ArticleMolecular and cellular biology2009
Loss of the tumor suppressor gene NF2, encoding merlin, constitutively activates integrin-dependent mTORC1 signaling.
Article in Molecular and cellular biology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 102 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
102 citing papers in PubMed, 184 citations in OpenAlex.
- SWOG S0722: phase II study of mTOR inhibitor everolimus (RAD001) in advanced malignant pleural mesothelioma (MPM).Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer · 2015Trial
- Phase II study of everolimus in children and adults with neurofibromatosis type 2 and progressive vestibular schwannomas.Neuro-oncology · 2014Trial
- Loss of tumor suppressor NF2 mediates resistance to CAR T cell and anti-PD-1 therapy: Strategies to restore immunotherapy sensitivity.Med (New York, N.Y.) · 2026Article
- Metabolic vulnerabilities in pleural mesothelioma.Oncogenesis · 2026Review
- T-cell-targeted immunotherapy in neurofibromatosis type 2-related vestibular schwannoma: current evidence and future direction.Brain communications · 2026Review
- Interactions among Merlin, Arkadia, and SKOR2 mediate NF2-associated human Schwann cell proliferation.Stem cell research & therapy · 2025Article
- Current molecular understanding of central nervous system schwannomas.Acta neuropathologica communications · 2025Review
- RNA splicing as a biomarker and phenotypic driver of meningioma DNA-methylation groups.Neuro-oncology · 2024Article
- Functional precision medicine assay for recurrent meningioma: a proof of principle. Illustrative case.Journal of neurosurgery. Case lessons · 2024Article
- NF2: An underestimated player in cancer metabolic reprogramming and tumor immunity.NPJ precision oncology · 2024Review
- Gene Therapy for Neurofibromatosis Type 2-Related Schwannomatosis: Recent Progress, Challenges, and Future Directions.Oncology and therapy · 2024Review
- Genomic characterization and detection of potential therapeutic targets for peritoneal mesothelioma in current practice.Clinical and experimental medicine · 2024Article
- Renal Cell Carcinoma of Variant Histology: Biology and Therapies.Hematology/oncology clinics of North America · 2023Review
- Hearing loss and vestibular schwannoma: new insights into Schwann cells implication.Cell death & disease · 2023Review
- Current progress in genomics and targeted therapies for neurofibromatosis type 2.Fukushima journal of medical science · 2023Review
- The genetic landscape and possible therapeutics of neurofibromatosis type 2.Cancer cell international · 2023Review
- Cellular mechanisms of heterogeneity in NF2-mutant schwannoma.Nature communications · 2023Article
- Indolyl-chalcone derivatives trigger apoptosis in cisplatin-resistant mesothelioma cells through aberrant tubulin polymerization and deregulation of microtubule-associated proteins.Frontiers in oncology · 2023Article
- Hippo Signaling in the Ovary: Emerging Roles in Development, Fertility, and Disease.Endocrine reviews · 2022Review
- The Rocky Road from Preclinical Findings to Successful Targeted Therapy in Pleural Mesothelioma.International journal of molecular sciences · 2022Review
42 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Integrin signaling promotes, through p21-activated kinase, phosphorylation and inactivation of the tumor suppressor merlin, thus removing a block to mitogenesis in normal cells. However, the biochemical function of merlin and the effector pathways critical for the pathogenesis of malignant mesothelioma and other NF2-related malignancies are not known. We report that integrin-specific signaling promotes activation of mTORC1 and cap-dependent mRNA translation. Depletion of merlin rescues mTORC1 signaling in cells deprived of anchorage to a permissive extracellular matrix, suggesting that integrin signaling controls mTORC1 through inactivation of merlin. This signaling pathway controls translation of the cyclin D1 mRNA and, thereby, cell cycle progression. In addition, it promotes cell survival. Analysis of a panel of malignant mesothelioma cell lines reveals a strong correlation between loss of merlin and activation of mTORC1. Merlin-negative lines are sensitive to the growth-inhibitory effect of rapamycin, and the expression of recombinant merlin renders them partially resistant to rapamycin. Conversely, depletion of merlin restores rapamycin sensitivity in merlin-positive lines. These results indicate that integrin-mediated adhesion promotes mTORC1 signaling through the inactivation of merlin. Furthermore, they reveal that merlin-negative mesotheliomas display unregulated mTORC1 signaling and are sensitive to rapamycin, thus providing a preclinical rationale for prospective, biomarker-driven clinical studies of mTORC1 inhibitors in these tumors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.