BPAG1-e restricts keratinocyte migration through control of adhesion stability

Michael, Magdalene, Begum, Rumena, Fong, Kenneth, Pourreyrone, Celine, South, Andrew P., McGrath, John A. and Parsons, Maddy (2014) BPAG1-e restricts keratinocyte migration through control of adhesion stability. Journal of Investigative Dermatology, 134 3: 773-782. doi:10.1038/jid.2013.382


Author Michael, Magdalene
Begum, Rumena
Fong, Kenneth
Pourreyrone, Celine
South, Andrew P.
McGrath, John A.
Parsons, Maddy
Title BPAG1-e restricts keratinocyte migration through control of adhesion stability
Journal name Journal of Investigative Dermatology   Check publisher's open access policy
ISSN 0022-202X
1523-1747
Publication date 2014-03-01
Year available 2013
Sub-type Article (original research)
DOI 10.1038/jid.2013.382
Open Access Status Not yet assessed
Volume 134
Issue 3
Start page 773
End page 782
Total pages 10
Place of publication London, United Kingdom
Publisher Nature
Language eng
Abstract Bullous pemphigoid antigen 1 (BPAG1-e, also known as BP230) is a member of the plakin family of hemidesmosome cytoskeletal linker proteins that is encoded by an isoform of the dystonin (DST) gene. Recently, we reported two unrelated families with homozygous nonsense mutations in this DST isoform that led to ultrastructural loss of hemidesmosomal inner plaques and clinical features of trauma-induced skin fragility. We now demonstrate that keratinocytes isolated from these individuals have significant defects in adhesion, as well as increased cell spreading and migration. These mutant keratinocytes also display reduced levels of β4 integrins at the cell surface but increased total protein levels of keratin-14 and β1 integrins. These alterations in cell behavior and protein expression were not seen in control keratinocytes in which BPAG1-e expression had been silenced by stable expression of short hairpin RNA to target DST. The failure of knockdown approaches to recapitulate the changes in morphology, adhesion, and migration seen in patient cells therefore suggests such approaches are not appropriate to study loss of this protein in vivo. The contrasting findings in keratinocytes harboring naturally occurring mutations, however, demonstrate a previously unappreciated key role for BPAG1-e in regulating keratinocyte adhesion and migration and suggest a requirement for this protein in controlling functional switching between integrin types in epithelial cells.
Formatted abstract
Bullous pemphigoid antigen 1 (BPAG1-e, also known as BP230) is a member of the plakin family of hemidesmosome cytoskeletal linker proteins that is encoded by an isoform of the dystonin (DST) gene. Recently, we reported two unrelated families with homozygous nonsense mutations in this DST isoform that led to ultrastructural loss of hemidesmosomal inner plaques and clinical features of trauma-induced skin fragility. We now demonstrate that keratinocytes isolated from these individuals have significant defects in adhesion, as well as increased cell spreading and migration. These mutant keratinocytes also display reduced levels of β4 integrins at the cell surface but increased total protein levels of keratin-14 and β1 integrins. These alterations in cell behavior and protein expression were not seen in control keratinocytes in which BPAG1-e expression had been silenced by stable expression of short hairpin RNA to target DST. The failure of knockdown approaches to recapitulate the changes in morphology, adhesion, and migration seen in patient cells therefore suggests such approaches are not appropriate to study loss of this protein in vivo. The contrasting findings in keratinocytes harboring naturally occurring mutations, however, demonstrate a previously unappreciated key role for BPAG1-e in regulating keratinocyte adhesion and migration and suggest a requirement for this protein in controlling functional switching between integrin types in epithelial cells.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
Institute for Molecular Bioscience - Publications
 
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