| Gene correction of integrin beta4-dependent pyloric atresia-junctional epidermolysis bullosa keratinocytes establishes a role for beta4 tyrosines 1422 and 1440 in hemidesmosome assembly. | |
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MedLine Citation:
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PMID: 11522777 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The cytoplasmic domain of beta4 integrin contains two pairs of fibronectin-like repeats separated by a connecting segment. The connecting segment harbors a putative tyrosine activation motif in which tyrosines 1422 and 1440 are phosphorylated in response to alpha6beta4 binding to laminin-5. Primary beta4-null keratinocytes, obtained from a newborn suffering from lethal junctional epidermolysis bullosa, were stably transduced with retroviruses carrying a full-length beta4 cDNA or a beta4 cDNA with phenylalanine substitutions at Tyr-1422 and Tyr-1440. Hemidesmosome assembly was evaluated on organotypic skin cultures. beta4-corrected keratinocytes were indistinguishable from normal cells in terms of alpha6beta4 expression, the localization of hemidesmosome components, and hemidesmosome structure and density, suggesting full genetic and functional correction of beta4-null keratinocytes. In cultures generated from beta4(Y1422F/Y1440F) keratinocytes, beta4 mutants as well as alpha6 integrin, HD1/plectin, and BP180 were not concentrated at the dermal-epidermal junction. Furthermore, the number of hemidesmosomes was strikingly reduced as compared with beta4-corrected keratinocytes. The rare hemidesmosomes detected in beta4(Y1422F/Y1440F) cells were devoid of sub-basal dense plates and of inner cytoplasmic plaques with keratin filament insertion. Collectively, our data demonstrate that the beta4 tyrosine activation motif is not required for the localization of alpha6beta4 at the keratinocyte plasma membrane but is essential for optimal assembly of bona fide hemidesmosomes. |
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Authors:
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E Dellambra; S Prislei; A L Salvati; M L Madeddu; O Golisano; E Siviero; S Bondanza; S Cicuzza; A Orecchia; F G Giancotti; G Zambruno; M De Luca |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2001-08-24 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 276 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2001 Nov |
Date Detail:
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Created Date: 2001-10-29 Completed Date: 2001-12-07 Revised Date: 2012-02-22 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 41336-42 Citation Subset: IM |
Affiliation:
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Laboratory of Tissue Engineering, Istituto Dermopatico dell'Immacolata, 00167 Rome, Italy. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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3T3 Cells Animals Antigens, CD / chemistry, metabolism* Epidermolysis Bullosa, Junctional / genetics*, therapy Gene Therapy Hemidesmosomes / metabolism* Humans Immunohistochemistry In Situ Hybridization Infant, Newborn Integrin beta4 Keratinocytes / pathology* Mice Microscopy, Electron Stomach Diseases / genetics*, therapy Tyrosine / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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A.106//Telethon |
| Chemical | |
Reg. No./Substance:
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0/Antigens, CD; 0/Integrin beta4; 55520-40-6/Tyrosine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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