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![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.](publication/324020315/figure/fig2/AS:608604814053376@1522114103234/A-model-of-the-NF2-merlin-signaling-pathway-Merlin-is-involved-in-contact-inhibition-by.png)
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.
Source publication
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 extr...
Contexts in source publication
Context 1
... example, it has been shown that merlin forms a complex with CD44, which is activated by the stimulation of extracellular hyaluronate, resulting in growth inhibition of rat schwannoma cells in vitro. Other studies have suggested that merlin regulates contact inhibition through small GTPase Rac1 [45,54], α-catenin, cell-polarity protein Par3 [55], and a tight-junction-associated complex composed of angiomotin (AMOT), Patj, and Pals1 [48] (Figure 2, shown in pink). These findings suggest that merlin could sense its environmental conditions and control cell growth via complex interactions with signaling proteins involved in cell-cell adhesion. ...
Context 2
... inhibits the activity of CRL4 DCAF1 , which regulates ubiquitination of target proteins. It was shown that LATS1/2 are functional targets of CRL4 DCAF1 and that in tumors with mutated NF2, such as mesothelioma, activated CRL4 induces LATS1/2 ubiquitination to promote their degradation and YAP/TAZ activation, thus stimulating oncogenesis [66] (Figure 2, shown in purple). These results suggest that DCAF1 and CRL4 DCAF1 are potential therapeutic targets for merlin-deficient mesothelioma. ...
Context 3
... analysis of human mesotheliomas revealed the hyperactivation of mTORC1 and the reduced expression of TSC2, which binds to TSC1 and negatively regulates the activation of mTORC1 by Rheb. These findings suggest that mTOR activation caused by merlin inactivation plays a significant role in mesothelioma development (Figure 2, shown in orange). ...
Context 4
... is involved in cell growth and reprogramming [82,83] and suppresses the biogenesis of the let-7 microRNAs (miRNAs) that function as tumor suppressors by silencing the expression of several oncogenes such as MYC and RAS [84,85]. Hikasa et al. [68] found that merlin bound to Lin28B through the FERM domain and translocated Lin28B from the nucleus to cytoplasm, leading to let-7 miRNA maturation (Figure 2, shown in purple). The association between merlin and Lin28B is induced when merlin is dephosphorylated, which occurs at high cell density, suggesting a novel mechanism in which merlin exerts cell-density-dependent tumor suppression through let-7 miRNA maturation. ...
Similar publications
Mutations in the neurofibromin 2 (NF2) gene were among the first genetic alterations implicated in meningioma tumorigenesis, based on analysis of neurofibromatosis type 2 (NF2) patients who not only develop vestibular schwannomas but later have a high incidence of meningiomas. The NF2 gene product, merlin, is a tumor suppressor that is thought to l...
Patients diagnosed with neurofibromatosis type 2 (NF2) are extremely likely to develop meningiomas, in addition to vestibular schwannomas. Meningiomas are a common primary brain tumor; many NF2 patients suffer from multiple meningiomas. In NF2, patients have mutations in the NF2 gene, specifically with loss of function in a tumor-suppressor protein...
Neurofibromatosis type II (NF2) is a tumor predisposition syndrome characterized by the development of distinctive nervous system lesions. NF2 results from loss-of-function alterations in the NF2 gene on chromosome 22, with resultant dysfunction of its protein product merlin. NF2 is most commonly associated with the development of bilateral vestibu...
Neurofibromatosis type 2 (NF2) is a genetic condition marked by the development of multiple benign tumors in the nervous system. The most common tumors associated with NF2 are bilateral vestibular schwannoma, meningioma, and ependymoma. The clinical manifestations of NF2 depend on the site of involvement. Vestibular schwannoma can present with hear...
Although precapillary pulmonary hypertension (PH) is a rare but severe complication of patients with neurofibromatosis type 1 (NF1), its association with NF2 remains unknown. Herein, we report a case of a 44-year-old woman who was initially diagnosed with idiopathic pulmonary arterial hypertension (IPAH) and treated with PAH-specific combination th...
