Oncogene. 2006 May 1; [Epub ahead of print] Received 31 January 2006; Revised 9 March 2006; Accepted 9 March 2006; Published online 1 May 2006. [Link]
P I Poulikakos1, G-H Xiao1, R Gallagher1, S Jablonski2, S C Jhanwar3 and J R Testa1
- 1Human Genetics Program, Fox Chase Cancer Center, Philadelphia, PA, USA
- 2Cell Imaging Facility, Fox Chase Cancer Center, Philadelphia, PA, USA
- 3Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Correspondence: Dr JR Testa, Human Genetics Program Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA. E-mail: Joseph.Testa@fccc.edu
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.