Abstract
The neurofibromatosis type 2 (NF2) gene encodes merlin, a tumor suppressor protein frequently inactivated in schwannoma, meningioma, and malignant mesothelioma (MM). The sequence of merlin is similar to that of ezrin/radixin/moesin (ERM) proteins which crosslink actin with the plasma membrane, suggesting that merlin plays a role in transducing extracellular signals to the actin cytoskeleton. Merlin adopts a distinct closed conformation defined by specific intramolecular interactions and regulates diverse cellular events such as transcription, translation, ubiquitination, and miRNA biosynthesis, many of which are mediated through Hippo and mTOR signaling, which are known to be closely involved in cancer development. MM is a very aggressive tumor associated with asbestos exposure, and genetic alterations in NF2 that abrogate merlin’s functional activity are found in about 40% of MMs, indicating the importance of NF2 inactivation in MM development and progression. In this review, we summarize the current knowledge of molecular events triggered by NF2/merlin inactivation, which lead to the development of mesothelioma and other cancers, and discuss potential therapeutic targets in merlin-deficient mesotheliomas.
Highlights
Mutations in the neurofibromatosis type 2 (NF2) gene are responsible for neurofibromatosis 2, a dominantly inherited familial cancer syndrome characterized by the formation of bilateral vestibular schwannomas and meningiomas [1,2]
Besides sporadic schwannomas [3] and meningiomas [4], frequent biallelic inactivation of NF2 was found in malignant mesothelioma (MM), a very aggressive tumor which is not associated with the NF2 cancer syndrome [5,6]
A recent study on the pharmacological effects of Focal adhesion kinase (FAK) inhibitors has demonstrated a significant correlation between E-cadherin mRNA levels and VS-4718 in merlin-negative mesothelioma [15], suggesting that E-cadherin may serve as a promising biomarker for predicting the response to FAK inhibitors in mesothelioma, which should be tested in clinical settings
Summary
Mutations in the neurofibromatosis type 2 (NF2) gene are responsible for neurofibromatosis 2, a dominantly inherited familial cancer syndrome characterized by the formation of bilateral vestibular schwannomas and meningiomas [1,2]. Since it was shown that a homozygous mutation in the NF2 gene of mice causes embryonic death by day 6.5 of their development [9], the role of NF2 as a tumor suppressor gene has been studied in mice that are heterozygous for NF2 mutations. It was shown that the restoration of NF2 expression in NF2-deficient mesothelioma cells significantly inhibited their growth [14,15,16]. These in vitro and in vivo data strongly support the role of NF2 inactivation in mesothelioma development
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