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Genetics in Otology and Neurotology
Published in John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie, Basic Sciences Endocrine Surgery Rhinology, 2018
The gene product is similar in sequence to a family of proteins including moesin, ezrin, radixin, talin and members of the protein 4.1 superfamily. These proteins are involved in linking cytoskeletal components with the plasma membrane and are located in actin rich surface projections such as microvilli, membrane ruffles, and cell contact regions. The N-terminal region of the merlin protein is thought to interact with components of the plasma membrane and the C-terminal with the cytoskeleton. While the exact function of the NF2 protein is as yet unknown, the evidence available suggests that it is involved in cell–cell or cell–matrix interactions, and that it is important for cell movement, cell shape and communication. There is considerable evidence, in both NF2 knockout mice and in vitro schwannoma preparations, that loss of function of the merlin protein results in a loss of contact inhibition and consequently leads to tumourigenesis.44-46
Neurofibromatosis 2
Published in John C Watkinson, Raymond W Clarke, Christopher P Aldren, Doris-Eva Bamiou, Raymond W Clarke, Richard M Irving, Haytham Kubba, Shakeel R Saeed, Paediatrics, The Ear, Skull Base, 2018
The NF2 protein (merlin or schwannomin) is a cell cytoskeleton-associating protein of 595 amino acids coded by the 17 exons of the NF2 gene. The name ‘merlin’ derived from the sequence homology and shared overall domain structure with ERM (moesin, ezrin and radixin) superfamily of membrane-cytoskeleton linker molecules. Alternative splicing of exon 16 gives rise to two isoforms, which differ by the last C-terminal 11 amino acids. The NF2 protein is expressed in many tissues including neurons, Schwann cells and meningeal cells. Mutant NF2 protein impairs cell adhesion, motility and spreading properties, which are known to be essential for tumour formation. Loss of NF2 protein is the main and possibly the only rate-limiting step in the formation of all schwannomas and most meningiomas. Merlin is localized to the cell membrane/cytoskeletal interface and appears to have a number of different roles involving interactions including the Ras/Raf/MEK/ERK, FAK/Src, PI3K/AKT, Rac/PAK/JNK, mTORC1 and Wnt/²-catenin pathways.18 NF2 links receptors at the plasma membrane to their cytoplasmic kinases to facilitate contact inhibition. However, NF2 can also interact with a large number of cytoplasmic and nuclear proteins that affect cell cycle progression. NF2 may also, through these pathways, reverse the functional inhibition of conventional tumour suppressor pathways.19
Ganglioglioma
Published in Dongyou Liu, Tumors and Cancers, 2017
Mandana Behbahani, Hasan R. Syed, Tadanori Tomita, Christopher Kalhorn
Most recently, the PI3K-mTOR pathway, which is responsible for cell size, growth control, cortical development, and neuronal migration, has been shown to play a critical role in the specific pathogenesis of gangliogioma [7,8]. Mutational analysis of downstream tumor suppressor complexes involving TSC1 (hamartin) and TSC2 (tuberin) reveals gene alteration in TSC2, including polymorphism in intron 4 and exon 41 to be overrepresented in ganglioglioma. Concurrently, somatic mutation in intron 32 is identified in the glial portion but not within the neurons of ganglioglioma. An increased polymorphism within tuberin has been noted in ganglioglioma relative to that of normal brain tissue. In contrast, ezrin–radixin–moesin (ERB) proteins interacting with TSC1 to regulate cell adhesion and migration display high levels of aberrancy within dysplastic elements of glioneuronal lesions, such as ganglioglioma. Additionally, LIM domain-binding 2, a gene known to play a role in brain development, is reduced in expression, possibly highlighting the development of an aberrant neuronal network as a major etiology in ganglioglioma, as previously hypothesized [9]. Interestingly, recent genetic studies suggest against the involvement of known pathogenic genes, such as TP53, EGFR, and PTN, as contributors to gangliogioma [8].
