Muranen Taru, Grönholm Mikaela, Renkema G Herma, Carpén Olli
Program of Neuroscience, Biomedicum Helsinki, Department of Pathology, University of Helsinki and Helsinki University Hospital, PB 63, Helsinki 00014, Finland.
Oncogene. 2005 Feb 10;24(7):1150-8. doi: 10.1038/sj.onc.1208283.
The neurofibromatosis 2 tumour suppressor merlin/schwannomin is structurally related to the ezrin-radixin-moesin family of proteins, which anchor actin cytoskeleton to specific membrane proteins and participate in cell signalling. Merlin inhibits cell growth with a yet unknown mechanism. As most tumour suppressors are linked to cell cycle control, we investigated merlin's behaviour during cell cycle. In glioma and osteosarcoma cells, endogenous merlin was targeted to the nucleus in a cell cycle-specific manner. Merlin accumulated perinuclearly at the G2/M phase, and shifted to the nucleus at early G1. During mitosis, merlin localized to mitotic spindles and at the contractile ring. Nuclear merlin was strongly reduced in confluent cells. Blocking of the CRM1/exportin nuclear export pathway led to accumulation of merlin in the nucleus. Activation of the p21-activated kinase or protein kinase A, which result in phosphorylation of merlin, did not affect its nuclear localization. Merlin regulates the activity of extracellular signal-regulated kinase 2 (ERK2) and nuclear localization of both proteins was induced by cell adhesion. Unlike ERK2, nuclear localization of merlin was not, however, dependent on intact actin cytoskeleton. These results link merlin to events related to cell cycle control and may help to resolve its tumour suppressor function.
神经纤维瘤病2型肿瘤抑制因子默林/施万宁与埃兹蛋白-根蛋白-膜突蛋白家族的蛋白质在结构上相关，该家族蛋白质将肌动蛋白细胞骨架锚定到特定的膜蛋白上并参与细胞信号传导。默林通过一种尚不清楚的机制抑制细胞生长。由于大多数肿瘤抑制因子都与细胞周期调控有关，我们研究了默林在细胞周期中的行为。在胶质瘤和骨肉瘤细胞中，内源性默林以细胞周期特异性方式定位于细胞核。默林在G2/M期在核周积累，并在G1早期转移到细胞核。在有丝分裂期间，默林定位于有丝分裂纺锤体和收缩环。在汇合细胞中，核内默林显著减少。阻断CRM1/输出蛋白核输出途径导致默林在细胞核中积累。p21激活激酶或蛋白激酶A的激活导致默林磷酸化，但不影响其核定位。默林调节细胞外信号调节激酶2（ERK2）的活性，细胞黏附可诱导这两种蛋白的核定位。然而，与ERK2不同，默林的核定位不依赖于完整的肌动蛋白细胞骨架。这些结果将默林与细胞周期调控相关事件联系起来，可能有助于阐明其肿瘤抑制功能。
