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Cell cycle-dependent nucleocytoplasmic shuttling of the neurofibromatosis 2 tumour suppressor merlin

Oncogene volume 24, pages 1150–1158 (2005)Cite this article

Abstract

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.

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Abbreviations

APC:

adenomatous polyposis coli

CCD:

cytochalasin D

ERK2:

extracellular signal-regulated kinase 2

ERM:

ezrin–radixin–moesin

LMB:

leptomycin B

LSC:

laser scanning cytometry

NF2:

neurofibromatosis 2

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Acknowledgements

We thank Dr Ellen Zwarthoff for generously providing the 1398 and KF10 antibodies, Dr Joseph Kissil for providing the HM2175 antibody, Hanne Ahola, Helena Ahola, Tuula Halmesvaara and Monica Schoultz for skillful technical assistance and Kaija Alfthan, Leena Heiska, Mikko Rönty and Anu Wartiovaara for fruitful discussions and assistance. This work was supported by the US Army Neurofibromatosis Research Grant DAMD17-00-0550 and the Academy of Finland.

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  1. Taru Muranen and Mikaela Grönholm: These authors contributed equally to this work

Authors and Affiliations

  1. Program of Neuroscience, Biomedicum Helsinki, Department of Pathology, University of Helsinki and Helsinki University Hospital, PB 63, Helsinki, 00014, Finland

    Taru Muranen, Mikaela Grönholm & Olli Carpén

  2. Institute of Medical Technology, University of Tampere and Tampere University Hospital, Finland

    G Herma Renkema

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  1. Taru Muranen
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  2. Mikaela Grönholm
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Correspondence to Taru Muranen.

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Muranen, T., Grönholm, M., Renkema, G. et al. Cell cycle-dependent nucleocytoplasmic shuttling of the neurofibromatosis 2 tumour suppressor merlin. Oncogene 24, 1150–1158 (2005). https://doi.org/10.1038/sj.onc.1208283

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