Ritch Patricia A, Carroll Steven L, Sontheimer Harald
Department of Neurobiology and Civitan International Research Center, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
J Biol Chem. 2003 Jun 6;278(23):20971-8. doi: 10.1074/jbc.M213074200. Epub 2003 Feb 24.
Gliomas are the most frequently diagnosed adult primary brain malignancy. These tumors have a tendency to invade diffusely into the surrounding healthy brain tissue, thereby precluding their successful surgical removal. In this report, we examine the potential for the neuregulin-1/erbB receptor signaling network to contribute to this process by modulating glioma cell motility. Neuregulin-1 is expressed throughout the immature and adult central nervous system and has been demonstrated to influence the migration of a variety of cell types in the developing brain. In addition, erbB2, an integral member of the heterodimeric neuregulin-1 receptor, has been shown to be overexpressed in human glioma biopsies. Using antibodies specific for erbB2 and erbB3, we show that these receptors localize preferentially in regions of the plasma membrane which are involved in facilitating cellular movement. Here, erbB2 colocalizes and coimmunoprecipitates with members of the focal complex including beta1-integrin and focal adhesion kinase. Further, erbB receptor activation by neuregulin-1 enhances cell motility in two-dimensional scratch motility assays and stimulates cell invasion in three-dimensional Transwell migration assays. These effects of neuregulin-1 appear to involve the activation of focal adhesion kinase, which occurs downstream from erbB2 receptor stimulation. Taken together these data suggest that neuregulin-1 plays an important modulatory role in glioma cell invasion.
神经胶质瘤是最常见的成人原发性脑恶性肿瘤。这些肿瘤倾向于弥漫性侵入周围健康脑组织，从而无法通过手术成功切除。在本报告中，我们研究了神经调节蛋白-1/erbB受体信号网络通过调节神经胶质瘤细胞运动性促进这一过程的可能性。神经调节蛋白-1在未成熟和成年中枢神经系统中均有表达，并已证明其影响发育中大脑中多种细胞类型的迁移。此外，erbB2是异二聚体神经调节蛋白-1受体的一个组成成员，已证实在人类神经胶质瘤活检中过表达。使用针对erbB2和erbB3的特异性抗体，我们发现这些受体优先定位于参与促进细胞运动的质膜区域。在这里，erbB2与包括β1整合素和粘着斑激酶在内的粘着斑复合物成员共定位并进行免疫共沉淀。此外，在二维划痕运动分析中，神经调节蛋白-1激活erbB受体可增强细胞运动性，并在三维Transwell迁移分析中刺激细胞侵袭。神经调节蛋白-1的这些作用似乎涉及粘着斑激酶的激活，这发生在erbB2受体刺激的下游。综上所述，这些数据表明神经调节蛋白-1在神经胶质瘤细胞侵袭中起重要的调节作用。
