A critical role for HSP90 in cancer cell invasion involves interaction with the extracellular domain of HER-2
A critical role for HSP90 in cancer cell invasion involves interaction with the extracellular domain of HER-2
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DOI：
10.1074/jbc.m701803200
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发表时间：
2008-01-25
影响因子：
4.8
通讯作者：
Patsavoudi, Evangelia
中科院分区：
文献类型：
--
作者：
Sidera, Katerina;Gaitanou, Maria;Patsavoudi, Evangelia
HSP90是一种普遍表达的分子伴侣，控制许多蛋白质的折叠、组装、细胞内配置和蛋白水解转换，其中大多数参与信号转导过程。最近，一种表面形式的HSP90已被确定并与细胞迁移事件有关。在本文中，我们探讨了表面HSP90与HER-2的相互作用，HER-2是一种受体样糖蛋白，是ErbB受体酪氨酸激酶家族的成员，在细胞增殖、分化、迁移以及癌症进展中发挥核心作用。到目前为止，HSP90参与HER-2的调控被认为是通过与其细胞质激酶结构域的相互作用来实现受体的稳定。在这里，我们提供证据，使用谷胱甘肽s -转移酶下拉和转染试验，表面HSP90和HER-2的细胞外结构域之间的一种新的相互作用。使用mAb 4C5特异性破坏这种相互作用，mAb 4C5是一种针对HSP90的功能阻断单克隆抗体，在heregulin配体刺激条件下，抑制人乳腺癌细胞的细胞入侵并改变肌动蛋白动力学。此外，表面HSP90/HER-2相互作用的破坏导致heregulin诱导的HER-2- her -3异源二聚体的形成受到抑制，HER-2磷酸化减少，下游激酶信号通路受损。有趣的是，这种破坏并不影响HER-2的内化。我们的数据表明，表面HSP90参与heregulin诱导的HER-2激活和信号传导，导致细胞骨架重排，这是细胞侵袭所必需的。
HSP90 is a ubiquitously expressed molecular chaperone that controls the folding, assembly, intracellular disposition, and proteolytic turnover of many proteins, most of which are involved in signal transduction processes. Recently, a surface form of HSP90 has been identified and associated with cell migration events. In this paper, we explore the interaction of surface HSP90 with HER-2, a receptor-like glycoprotein and member of the ErbB family of receptor tyrosine kinases that play central roles in cellular proliferation, differentiation, and migration as well as in cancer progress. The involvement of HSP90 in the regulation of HER-2 has been attributed so far to receptor stabilization via interaction with its cytoplasmic kinase domain. Here we present evidence, using glutathione S-transferase pull-down and transfection assays, for a novel interaction between surface HSP90 and the extracellular domain of HER-2. Specific disruption of this interaction using mAb 4C5, a function-blocking monoclonal antibody against HSP90, inhibits cell invasion accompanied by altered actin dynamics in human breast cancer cells under ligand stimulation conditions with heregulin. Additionally, disruption of surface HSP90/HER-2 interaction leads to inhibition of heregulin-induced HER-2-HER-3 heterodimer formation, reduced HER-2 phosphorylation, and impaired downstream kinase signaling. Interestingly, this disruption does not affect HER-2 internalization. Our data suggest that surface HSP90 is involved in heregulin-induced HER-2 activation and signaling, leading to cytoskeletal rearrangement, essential for cell invasion.