和细胞质的增殖成纤维细胞。在成纤维细胞最初粘附到纤连蛋白基质上时，观察到c-Abl从细胞核的快速和短暂损失，提示细胞核输出的可能性[刘易斯，J.，Baskaran，R.，Taagepera，S.，Schwartz，M，& Wang，J，（1996）Proc. Natl. Acad. Sci. USA 93，15174-15179]。在这里，我们表明，C末端的c-Abl确实包含一个功能性的核输出信号（内斯）的特征性亮氨酸丰富的基序。c-Abl内斯可以在功能上补充NES缺陷的HIV Rev蛋白（Rev Delta 3 NI），并可以介导谷胱甘肽-S-转移酶的核输出。c-Abl内斯功能对核输出抑制剂来普霉素B敏感。c-Abl内斯中单个亮氨酸（L1064 A）的突变废除了输出功能。NES突变的c-Abl，称为c-Abl内斯（-），仅定位于细胞核。用来普霉素B处理细胞也导致野生型c-Abl蛋白的核积累。当分离的成纤维细胞重新铺于纤连蛋白基质上时，c-Abl内斯（-）不从细胞核丢失。这些结果表明，c-Abl在细胞核和细胞质之间连续穿梭，并且细胞核的输入和输出速率可以通过成纤维细胞的粘附状态来调节。
The ubiquitously expressed nonreceptor tyrosine kinase c-Abl contains three nuclear localization signals, however, it is found in both the nucleus and the cytoplasm of proliferating fibroblasts. A rapid and transient loss of c-Abl from the nucleus is observed upon the initial adhesion of fibroblasts onto a fibronectin matrix, suggesting the possibility of nuclear export [Lewis, J,, Baskaran, R,, Taagepera, S., Schwartz, M, & Wang, J, (1996) Proc. Natl. Acad. Sci. USA 93, 15174-15179]. Here we show that the C terminus of c- Abl does indeed contain a functional nuclear export signal (NES) with the characteristic leucine-rich motif. The c-Abl NES can functionally complement an NES-defective HIV Rev protein (Rev Delta 3NI) and can mediate the nuclear export of glutathione-S-transferase. The c-Abl NES function is sensitive to the nuclear export inhibitor leptomycin B, Mutation of a single leucine (L1064A) in the c-Abl NES abrogates export function. The NES-mutated c-Abl, termed c-Abl NES(-), is localized exclusively to the nucleus. Treatment of cells with leptomycin B also leads to the nuclear accumulation of wild-type c-Abl protein. The c-Abl NES(-) is not lost from the nucleus when detached fibroblasts are replated onto fibronectin matrix, Taken together, these results demonstrate that c-Abl shuttles continuously between the nucleus and the cytoplasm and that the rate of nuclear import and export can be modulated by the adherence status of fibroblastic cells.