Citations
... NF2 mutations occur in up to 50-75% of MPM [74], more commonly associated with sarcomatoid histology [75]. Inactivation of NF2 and merlin, a membrane-cytoskeleton scaffolding protein encoded by NF2, prevents Yesassociated protein (YAP) phosphorylation, leading to nuclear translocation and interaction with TEA domain transcription factors (TEAD) which in turn results in expression of cell cycle regulation genes [76]. At AACR 2023, results of the phase 1 trial of VT3989, a YAP/TEAD inhibitor, were presented, demonstrating a response rate of approximately 14% in mesothelioma patients. ...
Opinion statement
Malignant pleural mesothelioma (MPM) is an aggressive asbestos-associated thoracic malignancy that is usually incurable. As demonstrated in the landmark MARS2 trial, surgical resection does not improve survival outcomes and its role in managing MPM is limited. Whilst platinum-pemetrexed chemotherapy in combination with bevacizumab was the standard first-line approach for unresectable disease, landmark phase 3 trials have now established the role of immune checkpoint inhibitors (CPIs) in the upfront management of unresectable disease: either nivolumab-ipilimumab or carboplatin-pemetrexed-pembrolizumab. Patient selection for optimal strategy remains an ongoing question. For relapsed disease novel genomic-based therapies targeting a range of aberrations including losses of the tumour suppressor genes BAP1, CDKN2A and NF2, are being evaluated. Nonetheless, the future of MPM therapeutics holds promise. Here we overview current treatment strategies in the management of MPM.
... In almost 40% of cases of malignant mesothelioma, the upstream initiator of Hippo, neurofibromatosis type 2 (NF2)/Merlin, is inactive. [40] Remarkably, after BRCA1 related protein-1, NF2 is the second most often mutated gene in mesothelioma (BAP1). Compared to wildtype controls, heterozygous NF2 (+/-) mice showed an accelerated carcinogenesis and were more susceptible to asbestos exposure. ...
Mesothelioma is a cancer arising from mesothelial cells lining the thoracic (pleura) or the abdominal (peritoneum) cavities, and more rarely from transformed mesothelial cells of pericardium or tunica vaginalis testis. The development of mesothelioma has been related to the exposure to carcinogenic mineral fibers, mainly asbestos. Malignant mesothelioma is an aggressive disease with diffuse nature, low median survival, and prolonged latency presenting difficulty in prognosis, diagnosis, and treatment. We here review all these aspects to underline the progress being made in investigation and to emphasise how much work remains to be done to improve prognosis and treatment.
... However, a phase II clinical trial using the FAK inhibitor defactinib, did not show any benefits for patients with NF2-low PM [36]. NF2 is also a key regulator of signal pathways such as the mTOR pathway or the Hippo pathway, both of them would be interesting to target in NF2-deficient PM [49]. Concerning the Hippo pathway, the inactivation of NF2 or other members of this pathway, less frequently mutated in PM such as LATS2, lead to the activation of the transcription factors YAP (YAP1) and TAZ (WWTR1), which enhance expression of pro-oncogenic genes notably by interacting with TEADs transcription factors. ...
... This cell process is regulated thanks to the enzyme glutathione peroxidase 4 which protects the cells by neutralizing lipid peroxides [52]. Wu et al [49] said that E-cadherin (mediated cell-cell interactions) suppress ferroptosis in epithelial cells by activating the intracellular NF2-Hippo signaling pathway. Indeed, E-cadherin can activate NF2 and therefore will lead to the inactivation of YAP, which is a mediator of ferroptosis. ...
Introduction:
Pleural mesothelioma is a rare and aggressive cancer originating in the pleura, with a devastating prognosis and limited treatment options. There have been significant advancements in the management of this disease in recent years. Since 2021, nivolumab and ipilimumab immune checkpoint inhibitors have become the new standard of care for first-line treatment of pleural mesothelioma.
Areas covered:
While a combination of chemotherapy and immune checkpoint inhibitors appears to be the next step, targeted therapies are emerging thanks to our understanding of the oncogenesis of pleural mesothelioma. Moreover, several new strategies are currently being investigated, including viral therapy, antibody-drug conjugates, and even cell therapies with CAR-T cells or dendritic cells. In this review, we will explore the various future opportunities that could potentially transform patients' lives in light of the clinical trials that have been conducted.