Peritoneal dissemination of ovarian cancer: role of MUC16-mesothelin interaction and implications for treatment
Published in Expert Review of Anticancer Therapy, 2018
Ricardo Coelho, Lara Marcos-Silva, Sara Ricardo, Filipa Ponte, Antonia Costa, Jose Manuel Lopes, Leonor David
The TR portion contains at least 12 repeats of around 156 aa, usually interspersed with sea urchin sperm, enterokinase, and agrin domains (SEA) of 122 aa, which have on average three N-glycans [40]. Flanking the SEA domain, there is a linker-region of approximately 30 aa abundant in PST residues and with high density of O-glycosylation [40]. Although there is sequence variability within the TRs, they are homologous and share common features, such as two conserved cysteine residues that might form a disulfide bond and three consensus sequence motifs for N-glycosylation [41]. Recently, it was found that a stretch of 12 amino acids present in the juxta-membrane ectodomain is critical for MUC16 cleavage within the acidic pH of Golgi/post-Golgi compartments [42]. The intracellular part of MUC16 is a 35 residues long cytoplasmic tail with serine, threonine, and tyrosine potential phosphorylation sites [43]. The cytoplasmic tail has a polybasic sequence of amino acids predicted to bind to the ezrin/radixin/moesin (ERM) family of proteins, linking it to the actin cytoskeleton [44].
ROBO2 hampers malignant biological behavior and predicts a better prognosis in pancreatic adenocarcinoma
Published in Scandinavian Journal of Gastroenterology, 2021
Cheng Ding, Yatong Li, Shunda Wang, Cheng Xing, Lixin Chen, Hanyu Zhang, Yizhi Wang, Menghua Dai
Metastasis is an important cause of death from pancreatic cancer. Various regulatory mechanisms are involved in the migration of malignant tumors, and EMT is one such mechanism of great importance [29,30]. Through migration and invasion assays, we demonstrated that ROBO2 could hamper the migration and invasion ability of pancreatic cancer cell in vitro. Western blot indicated that ROBO2 could inhibit the expression of N-cadherin and Vimentin, while could evaluates the level of E-cadherin. The main features of EMT are loss of the epithelial phenotype and acquisition of the mesenchymal phenotype, resulting in enhanced tumor cell migration and invasiveness via impaired cell–matrix adhesion and remodeling of the ECM [31–33]. E-cadherin, N-cadherin, and vimentin, important markers of EMT, are associated with the metastatic phenotype. ECM1 overexpression is related to strong malignant behavior and a poor prognosis in multiple malignancies, such as gastric cancer, breast cancer, laryngeal carcinoma, hepatocellular carcinoma, and others [34–37]. Lee et al. reported that ECM1 could advance EMT progression via stabilization of the β-catenin protein in metastatic breast cancer. Their study also demonstrated that ECM1 regulates chemotherapy resistance, sphere-forming ability, and cancer stem cell maintenance [38]. Wu et al. reported that ECM1 could interact with moesin to promote aggressive breast cancer phenotypes [39]. Another primary study suggested that migration and metastasis of cancer cells could be induced by a simple change in the structure of the ECM [40]. Since ECM1 could promote cancer cell invasion via EMT, we suggest that ROBO2 could inhibit ECM1 in pancreatic cancer to hamper the migration and invasion ability via inhibiting EMT. These findings could partly explain the anti-cancer mechanism of ROBO2 in pancreatic cancer.
The enigmatic nature of the triggering receptor expressed in myeloid cells -1 (TLT- 1)
Published in Platelets, 2021
Siobhan Branfield, A. Valance Washington
The scaffolding protein moesin was shown to interact with the TLT-1 cytoplasmic tail. Moesin is known to link membrane proteins via its ERM (Ezrin, Radixin, and Moesin) domain to the actin cytoskeleton [18]. This data postulates that the mechanism by which TLT-1 facilitates platelet aggregation involves linking fibrinogen to the platelet cytoskeleton via the ERMs. However, none of the ERM protein deficient mice have a demonstrated bleeding diathesis [56,57] and therefore the importance of these interactions is yet to be determined.