Die Rolle des hnRNPK-Signalkomplexes in Erk1/2-aktivierten Melanomzellen

hnRNPK 信号复合物在 Erk1/2 激活的黑色素瘤细胞中的作用

• 批准号: 159234558
• 负责人: Professor Dr. Andreas Baur
• 金额: --
• 依托单位: Hautklinik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/159234558?language=en
• 关键词: Die; Rolle; des; hnRNPK; Signalkomplexes

The long-term goal of our research is the analysis of molecular mechanisms in melanoma cells in order to discover new means of therapeutic intervention. In our first grant application we suggested to determine the role of the adapter protein hnRNPK in melanoma cells. We hypothesized that hnRNPK is involved in the activation of ADAM proteases, an important subclass of the matrixmetalloproteases. As demonstrated in our recent publication, we could confirm this assumption. We show that hnRNPK and the integrin-associated Paxillin protein serve as a signaling platform for the activation of two ADAM proteases, namely TNFalpha converting enzyme (TACE or ADAM17) and ADAM10. Almost all of 31 analyzed melanoma cell lines revealed activated ADAM10 and also activated (phosphorylated) Paxillin. Thus the activation of both markers seemed to be a common denominator of melanoma cells. Surprisingly also the polycomb protein Eed was identified as beeing directly involved in the activation of the ADAM proteases. Notably, all of these factors are activated through - or recruited by integrin receptors. These findings led to the conclusion that activated integrins recruit and form an ADAM-activating signaling complex. Based on own as well as published data we hypothesize that activation and increased expression of integrins in tumor cells leads to the recruitment of signaling proteins like hnRNPK and Paxillin, which then form the ADAM-activating signaling complex. In this grant proposal we intend to test this hypothesis. Furthermore we will investigate a possible link to a recently described signaling mechanism involving the interaction of Eed with nSMase2.

我们研究的长期目标是分析黑色素瘤细胞的分子机制，以发现新的治疗干预手段。在我们的第一个资助申请中，我们建议确定衔接蛋白hnRNPK在黑色素瘤细胞中的作用。我们假设hnRNPK参与了基质金属蛋白酶的一个重要亚类--ADAM蛋白酶的激活。正如我们最近的出版物所证明的那样，我们可以证实这一假设。我们表明，hnRNPK和整合素相关的桩蛋白作为一个信号平台激活两个ADAM蛋白酶，即TNF α转化酶（TACE或ADAM 17）和ADAM 10。几乎所有31个分析的黑色素瘤细胞系都显示激活的ADAM 10和激活的（磷酸化的）桩蛋白。因此，这两种标记物的激活似乎是黑色素瘤细胞的共同特征。令人惊讶的是，多梳蛋白Eed也被鉴定为直接参与ADAM蛋白酶的活化。值得注意的是，所有这些因子都通过整合素受体激活或被整合素受体募集。这些发现得出的结论是，激活的整联蛋白募集并形成ADAM激活信号复合物。基于自己的以及已发表的数据，我们假设肿瘤细胞中整合素的激活和表达增加导致信号蛋白如hnRNPK和桩蛋白的募集，然后形成ADAM激活信号复合物。在这份拨款申请中，我们打算验证这一假设。此外，我们将调查一个可能的链接到最近描述的信号转导机制，涉及Eed与nSMase 2的相互作用。