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.

Keywords: Hippo signaling pathway; PI3K/AKT/mTOR signaling pathway; malignant mesothelioma; merlin; neurofibromatosis type 2 (NF2).

Figure 1

Mechanisms underlying the activation/inactivation of merlin. (a) Domain organization of merlin. The protein consists of the N-terminal FERM (band 4.1/ezrin/radixin/moesin) domain (green) comprising three subdomains (A, B, and C), a central helical domain (yellow), and a C-terminal domain (CTD, orange). Major phosphorylation sites are indicated; (b) NF2 mutations and their frequency in pleural and peritoneal cancers. Nonsense/frameshift (blue) and missense (red) mutations registered in COSMIC (Catalogue of Somatic Mutations in Cancer; http://cancer.sanger.ac.uk/cosmic/) as of 27 February 2018, are mapped; (c) Phosphorylation-dependent inactivation of merlin. Phosphorylation at Ser518 inactivates merlin and inhibits its growth suppression activity; (d) Frequency of genetic alterations in the NF2 gene, including mutations, fusions, and copy number variations in different subtypes of malignant pleural mesothelioma based on an analysis of 211 malignant plural mesothelioma samples. The data were adapted from Bueno et al. [24].

Figure 2

A model of the NF2/merlin signaling pathway. Merlin is involved in contact inhibition by interacting with many membrane-associated proteins such as CD44 [26,27], the angiomotin (AMOT) –Patj–Pals1 complex [48], E-cadherin–α-catenin [30,55], and actin fibers. A loss of merlin expression disrupts cancer-related signaling through the Hippo and mTOR pathways. Merlin is also localized in the nucleus where it binds to and inhibits E3 ubiquitin ligase CRL4^DCAF1, which promotes LATS1/2 degradation [66,67], and RNA-binding protein Lin28B, which suppresses let-7 miRNAs that are involved in the silencing of oncogenes such as MYC and RAS [68]. TJ: tight junction; AJ: adherens junction; ZO-1: Zonula occludens-1; AMOT: angiomotin; mTOR: mechanistic target of rapamycin; TSC1/2: tuberous sclerosis complex 1/2; Rheb: Ras homolog enriched in brain; Sav1: Salvador Family WW Domain Containing Protein 1; Mst1/2: mammalian Ste20-like kinase 1/2; Mob: Mps one binder kinase activator-like protein; YAP: yes-associated protein 1; TAZ: WW domain-containing transcription regulator 1; CRL4: Cullin-RING ubiquitin ligase 4; DCAF1: DDB1- and CUL4-associated factor 1; LATS1/2: large tumor suppressor kinase 1/2; TEAD: TEA domain transcription factor; Lin28B: lin-28 homolog B.