Zhou Fei, Hu Jianjie, Ma Haiyan, Harrison Marietta L, Geahlen Robert L
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 201 S. University St., West Lafayette, IN 47907-2064, USA.
Mol Cell Biol. 2006 May;26(9):3478-91. doi: 10.1128/MCB.26.9.3478-3491.2006.
The protein tyrosine kinase Syk couples the B-cell receptor (BCR) for antigen to multiple intracellular signaling pathways and also modulates cellular responses to inducers of oxidative stress in a receptor-independent fashion. In B cells, Syk is found in both the nuclear and cytoplasmic compartments but contains no recognizable nuclear localization or export signals. Through the analysis of a series of deletion mutants, we identified the presence of an unconventional shuttling sequence near the junction of the catalytic domain and the linker B region that accounts for Syk's subcellular localization. This localization is altered following prolonged engagement of the BCR, which causes Syk to be excluded from the nucleus. Nuclear exclusion requires the receptor-mediated activation of protein kinase C and new protein synthesis. Both of these processes also potentiate the activation of caspase 3 in cells in response to oxidative stress in a manner that is dependent on the localization of Syk outside of the nucleus. In contrast, restriction of Syk to the nucleus greatly diminishes the stress-induced activation of caspase 3.
蛋白酪氨酸激酶Syk将抗原的B细胞受体（BCR）与多种细胞内信号通路偶联起来，并且还以受体非依赖的方式调节细胞对氧化应激诱导剂的反应。在B细胞中，Syk存在于细胞核和细胞质区室中，但没有可识别的核定位或输出信号。通过对一系列缺失突变体的分析，我们发现在催化结构域与连接子B区域的交界处附近存在一个非常规的穿梭序列，该序列决定了Syk的亚细胞定位。在BCR长期结合后，这种定位会发生改变，导致Syk被排除在细胞核外。核排除需要受体介导的蛋白激酶C激活和新的蛋白质合成。这两个过程还以依赖于Syk在细胞核外定位的方式增强细胞中半胱天冬酶3对氧化应激的激活。相反，将Syk限制在细胞核内会大大减少应激诱导的半胱天冬酶3激活。
