Impaired intercellular adhesion and immature adherens junctions in merlin-deficient human primary schwannoma cells
Impaired intercellular adhesion and immature adherens junctions in merlin-deficient human primary schwannoma cells
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DOI：
10.1002/glia.20629
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发表时间：
2008-04-01
期刊：
影响因子：
6.2
通讯作者：
Hanemann, C. O.
中科院分区：
文献类型：
--
作者：
Flaiz, C.;Utermark, T.;Hanemann, C. O.
自发发生的神经鞘瘤或神经纤维瘤病2型患者，缺乏肿瘤抑制基因和质膜-细胞骨架连接基因merlin的等位基因。我们已经证明，人类原发性神经鞘瘤细胞显示RhoGTPases Rac 1和Cdc 42的激活，这会导致高度动态和持续的突出活动，例如起皱。皱褶是形成细胞间接触（如基于钙粘蛋白-连环蛋白系统的粘附连接）的初始和时间有限的步骤。我们测试了Rac 1诱导的持续皱褶与粘附连接的维持、稳定和功能之间是否存在联系，以及这是否与人类merlin缺陷型神经鞘瘤细胞相关。我们表明，激烈的持续皱褶不仅限于单一的人类原发性神经鞘瘤细胞的膜，但也发生在接触细胞的膜，即使汇合。活细胞成像显示，新形成的触点在短时间后释放，表明粘附连接的形成或稳定受到干扰。形态学，高磷酸酪氨酸水平和corneum染色表明，粘附连接是不成熟的人原发性神经鞘瘤细胞，而他们显示的特征，在人原发性雪旺细胞的成熟粘附连接。当重新引入梅林蛋白时，人类原发性神经鞘瘤细胞在接触细胞中仅显示初始皱褶，并且粘附连接出现更成熟。因此，我们提出，正在进行的RAC诱导的皱褶导致不成熟的adherens连接，并导致受损的，非功能性的细胞间粘附在聚集测定merlin缺陷神经鞘瘤细胞，这可能是一个增加的增殖率的解释，由于失去接触抑制或肿瘤的发展一般。(C)2008 Wiley-Liss，Inc.
Schwannomas that occur spontaneously or in patients with neurofibromatosis Type 2, lack both alleles for the tumor suppressor and plasma membrane-cytoskeleton linker merlin. We have shown that human primary schwannoma cells display activation of the RhoGTPases Rac1 and Cdc42 which results in highly dynamic and ongoing protrusive activity like ruffling. Ruffling is an initial and temporally limited step in the formation of intercellular contacts like adherens junctions that are based on the cadherin-catenin system. We tested if there is a connection between Rac1-induced ongoing ruffling and the maintenance, stabilization and functionality of adherens junctions and if this is of relevance in human, merlin-deficient schwannoma cells. We show intense ongoing ruffling is not limited to membranes of single human primary schwannoma cells, but occurs also in membranes of contacting cells, even when confluent. Live cell imaging shows that newly formed contacts are released after a short time, suggesting disturbed formation or stabilization of adherens junctions. Morphology, high phospho-tyrosine levels and cortactin staining indicate that adherens junctions are immature in human primary schwannoma cells, whereas they display characteristics of mature adherens junctions in human primary Schwann cells. When merlin is reintroduced, human primary schwannoma cells show only initial ruffling in contacting cells and adherens junctions appear more mature. We therefore propose that ongoing Rac-induced ruffling causes immature adherens junctions and leads to impaired, nonfunctional intercellular adhesion in aggregation assays in merlin-deficient schwannoma cells that could be an explanation for increased proliferation rates due to loss of contact inhibition or tumor development in general. (C) 2008 Wiley-Liss, Inc.