Expert opinion:
Future clinical studies aim to rebiopsy patients after disease progression to identify new molecular alterations and to be associated with ancillary studies, guiding subsequent therapy decisions. Predicting and investigating treatment resistance mechanisms will lead to innovative approaches and improved treatment outcomes.
... The ERM proteins and merlin are binding partners for a number of transmembrane receptors (like ICAM, syndecans, L-selectin, and integrins) acting as cross-linkers between the plasma membrane and the cortical actin filaments [45][46][47][48]. The neurofibromatosis type 2 (NF2) gene encodes the merlin protein, which has tumor-suppressing functions through regulating Hippo signaling, as well as receptor tyrosine kinases and downstream signal transduction pathways [49][50][51]. ERM proteins and merlin show a similar domain organization, with the highest homology in the conserved three-lobe N-terminal FERM domain (head). The ERM and merlin contain extended C-terminal domains, in which ERM has an interaction site for F-actin, whereas merlin lacks a direct actin-binding site. ...
Simple Summary
This review is focused on the interactions of the CD44 cytoplasmic tail in order to unravel the high complexity of CD44 functions. CD44 serves as a cell surface receptor for various extracellular matrix molecules, mainly hyaluronan, and messenger molecules, such as growth factors, and has important functions in normal and disease states, the predominant one being cancer. CD44 coordinates both structural and signaling events through its highly conserved intracellular domain. Although short and devoid of any enzymatic activity, the CD44 intracellular domain possesses structural motifs that promote the interactions with cytoplasmic effectors involved in important cellular pathways, including cell trafficking, transcription, and metabolism, which regulate cellular functions like growth, survival, differentiation, stemness, and therapeutic resistance.
Abstract
CD44 is a single-chain transmembrane receptor that exists in multiple forms due to alternative mRNA splicing and post-translational modifications. CD44 is the main cell surface receptor of hyaluronan as well as other extracellular matrix molecules, cytokines, and growth factors that play important roles in physiological processes (such as hematopoiesis and lymphocyte homing) and the progression of various diseases, the predominant one being cancer. Currently, CD44 is an established cancer stem cell marker in several tumors, implying a central functional role in tumor biology. The present review aims to highlight the contribution of the CD44 short cytoplasmic tail, which is devoid of any enzymatic activity, in the extraordinary functional diversity of the receptor. The interactions of CD44 with cytoskeletal proteins through specific structural motifs within its intracellular domain drives cytoskeleton rearrangements and affects the distribution of organelles and transport of molecules. Moreover, the CD44 intracellular domain specifically interacts with various cytoplasmic effectors regulating cell-trafficking machinery, signal transduction pathways, the transcriptome, and vital cell metabolic pathways. Understanding the cell type- and context-specificity of these interactions may unravel the high complexity of CD44 functions and lead to novel improved therapeutic interventions.
... Not surprisingly, loss of merlin leads to dysregulation of YAP activity with its co-transcription factors TAZ and TEAD (34). The ability to block YAP/TAZ function has been of interest in treating NF2-de cient cancers (35). A number of studies have targeted YAP association with TEAD as a speci c method to suppress its activation and role in tumor formation(36). ...
Neurofibromatosis Type 2 (NF2)-related schwannomatosis is a genetic disorder that causes development of multiple types of nervous system tumors. The primary and diagnostic tumor type is bilateral vestibular schwannoma. There is no cure or drug therapy for NF2. Recommended treatments include surgical resection and radiation, both of which can leave patients with severe neurological deficits or increase the risk of future malignant tumors. Results of our previous pilot high-throughput drug screen identified phosphoinositide 3-kinase (PI3K) inhibitors as strong candidates based on loss of viability of mouse merlin-deficient Schwann cells (MD-SCs). Here we used novel human schwannoma model cells to conduct combination drug screens. We identified a class I PI3K inhibitor, pictilisib and p21 activated kinase (PAK) inhibitor, PF-3758309 as the top combination due to high synergy in cell viability assays. Both single and combination therapies significantly reduced growth of mouse MD-SCs in an orthotopic allograft mouse model. The inhibitor combination promoted cell cycle arrest and apoptosis in mouse merlin-deficient Schwann (MD-SCs) cells and cell cycle arrest in human MD-SCs. This study identifies the PI3K and PAK pathways as potential targets for combination drug treatment of NF2-related schwannomatosis.
