Decorin antagonizes Met receptor activity and down-regulates {beta}-catenin and Myc levels.
Decorin antagonizes Met receptor activity and down-regulates {beta}-catenin and Myc levels.
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DOI：
10.1074/jbc.m110.172841
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发表时间：
2010-12-31
期刊：
影响因子：
--
通讯作者：
Iozzo, Renato V
中科院分区：
文献类型：
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作者：
Buraschi, Simone;Pal, Nutan;Iozzo, Renato V
在过去几年中出现的一个主题是富含亮氨酸的小蛋白聚糖基因家族的成员通过与多种受体酪氨酸激酶（RTK）相互作用来影响细胞生长，主要是通过受体的物理下调，从而剥夺肿瘤细胞的促存活信号。核心蛋白聚糖结合并下调几种RTK，包括肝细胞生长因子的受体Met。在这里，我们表明，核心蛋白聚糖块的Met信号轴介导的几种生物活性，包括细胞分散，逃避和迁移。这些作用是由非经典β-连环蛋白水平的显著下调介导的。此外，β-连环蛋白的下游靶点Myc被核心蛋白聚糖显著下调，而Myc在苏氨酸58处的磷酸化被显著诱导。已知后者使Myc不稳定并靶向其进行蛋白酶体降解。我们还发现，使用三种不同的肿瘤异种移植模型全身递送核心蛋白聚糖引起Met的下调和β-连环蛋白和Myc水平的同时抑制。我们发现用近红外染料IR 800标记的核心蛋白聚糖蛋白质核心特异性地靶向表达Met的肿瘤细胞。甚至在注射后68小时，发现核心蛋白聚糖驻留在肿瘤异种移植物内，很少或没有与其他组织结合。总的来说，我们的研究结果表明分泌的蛋白聚糖在抑制肿瘤进展所需的关键致癌因子的表达中的作用。
A theme emerging during the past few years is that members of the small leucine-rich proteoglycan gene family affect cell growth by interacting with multiple receptor tyrosine kinases (RTKs), mostly by a physical down-regulation of the receptors, thereby depriving tumor cells of pro-survival signals. Decorin binds and down-regulates several RTKs, including Met, the receptor for hepatocyte growth factor. Here we demonstrate that decorin blocks several biological activities mediated by the Met signaling axis, including cell scatter, evasion, and migration. These effects were mediated by a profound down-regulation of noncanonical beta-catenin levels. In addition, Myc, a downstream target of beta-catenin, was markedly down-regulated by decorin, whereas phosphorylation of Myc at threonine 58 was markedly induced. The latter is known to destabilize Myc and target it for proteasomal degradation. We also discovered that systemic delivery of decorin using three distinct tumor xenograft models caused down-regulation of Met and a concurrent suppression of beta-catenin and Myc levels. We found that decorin protein core labeled with the near infrared dye IR800 specifically targeted the tumor cells expressing Met. Even 68-h post-injection, decorin was found to reside within the tumor xenografts with little or no binding to other tissues. Collectively, our results indicate a role for a secreted proteoglycan in suppressing the expression of key oncogenic factors required for tumor progression.