Altered Adhesive Structures and Their Relation to RhoGTPase Activation in Merlin-Deficient Schwannoma
Altered Adhesive Structures and Their Relation to RhoGTPase Activation in Merlin-Deficient Schwannoma
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DOI：
10.1111/j.1750-3639.2008.00165.x
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发表时间：
2009-01-01
期刊：
影响因子：
6.4
通讯作者：
Hanemann, C. Oliver
中科院分区：
文献类型：
--
作者：
Flaiz, Christine;Ammoun, Sylwia;Hanemann, C. Oliver
神经鞘瘤是神经系统的施万细胞肿瘤，自发发生于神经纤维瘤病 2 (NF2) 患者，且缺乏肿瘤抑制因子 merlin。 Merlin 已知可结合桩蛋白、β1 整联蛋白和粘着斑激酶、粘着斑激酶的成员、介导细胞粘附到细胞外基质的多蛋白复合物。此外，merlin 缺陷神经鞘瘤表现出与细胞外基质的病理粘附，使得焦点接触的表征必不可少。使用我们的人原代雪旺细胞和神经鞘瘤细胞的神经鞘瘤体外模型，我们在此表明神经鞘瘤细胞显示出成熟且稳定的焦点接触数量增加。除了通过 Rho 激酶 ROCK 参与 RhoA 信号传导外，Rac1 在神经鞘瘤细胞的病理粘附中也发挥着重要作用。 Rac1 鸟嘌呤交换因子 - beta-Pix 定位于人原代神经鞘瘤细胞中的局灶性接触，我们表明，Rac1 激活的一部分（merlin 缺陷的影响）发生在人原发性神经鞘瘤细胞中的局灶性接触水平。我们的结果有助于解释神经鞘瘤细胞的病理粘附，进一步加强了 RhoGTPase 信号在神经鞘瘤发育中的重要性，并表明 merlin 在肿瘤抑制中的作用与局灶性接触有关。
Schwannomas are Schwann cell tumors of the nervous system that occur spontaneously and in patients with neurofibromatosis 2 (NF2) and lack the tumor suppressor merlin. Merlin is known to bind paxillin, beta1 integrin and focal adhesion kinase, members of focal contacts, multi-protein complexes that mediate cell adhesion to the extracellular matrix. Moreover, merlin-deficient Schwannomas show pathological adhesion to the extracellular matrix making the characterization of focal contacts indispensable. Using our Schwannoma in vitro model of human primary Schwann and Schwannoma cells, we here show that Schwannoma cells display an increased number of mature and stable focal contacts. In addition to an involvement of RhoA signaling via the Rho kinase ROCK, Rac1 plays a significant role in the pathological adhesion of Schwannoma cells. The Rac1 guanine exchange factor- beta-Pix, localizes to focal contacts in human primary Schwannoma cells, and we show that part of the Rac1 activation, an effect of merlin-deficiency, occurs at the level of focal contacts in human primary Schwannoma cells. Our results help explaining the pathological adhesion of Schwannoma cells, further strengthen the importance of RhoGTPase signaling in Schwannoma development, and suggest that merlin's role in tumor suppression is linked to focal contacts.