... Similarly, the CDKN2A pathway has been evaluated as a potential target for novel therapies. P16ink4A is a transcriptional product of the CDKN2A pathway, which is an inhibitor of CDK4 and CDK6, which regulate cell cycle progression and promote tumor growth [93] . In a phase 2, single-armed clinical trial, Fennell et al. studied the effects of abemaciclib, a CDK4i/CDK6i, on p16ink4A-deficient PM patients [93] . ...
... P16ink4A is a transcriptional product of the CDKN2A pathway, which is an inhibitor of CDK4 and CDK6, which regulate cell cycle progression and promote tumor growth [93] . In a phase 2, single-armed clinical trial, Fennell et al. studied the effects of abemaciclib, a CDK4i/CDK6i, on p16ink4A-deficient PM patients [93] . All patients had completed at least one cycle of cisplatin-based therapy and were molecularly screened for p16ink4A deficiency prior to inclusion in this study. ...
... All patients had completed at least one cycle of cisplatin-based therapy and were molecularly screened for p16ink4A deficiency prior to inclusion in this study. They found a disease control rate of 54% (14 of 26 patients) at 12 weeks (95%CI: 36-71), with 80% of patients showing a reduction in tumor volume [93] . ...
Pleural mesothelioma (PM) is an aggressive malignancy of the pleural lining that typically arises secondary to asbestos exposure. With the advent of next-generation sequencing, major progress has been made in the molecular characterization of pleural mesothelioma over the past three decades. However, these advances have been largely unable to identify effective targeted therapies for PM. Additionally, there remains an absence of accepted gold-standard consensus for staging and treatment, which partly explains the overall poor outcomes in patients with PM. In recent years, genetic profiling of PM tumors has proved to be an effective tool in the diagnosis and prognosis of PM. Genomic sequencing has identified several potential targets for the development of novel therapeutics in PM. This review summarizes the progress in diagnosis, prognosis, and therapeutics derived by genomics and tumor profiling of PM tumors.
... Cocciadiferro et al showed that by removing the NF2 gene from conditional knockout mouse hepatoblasts, the massive liver enlarges, which indicates the enlargement of liver stem cells [11]. Sato and Sekido reported that NF2 Gene NF2/Merlin inactivation leads to the improvement of mesothelioma and other cancers [35]. MST1/2 acts as an imperative character in adjusting the liver progenitor/stem cell segment in the mature liver [36,37]. ...
Objectives
COVID-19 is initiated by coronavirus infections and it can principally damage the cell’s function of the lung. Assessment of some important genes may capability more operational administration in patients. Therefore, in the recent study, we investigated mRNA and protein expression of MAP3K7, NF2, STK3 and STK4 in virus-infected patients compared with the control group. In addition, we used Quantum Resonance Magnetic Analyzer (QRMA) in order to analyze blood lipids, basic physical quality, lung function and immune system which are divided into twenty-five different variables in patients compared to healthy individuals.
Materials and Methods
The statistical population was divided into two different groups: patients and healthy individuals. The Expression of the mRNA level of objective genes was assessed with the SYBR Green Real-time Polymerase Chain Reaction method. The protein level expression of target genes was calculated by Enzyme-linked Immunosorbent Assay. Furthermore, in this study, we use QRMA to analyze some quantities such as blood lipids, basic physical quality, lung function and immune system in patients compared to healthy individuals. Statistical analyses were accomplished with SPSS software (version, 18) and Graph-Pad Prism software (Graph-Pad Prism, version 8.0.1).
Results
The mRNA and protein expressions level of NF2, MAP3K7, STK3 and STK4 genes in the group of patients decreased significantly compared to healthy individuals. The evaluation of blood lipids, basic physical quality, lung function and immune system in the study by QRMA showed that the Arterial oxygen content Paco2, low-density lipoprotein-C, tonsil immune index and immunoglobulin index were significantly higher in patients group compared to healthy individuals. In contrast, the amount of High-density lipoprotein-C, bone marrow index, respiratory immune index and gastrointestinal immune index were significantly lower in patients group compared to healthy individuals.
