Acquisition of the metastatic phenotype is accompanied by H2O2-dependent activation of the p130Cas signaling complex.
Acquisition of the metastatic phenotype is accompanied by H2O2-dependent activation of the p130Cas signaling complex.
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DOI：
10.1158/1541-7786.mcr-12-0478
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发表时间：
2013-03
期刊：
影响因子：
--
通讯作者：
Melendez JA
中科院分区：
文献类型：
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作者：
Hempel N;Bartling TR;Mian B;Melendez JA
活性氧（ROS）已成为细胞信号分子，并通过其驱动侵袭和迁移的能力与转移性疾病有关。在这里，我们定义的信号衔接蛋白p130 Cas作为一个关键的氧化还原反应的分子触发器，是从事高侵袭性转移性膀胱肿瘤细胞系。伴随转移表型的稳态H2 O2的内源性变化增加了p130 Cas磷酸化、膜募集和与支架蛋白-Crk的关联以及随后的Rac 1活化和肌动蛋白重组。酶和非酶清除H2 O2消除p130 Cas依赖的信号传导和转移性膀胱肿瘤细胞的迁移和侵袭活性。p130 Cas的破坏减弱了转移性变体（253 J-BV）的侵袭和迁移。253 J-BV细胞显示出整体巯基氧化的增加和伴随的总磷酸酶活性的降低，这是活性位点半胱氨酸氧化的共同靶蛋白。当PTPN 12的耗竭增强p130 Cas磷酸化和非侵入性亲本膀胱肿瘤对照的迁移行为时，磷酸酶对p130 Cas调节的依赖性被强调（253 J）。这些数据表明，转移性表型伴随着稳态H2 O2产生的增加，这驱动促迁移信号传导，并表明基于抗氧化剂的治疗可能证明在限制膀胱肿瘤侵袭性方面是有用的。
Reactive Oxygen Species (ROS) have emerged as cellular signaling molecules and are implicated in metastatic disease by their ability to drive invasion and migration. Here we define the signaling adaptor protein p130Cas as a key redox-responsive molecular trigger that is engaged in highly invasive metastatic bladder tumor cell lines. Endogenous shifts in steady-state H2O2 that accompany the metastatic phenotype increase p130Cas phosphorylation, membrane recruitment and association with the scaffolding protein-Crk and subsequent Rac1 activation and actin reorganization. Both enzymatic and non-enzymatic scavenging of H2O2 abrogates p130Cas-dependent signaling and the migratory and invasive activity of the metastatic bladder tumor cells. Disruption of p130Cas attenuates both invasion and migration of the metastatic variant (253J-BV). 253J-BV cells displayed an increase in global thiol oxidation and a concomitant decrease in total phosphatase activity, common target proteins of active-site cysteine oxidation. The dependence of phosphatases on regulation of p130Cas was highlighted when depletion of PTPN12 enhanced p130cas phosphorylation and the migratory behavior of a non-invasive parental bladder tumor control (253J). These data demonstrate that the metastatic phenotype is accompanied by increases in steady-state H2O2 production that drive pro-migratory signaling and suggest that antioxidant-based therapeutics may prove useful in limiting bladder tumor invasiveness.