br Introduction Neurofibromin Merlin NF is

Introduction Neurofibromin 2 (Merlin, NF2) is a tumour suppressor protein expressed during embryonic development and thereafter (Gronholm et al., 2005). In adults, significant levels of expression are found in Schwann and meningeal cells, nerve and lens (Claudio et al., 1997; Sakuda et al., 1996; Scherer and Gutmann, 1996). Mutations in the encoding gene (NF2) lead to formation of schwannomas and meningiomas, and less often of ependymomas and retinal astrocytic hamartomas (Hanemann, 2008; Martin et al., 2010; Rouleau et al., 1993). These tumours originate sporadically or as part of the genetic condition Neurofibromatosis type 2 (NF2) (Hanemann, 2008). They are largely unresponsive to classic chemotherapeutic agents, leaving surgery and radiotherapy as the only remaining treatment options which can leave the patient with mild to severe morbidity (Hanemann, 2008). Additionally, NF2 patients often develop multiple tumours simultaneously (Hanemann, 2008), strengthening the need for effective systemic therapeutic options. Loss of Merlin has also been related to a variety of other cancers, including glioblastomas, malignant mesotheliomas and thyroid carcinomas, highlighting its role as tumour suppressor (Garcia-Rendueles et al., 2015; Guerrero et al., 2015; Lee et al., 2016; Morrow et al., 2016; Sheikh et al., 2004). Merlin shares structural similarity with the Ezrin/Radixin/Moesin (ERM) family of proteins that link the Atglistatin with components of the cell membrane (Bretscher et al., 2000; McClatchey, 2003; McClatchey and Giovannini, 2005). Although Merlin lacks the C-terminal actin-binding domain present in the other members of the ERM family, it can localize to the cortical cytoskeleton and interact directly with the actin-binding protein α-catenin (Gladden et al., 2010). At sites of cell-cell contact Merlin acts as tumour suppressor controlling cadherin-mediated contact-dependent inhibition of proliferation and adherens junction formation (Flaiz et al., 2008; Lallemand et al., 2003). Several receptor tyrosine kinases (RTKs) have been found to be Merlin-dependent (Curto et al., 2007; Lallemand et al., 2009). Our group and others showed overexpression and reduced degradation of the platelet-derived growth factor receptor β (PDGFRβ) in schwannoma compared to normal Schwann cells which, together with the loss of Merlin, leads to increased cellular proliferation and aberrant activation of the MAPK and PI3K signalling pathways (Ammoun et al., 2008; Fraenzer et al., 2003). RTKs are found to be linked to Merlin and thus the cytoskeleton via the PDZ domain–containing adapter NHERF-1 (Na+/H+ exchanger regulatory factor) (Maudsley et al., 2000; Weinman et al., 2000). Merlin loss further contributes to tumorigenesis via the activation of a number of other pathways including the Hippo, Ras and Wnt/β-catenin (Li et al., 2014; Mohler et al., 1999; Zhao et al., 2010, 2011). Merlin activity is also in the nucleus, where it binds to the E3 ubiquitin ligase CRL4 (DCAF1) suppressing its activity. Depletion of DCAF1 in Merlin-deficient schwannoma cells was sufficient to block proliferation (Cooper et al., 2011). Unbiased genomic studies have been performed aiming to identify novel differentially-expressed genes in schwannomas and meningiomas (Fevre-Montange et al., 2009; Hanemann et al., 2006; Torres-Martin et al., 2013a,b, 2014; Wang et al., 2012) as well as novel driver mutations, exclusive of NF2 (Clark et al., 2013). Mass spectrometry (MS) is a powerful, high-throughput technique to identify thousands of proteins aberrantly expressed and regulated. Recently Sharma and colleagues performed comparative proteomic analysis on different grades of meningiomas to investigate alterations in the meningioma tissue and in the human serum of meningioma patients compared to normal brain tissue. They identified several deregulated proteins including transgelin-2 and caveolin in tissue, plus apoliopoproteins A and E in serum (Sharma et al., 2014, 2015).