| Unregulated ARF6 activation in epithelial cysts generates hyperactive signaling endosomes and disrupts morphogenesis. | |
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MedLine Citation:
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PMID: 20462959 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Tumor development in glandular tissues is associated with structural alterations in the hollow ducts and spherical structures that comprise such tissues. We describe a signaling axis involving sustained activation of the GTP-binding protein, ARF6, that provokes dramatic changes in the organization of epithelial cysts, reminiscent of tumorigenic glandular phenotypes. In reconstituted basement membrane cultures of renal epithelial cysts, enhanced ARF6 activation induces the formation of cell-filled glandular structures with multiple lumens and disassembled cadherin-based cell-cell contacts. All of these alterations are accompanied by growth factor receptor internalization into signaling endosomes and reversed by blocking ARF6 activation or receptor endocytosis. Receptor localization in signaling endosomes results in hyperactive extracellular signal-regulated kinase signaling leading to Bcl-2 stabilization and aberrant cysts. Similarly, formation of hyperproliferative and disorganized mammary acini induced by chronic stimulation of colony-stimulating factor 1 receptor is coupled to endogenous ARF6 activation and constitutive receptor internalization and is reversed by ARF6 inhibition. These findings identify a previously unrecognized link between ARF6-regulated receptor internalization and events that drive dramatic alterations in cyst morphogenesis providing new mechanistic insight into the molecular processes that can promote epithelial glandular disruption. |
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Authors:
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Jogender S Tushir; James Clancy; Andrew Warren; Carolyn Wrobel; Joan S Brugge; Crislyn D'Souza-Schorey |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-05-12 |
Journal Detail:
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Title: Molecular biology of the cell Volume: 21 ISSN: 1939-4586 ISO Abbreviation: Mol. Biol. Cell Publication Date: 2010 Jul |
Date Detail:
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Created Date: 2010-06-30 Completed Date: 2010-12-16 Revised Date: 2011-08-01 |
Medline Journal Info:
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Nlm Unique ID: 9201390 Medline TA: Mol Biol Cell Country: United States |
Other Details:
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Languages: eng Pagination: 2355-66 Citation Subset: IM |
Affiliation:
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Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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ADP-Ribosylation Factors
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genetics,
metabolism* Animals Cell Line Dogs Endosomes / metabolism* Enzyme Activation Epithelial Cells / cytology, metabolism* Epithelium / anatomy & histology, embryology*, metabolism Extracellular Signal-Regulated MAP Kinases / metabolism Humans Mammary Glands, Human / anatomy & histology, embryology, metabolism Morphogenesis / physiology* Phospholipase D / metabolism Proto-Oncogene Proteins c-bcl-2 / genetics, metabolism Signal Transduction / physiology* |
| Grant Support | |
ID/Acronym/Agency:
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R01 CA105134-09/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Proto-Oncogene Proteins c-bcl-2; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases; EC 3.1.4.4/Phospholipase D; EC 3.6.5.2/ADP-Ribosylation Factors; EC 3.6.5.2/ADP-ribosylation factor 6 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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