Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK Journal Article
| Authors: | Poulikakos, P. I.; Xiao, G. H.; Gallagher, R.; Jablonski, S.; Jhanwar, S. C.; Testa, J. R. |
| Article Title: | Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK |
| 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. © 2006 Nature Publishing Group All rights reserved. |
| Keywords: | signal transduction; protein expression; unclassified drug; human cell; nonhuman; animal cell; mouse; phenotype; animals; mice; cells, cultured; gene overexpression; embryo; protein protein interaction; small interfering rna; down-regulation; gene product; cell line, tumor; tyrosine; phosphatidylinositol 3 kinase; carcinogenesis; cancer invasion; enzyme phosphorylation; regulatory mechanism; cancer cell; mesothelioma; fibroblast; inhibition kinetics; down regulation; gene inactivation; neoplasm invasiveness; protein deficiency; gene silencing; tumor suppressor protein; steroid receptor coactivator 1; focal adhesion kinase; cell invasion; cell motility; invasion; cell activity; merlin; neurofibromin 2; embryo cell; focal adhesion protein-tyrosine kinases; protein defect; nf2; molecular stability; protein p85; fak; neurofibromatosis type 2 protein; cell migration inhibition |
| Journal Title: | Oncogene |
| Volume: | 25 |
| Issue: | 44 |
| ISSN: | 0950-9232 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2006-09-28 |
| Start Page: | 5960 |
| End Page: | 5968 |
| Language: | English |
| DOI: | 10.1038/sj.onc.1209587 |
| PUBMED: | 16652148 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 43" - "Export Date: 4 June 2012" - "CODEN: ONCNE" - "Source: Scopus" |
