Document Detail

Gene correction of integrin beta4-dependent pyloric atresia-junctional epidermolysis bullosa keratinocytes establishes a role for beta4 tyrosines 1422 and 1440 in hemidesmosome assembly.
MedLine Citation:
PMID:  11522777     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2001-08-24
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  276     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2001 Nov 
Date Detail:
Created Date:  2001-10-29     Completed Date:  2001-12-07     Revised Date:  2012-02-22    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  41336-42     Citation Subset:  IM    
Laboratory of Tissue Engineering, Istituto Dermopatico dell'Immacolata, 00167 Rome, Italy.
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MeSH Terms
3T3 Cells
Antigens, CD / chemistry,  metabolism*
Epidermolysis Bullosa, Junctional / genetics*,  therapy
Gene Therapy
Hemidesmosomes / metabolism*
In Situ Hybridization
Infant, Newborn
Integrin beta4
Keratinocytes / pathology*
Microscopy, Electron
Stomach Diseases / genetics*,  therapy
Tyrosine / metabolism*
Grant Support
Reg. No./Substance:
0/Antigens, CD; 0/Integrin beta4; 55520-40-6/Tyrosine

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