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Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

Oncogene volume 25, pages 5960–5968 (2006)Cite this article

Abstract

The neurofibromatosis type 2 NF2 gene product, merlin, is a tumor suppressor frequently inactivated in malignant mesothelioma (MM). To investigate a possible correlation between merlin inactivation and MM invasiveness, we restored merlin expression in NF2-deficient MM cells. Re-expression of merlin markedly inhibited cell motility, spreading and invasiveness, properties connected with the malignant phenotype of MM cells. To test directly whether merlin inactivation promotes invasion in a nonmalignant system, we used small interfering RNA to silence Nf2 in mouse embryonic fibroblasts (MEFs) and found that downregulation of merlin resulted in enhanced cell spreading and invasion. To delineate signaling events connected with this phenotype, we investigated the effect of merlin expression on focal adhesion kinase (FAK), a key component of cellular pathways affecting migration and invasion. Expression of merlin attenuated FAK phosphorylation at the critical phosphorylation site Tyr397 and disrupted the interaction of FAK with its binding partners Src and p85, the regulatory subunit of phosphatidylinositol-3-kinase. In addition, NF2-null MM cells stably overexpressing FAK showed increased invasiveness, which decreased significantly when merlin expression was restored. Collectively, these findings suggest that merlin inactivation is a critical step in MM pathogenesis and is related, at least in part, with upregulation of FAK activity.

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Abbreviations

MM:

malignant mesothelioma

NF2:

neurofibromatosis type 2

FAK:

focal adhesion kinase

MEFs:

mouse embryonic fibroblasts

ERM:

Ezrin–Radixin–Moesin

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Acknowledgements

We thank Edna Cukierman for helpful suggestions regarding some of the experiments conducted in this study. We also thank Bert Vogelstein for providing the pAdEasy system to generate the NF2 adenoviral vectors. This work was supported by National Institute of Health Grants CA-45745, CA-114047 and CA-06927, by an appropriation from the Commonwealth of Pennsylvania and by a gift from the Local No. 14 Mesothelioma Fund of the International Association of Heat and Frost Insulators and Asbestos Workers in memory of Hank Vaughan and Alice Haas. The following Fox Chase Cancer Center shared facilities were used in the course of this work: Cell Culture Facility, DNA Sequencing Facility, DNA Synthesis Facility and Cell Imaging Facility.

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Authors and Affiliations

  1. Human Genetics Program, Fox Chase Cancer Center, Philadelphia, PA, USA

    P I Poulikakos, G-H Xiao, R Gallagher & J R Testa

  2. Cell Imaging Facility, Fox Chase Cancer Center, Philadelphia, PA, USA

    S Jablonski

  3. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    S C Jhanwar

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  1. P I Poulikakos
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  2. G-H Xiao
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Correspondence to J R Testa.

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Poulikakos, P., Xiao, GH., Gallagher, R. et al. Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK. Oncogene 25, 5960–5968 (2006). https://doi.org/10.1038/sj.onc.1209587

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