ArticleMolecular cancer2016
Rac1-mediated cytoskeleton rearrangements induced by intersectin-1s deficiency promotes lung cancer cell proliferation, migration and metastasis.
Article in Molecular cancer, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 34 citations in OpenAlex.
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- Adaptor protein Abelson interactor 1 in homeostasis and disease.Cell communication and signaling : CCS · 2024Review
- Partial reprogramming strategy for intervertebral disc rejuvenation by activating energy switch.Aging cell · 2022Article
- The Mechanism of Rac1 in Regulating HCC Cell Glycolysis Which Provides Underlying Therapeutic Target for HCC Therapy.Journal of oncology · 2022Article
- Endocytic protein intersectin1-S shuttles into nucleus to suppress the DNA replication in breast cancer.Cell death & disease · 2021Article
- Progress in the therapeutic inhibition of Cdc42 signalling.Biochemical Society transactions · 2021Review
- Sex differences in the proliferation of pulmonary artery endothelial cells: implications for plexiform arteriopathy.Journal of cell science · 2020Article
- MicroRNAs Regulating Cytoskeleton Dynamics, Endocytosis, and Cell Motility-A Link Between Neurodegeneration and Cancer?Frontiers in neurology · 2020Review
- The focal adhesion scaffold protein Hic-5 regulates vimentin organization in fibroblasts.Molecular biology of the cell · 2019Article
- FoxO3a inhibiting expression of EPS8 to prevent progression of NSCLC: A new negative loop of EGFR signaling.EBioMedicine · 2019Article
- A Novel Method to Efficiently Highlight Nonlinearly Expressed Genes.Frontiers in genetics · 2019Article
- Intersectin 1 (ITSN1) identified by comprehensive bioinformatic analysis and experimental validation as a key candidate biological target in breast cancer.OncoTargets and therapy · 2019Article
- Alk5/Runx1 signaling mediated by extracellular vesicles promotes vascular repair in acute respiratory distress syndrome.Clinical and translational medicine · 2018Article
- Overexpression of geranylgeranyl diphosphate synthase contributes to tumour metastasis and correlates with poor prognosis of lung adenocarcinoma.Journal of cellular and molecular medicine · 2018Article
- Epsin15 Homology Domains: Role in the Pathogenesis of Pulmonary Arterial Hypertension.Frontiers in physiology · 2018Article
- Intersectin-1s deficiency in pulmonary pathogenesis.Respiratory research · 2017Review
- Exploring the key genes and pathways in enchondromas using a gene expression microarray.Oncotarget · 2017Article
- Targeting reactive oxygen species in development and progression of pancreatic cancer.Expert review of anticancer therapy · 2017Review
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10 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundThe mechanisms involved in lung cancer (LC) progression are poorly understood making discovery of successful therapies difficult. Adaptor proteins play a crucial role in cancer as they link cell surface receptors to specific intracellular pathways. Intersectin-1s (ITSN-1s) is an important multidomain adaptor protein implicated in the pathophysiology of numerous pulmonary diseases. To date, the role of ITSN-1s in LC has not been studied.
methodsHuman LC cells, human LC tissue and A549 LC cells stable transfected with myc-ITSN-1s construct (A549 + ITSN-1s) were used in correlation with biochemical, molecular biology and morphological studies. In addition scratch assay with time lapse microscopy and in vivo xenograft tumor and mouse metastasis assays were performed.
resultsITSN-1s, a prevalent protein of lung tissue, is significantly downregulated in human LC cells and LC tissue. Restoring ITSN-1s protein level decreases LC cell proliferation and clonogenic potential. In vivo studies indicate that immunodeficient mice injected with A549 + ITSN-1s cells develop less and smaller metastatic tumors compared to mice injected with A549 cells. Our studies also show that restoring ITSN-1s protein level increases the interaction between Cbl E3 ubiquitin ligase and Eps8 resulting in enhanced ubiquitination of the Eps8 oncoprotein. Subsequently, downstream unproductive assembly of the Eps8-mSos1 complex leads to impaired activation of the small GTPase Rac1. Impaired Rac1 activation mediated by ITSN-1s reorganizes the cytoskeleton (increased thick actin bundles and focal adhesion (FA) complexes as well as collapse of the vimentin filament network) in favor of decreased LC cell migration and metastasis.
conclusionITSN-1s induced Eps8 ubiquitination and impaired Eps8-mSos1 complex formation, leading to impaired activation of Rac1, is a novel signaling mechanism crucial for abolishing the progression and metastatic potential of LC cells.
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