Conclusions
Compared to healthy individuals, the amount of mRNA and protein expressed by NF2, MAP3K7, STK3 and STK4 genes was reduced in COVID-19 patients. In truth, these genes have some critical function in some cellular and sub-cellular pathways. Accordingly, when the expression of genes decreased maybe it can increase the influence of coronavirus. Various mechanisms are involved in COVID-19, the increasing of the amount of the arterial oxygen content Paco2, low-density lipoprotein-C, tonsil immune index, immunoglobulin index and decreasing the amount of the High-density lipoprotein-C, bone marrow index, respiratory immune index and gastrointestinal immune index in COVID-19 patients, can be involved in the effects of coronavirus. Therefore, a deep perception of the relationship between these objective genes and QRMA therewith pathogenesis of COVID-19 infections in a larger population with longer supplements is required.
... Genetic alterations in neurofibromatosis type 2 (NF2) are found in approximately 40% of DPM specimens [100][101][102] .The NF2 gene encodes moesin-ezrin-radixin-like (Merlin) tumor suppressor, and its inactivation is associated with the loss of Merlin protein expression in mesothelioma cells [103][104][105] . Merlin regulates the HIPPO pathway by negatively regulating transcriptional co-activators YAP and TAZ through the E3 ubiquitin ligase CRL4 DCAF1 ; YAP and TAZ disinhibition results in an oncogenic cascade predisposing to the development of DPM [106][107][108][109] . Due to the genomic enrichment of NF2 alterations in DPM (19%-25%) [8,22] , several trials evaluating this pathway in patients with NF2-altered DPM have been conducted or are underway [ Table 5]. ...
Despite our growing understanding of the genomic landscape of diffuse pleural mesotheliomas (DPM), there has been limited success in targeted therapeutic strategies for the disease. This review summarizes attempts to develop targeted therapies in DPM, focusing on the following targets being clinically explored in recent and ongoing clinical trials: vascular endothelial growth factor, mesothelin, BRCA1-associated protein 1, Wilms tumor 1 protein, NF2/YAP/TAZ, CDKN2, methylthioadenosine phosphorylase, v-domain Ig suppressor T-cell activation, and argininosuccinate synthetase 1. Although preclinical data for these targets are promising, few have efficaciously translated to benefit our patients. Future efforts should seek to expand the availability of preclinical models that faithfully recapitulate DPM biology, develop clinically relevant biomarkers, and refine patient selection criteria for clinical trials.
... 11 NF2 functions as a tumor suppressor by positively regulating the Hippo signaling pathway. [12][13][14][15] In addition to NF2, genetic alterations in LATS2, which encodes a component of the Hippo pathway, have been detected in mesothelioma, strongly supporting the idea that disruption of the Hippo pathway induces the development of mesothelioma. 12,16 Molecularly, the Hippo pathway plays a role in promoting the nuclear export and degradation of the transcriptional coactivators YAP1 and TAZ, whereas disruption of the Hippo pathway increases the nuclear accumulation of these proteins. ...
... [12][13][14][15] In addition to NF2, genetic alterations in LATS2, which encodes a component of the Hippo pathway, have been detected in mesothelioma, strongly supporting the idea that disruption of the Hippo pathway induces the development of mesothelioma. 12,16 Molecularly, the Hippo pathway plays a role in promoting the nuclear export and degradation of the transcriptional coactivators YAP1 and TAZ, whereas disruption of the Hippo pathway increases the nuclear accumulation of these proteins. YAP1 and TAZ in the nucleus bind to TEAD family DNA-binding proteins (TEAD1-4) and activate the transcription of tumor-promoting genes. ...
Background:
Mesothelioma is a neoplastic disease associated with asbestos exposure. It is highly malignant and has a poor prognosis; thus, early detection is desirable. Recent whole-genome analysis has revealed that mesothelioma is characterized by a high frequency of mutations in a set of genes involved in the Hippo pathway, such as NF2 and LATS2. However, a rapid, simple, and precise method for finding mesothelioma with these mutations has not yet been established.
