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首页> 外文期刊>Cellular Signalling >Breast tumor kinase BRK requires kinesin-2 subunit KAP3A in modulation of cell migration
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Breast tumor kinase BRK requires kinesin-2 subunit KAP3A in modulation of cell migration

机译：乳腺肿瘤激酶BRK在细胞迁移调节中需要kinesin-2亚基KAP3A

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BReast tumor Kinase (BRK) also known as protein kinase 6 (PTK6) is a nonreceptor tyrosine kinase overexpressed in the majority of human breast tumors. Although some studies have implicated BRK in signalling, cell proliferation and migration, the precise intracellular role of BRK has not been fully elucidated. The RNA-binding protein Sam68, and adaptor proteins paxillin and STAT3 are the only BRK substrates that link BRK to signal transduction. To identify new BRK substrates, we screened high-density protein filter arrays by large-scale in vitro kinase assays using active recombinant BRK. We identified at least 4 BRK targets comprising the alpha-subunit of stimulatory guanine nucleotide binding protein (GNAS), FL139441, beta-tubulin and kinesin associated protein 3A (KAP3A) and validated them as BRK substrates using a secondary assay. Further characterization revealed that KAP3A is an in vivo substrate of BRK and associates with BRK in breast cancer cells. We show that BRK specifically phosphorylated tyrosine residues at the C-terriumis of KAP3A and induces delocalization of KAP3A from punctate nuclear localization to a diffuse nucleo-cytoplasmic pattern. Functionally, we demonstrate that KAP3A knockdown results in suppression of BRK-induced migration of breast cancer cells and show that the C-terminal deletion mutant of KAP3A acts as a dominant negative in BRK-induced cell migration. Our findings therefore reveal new substrates of BRK and define KAP3A as a physiological substrate of BRK during cell migration. (C) 2007 Elsevier Inc. All rights reserved.
机译：乳腺癌肿瘤激酶（BRK）也称为蛋白激酶6（PTK6）是在大多数人乳腺肿瘤中过表达的非受体酪氨酸激酶。尽管一些研究表明BRK参与信号传导，细胞增殖和迁移，但是BRK的确切细胞内作用尚未完全阐明。 RNA结合蛋白Sam68，衔接蛋白paxillin和STAT3是将BRK与信号转导连接的唯一BRK底物。为了鉴定新的BRK底物，我们使用活性重组BRK通过大规模的体外激酶测定筛选了高密度蛋白滤膜阵列。我们确定了至少4个BRK靶标，包括刺激性鸟嘌呤核苷酸结合蛋白（GNAS），FL139441，β-微管蛋白和驱动蛋白相关蛋白3A（KAP3A）的α亚基，并通过二次测定将其验证为BRK底物。进一步的特征表明，KAP3A是BRK的体内底物，并与乳腺癌细胞中的BRK缔合。我们显示，BRK在KAP3A的C-terriumis上特异性磷酸化酪氨酸残基，并诱导KAP3A从点状核定位到分散的核胞质模式的离域。在功能上，我们证明KAP3A敲低导致抑制BRK诱导的乳腺癌细胞迁移，并表明KAP3A的C端缺失突变体在BRK诱导的细胞迁移中起显性负作用。因此，我们的发现揭示了BRK的新底物，并将KAP3A定义为BRK在细胞迁移过程中的生理底物。 （C）2007 Elsevier Inc.保留所有权利。

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