Tyrosine phosphorylation of paxillin affects the metastatic potential of human osteosarcoma
Tyrosine phosphorylation of paxillin affects the metastatic potential of human osteosarcoma
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DOI：
10.1038/sj.onc.1208654
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发表时间：
2005-07-14
期刊：
影响因子：
8
通讯作者：
Sakai, R
中科院分区：
文献类型：
--
作者：
Azuma, K;Tanaka, M;Sakai, R
为了获得与转移电位变化相对应的信号改变信息，我们分析了低转移性和高转移性人骨肉瘤HuO9亚群的蛋白酪氨酸磷酸化，这是最近建立的第一个人骨肉瘤转移模型。60,70和120 - 130 kDa附近蛋白的酪氨酸磷酸化在高转移亚群中增强。在这些蛋白中，磷酸化最显著的70kDa蛋白被鉴定为paxillin，这是一种整合素信号传导的支架蛋白。Src家族激酶的活性与转移潜力密切相关，Src家族激酶抑制剂PP2不仅可以消除paxillin的酪氨酸磷酸化，还可以损害高转移亚群的运动能力。paxillin在高转移亚群中的表达也升高，RNAi法下调paxillin的表达导致高转移细胞的运动性减弱。我们也证明了磷酸化形式的paxillin对促进人类骨肉瘤的迁移作用是必不可少的。这些发现表明，Src家族激酶活性的增强和paxillin的过表达通过paxillin的过度磷酸化协同促进了人骨肉瘤的高转移潜力。
To acquire information on signal alteration corresponding to the changes in metastatic potential, we analysed protein tyrosine phosphorylation of low- and high-metastatic human osteosarcoma HuO9 sublines, which were recently established as the first metastatic model of human osteosarcoma. Tyrosine phosphorylation of proteins around 60, 70, and 120 - 130 kDa was enhanced in high-metastatic sublines. Among these proteins, the protein around 70kDa, which was most remarkably phosphorylated, was identified as paxillin, a scaffold protein in integrin signaling. Activity of Src family kinase correlated well with metastatic potential, and a Src family kinase inhibitor, PP2, not only abolished tyrosine phosphorylation of paxillin but also impaired the motility of high-metastatic sublines. The expression of paxillin was also elevated in high-metastatic sublines, and knocking down of paxillin expression by RNAi method resulted in attenuated motility of high-metastatic cells. We also demonstrated that the phosphorylated form of paxillin is essential for the migration-promoting effect in human osteosarcoma. These findings suggest that enhanced activity of Src family kinases and overexpression of paxillin synergistically contribute to the high metastatic potential of human osteosarcoma through the hyperphosphorylation of paxillin.