Methods:
Clustering of Hippo pathway gene alteration groups and the differential expression of each gene in mesothelioma patients were analyzed using The Cancer Genome Atlas database. Gene expression levels in various tumors and normal tissues were analyzed using public databases. Knockdown or transient expression of YAP1 or TAZ was performed to evaluate the regulation of gene expression by these genes. NT-proBNP was measured in the pleural effusions of 18 patients and was compared with NF2 expression in five cases where cell lines had been successfully established.
Results:
NPPB mRNA expression was markedly higher in the group of mesothelioma patients with Hippo pathway gene mutations than in the group without them. NPPB expression was low in all normal tissues except heart, and was highest in mesothelioma. Mesothelioma patients in the high NPPB expression group had a significantly worse prognosis than those in the low NPPB expression group. NPPB expression was suppressed by knockdown of YAP1 or TAZ. NT-proBNP was abundant in the effusions of mesothelioma patients and was particularly high in those with impaired NF2 expression.
Conclusions:
NPPB, whose levels can be measured in pleural effusions of mesothelioma patients, has the potential to act as a biomarker to detect NF2-Hippo pathway gene alterations and/or predict patient prognosis. Additionally, it may provide useful molecular insights for a better understanding of mesothelioma pathogenesis and for the development of novel therapies.
... The tumor suppressor function of Merlin is not restricted to the regulation of Hippo signaling. Merlin has been shown to restrict cell proliferation and migration by inhibiting expression and activation of receptor tyrosine kinases and downstream signaling pathways, including RAS/RAF/MEK/ERK, RAC/PAK/JNK, PI3K/AKT/JNK, FAK/SRC, mTORC1 and WNT/β-catenin [23,24]. It has also been shown to attenuate oncogenic gene expression via inhibition of the CRL4/DCAF1 (Cullin-RING ubiquitin ligase 4 / DDB1-and Cul4-associated factor 1) ubiquitin ligase complex [20,24,25]. ...
... Merlin has been shown to restrict cell proliferation and migration by inhibiting expression and activation of receptor tyrosine kinases and downstream signaling pathways, including RAS/RAF/MEK/ERK, RAC/PAK/JNK, PI3K/AKT/JNK, FAK/SRC, mTORC1 and WNT/β-catenin [23,24]. It has also been shown to attenuate oncogenic gene expression via inhibition of the CRL4/DCAF1 (Cullin-RING ubiquitin ligase 4 / DDB1-and Cul4-associated factor 1) ubiquitin ligase complex [20,24,25]. Of interest, the majority of mutations, both in the germline of NF2 patients and in sporadically occurring human tumors, have been identified in the NF2 gene region encoding the so-called FERM (4.1 protein, ezrin, radixin, moesin) domain, which mediates interactions with membrane-bound proteins [26]. ...
Primary liver cancer is the third leading cause of cancer-related death worldwide. An increasing body of evidence suggests that the Hippo tumor suppressor pathway plays a critical role in restricting cell proliferation and determining cell fate during physiological and pathological processes in the liver. Merlin (Moesin-Ezrin-Radixin-like protein) encoded by the NF2 (neurofibromatosis type 2) gene is an upstream regulator of the Hippo signaling pathway. Targeting of Merlin to the plasma membrane seems to be crucial for its major tumor-suppressive functions; this is facilitated by interactions with membrane-associated proteins, including CD44 (cluster of differentiation 44). Mutations within the CD44-binding domain of Merlin have been reported in many human cancers. This study evaluated the relative contribution of CD44- and Merlin-dependent processes to the development and progression of liver tumors. To this end, mice with a liver-specific deletion of the Nf2 gene were crossed with Cd44-knockout mice and subjected to extensive histological, biochemical and molecular analyses. In addition, cells were isolated from mutant livers and analyzed by in vitro assays. Deletion of Nf2 in the liver led to substantial liver enlargement and generation of hepatocellular carcinomas (HCCs), intrahepatic cholangiocarcinomas (iCCAs), as well as mixed hepatocellular cholangiocarcinomas. Whilst deletion of Cd44 had no influence on liver size or primary liver tumor development, it significantly inhibited metastasis formation in Nf2-mutant mice. CD44 upregulates expression of integrin β2 and promotes transendothelial migration of liver cancer cells, which may facilitate metastatic spreading. Overall, our results suggest that CD44 may be a promising target for intervening with metastatic spreading of liver cancer.
