NF2/Merlin Inactivation and Potential Therapeutic Targets in Mesothelioma

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.

Cluster of differentiation 44 promotes osteosarcoma progression in mice lacking the tumor suppressor Merlin

“…Studies in mice indicate that spontaneous osteosarcoma formation might be initiated by loss of the tumor suppressor protein Merlin (moesin‐ezrin‐radixin‐like protein) 3,4 —which belongs to a larger protein superfamily called Band 4.1 and shares significant sequence homology and similar domain organization as other members of the family, such as the ERM (ezrin‐radixin‐moesin) proteins 5‐7 (Figure SI1). Merlin's tumor suppressor function is primarily referred to as its ability to inhibit cell proliferation in response to adhesive signaling.…”

“…At the cell cortex, Merlin participates in the organization of cell junctions and negatively regulates expression and activation of receptor tyrosine kinases (RTKs) and the activation of downstream pathways, including RAS/RAF/MEK/ERK, RAC/PAK/JNK, PI3K/AKT/JNK, FAK/SRC, mTORC1 and WNT/β‐catenin (Figure SI2). 5,9 Moreover, Merlin can translocate to the nucleus, where it attenuates oncogenic gene expression primarily via inhibition of the CRL4 DCAF1 (DDB1‐ and Cul4‐Associated Factor 1) ubiquitin ligase complex 5‐7 . In addition, Merlin acts both at the cell cortex and in the nucleus to regulate the Hippo tumor suppressor signaling pathway (Figure SI2).…”

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

“…In mouse embryonic fibroblasts, loss of NF2 function decreases the strength of cadherin mediated adherens junctions and increases confluency [73]. Merlin is also involved in signaling through the Hippo pathway to restrict growth of tissues [74] and the mTOR pathway [75]. Finally, translocation of merlin to the nucleus indirectly modulates expression of several oncogenes including MYC and RAS [76,77].…”

“…Finally, translocation of merlin to the nucleus indirectly modulates expression of several oncogenes including MYC and RAS [76,77]. Some early reports identified biallelic inactivation of NF2 in mesotheliomas but not lung cancers [78,79] and has been singled as a therapeutic target in these cancers [75]. The NF2 resistant mutations identified in afatinib and cetuximab combination therapy patients [66] show that modulating the mTOR pathway is one mechanism to escape EGFR TK inhibition.…”

Therapy of Sporadic and NF2-Related Vestibular Schwannoma

“…The product of the NF2 gene, which is a 595-amino acid protein called the merlin protein, acts as a mediator in signal transmission [16,18,19]. It contains a relatively conserved N-terminal domain resembling the domain of ezrin-radixin-moesin protein family except for the C-terminal domain [20,21]. The domain is usually on the amino terminus, which allows it to act as a mediator to regulate cell motility, cell-cell attachment and cell membrane receptor availability [22].…”