MMP9 cleavage of the ß4 integrin ectodomain leads to recurrent epithelial erosions in mice.
J Cell Sci
; 124(Pt 15): 2666-75, 2011 Aug 01.
Article
em En
| MEDLINE
| ID: mdl-21750188
ABSTRACT
Integrin α6ß4 is an integral membrane protein within hemidesmosomes and it mediates adhesion of epithelial cells to their underlying basement membrane. During wound healing, disassembly of hemidesmosomes must occur for sheet movement-mediated cell migration. The mechanisms of disassembly and reassembly of hemidesmosomes are not fully understood. The current study was initiated to understand the underlying cause of recurrent corneal erosions in the mouse. Here, we show that in vivo (1) MMP9 levels are elevated and ß4 integrin is partially cleaved in epithelial cell extracts derived from debridement wounded corneas; (2) the ß4 ectodomain is missing from sites where erosions develop; and (3) ß4 cleavage can be reduced by inhibiting MMP activity. Although ß4, α3 and ß1 integrins were all cleaved by several MMPs, only MMP9 was elevated in cell extracts derived from corneas with erosions. Coimmunoprecipitation studies showed that ß4 integrin associates with MMP9, and protein clustering during immunoprecipitation induced proteolytic cleavage of the ß4 integrin extracellular domain, generating a 100 kDa ß4 integrin cytoplasmic domain fragment. Confocal imaging with three-dimensional reconstruction showed that MMP9 localizes at erosion sites in vivo where the ectodomain of ß4 integrin is reduced or absent. MMP activation experiments using cultured corneal and epidermal keratinocytes showed reduced levels of α6ß4 and ß1 integrins within 20 minutes of phorbol ester treatment. This report is the first to show that ß4 integrin associates with MMP9 and that its ectodomain is a target for cleavage by MMP9 in vivo under pathological conditions.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Epitélio Corneano
/
Metaloproteinase 9 da Matriz
/
Integrina beta4
Limite:
Animals
Idioma:
En
Revista:
J Cell Sci
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Estados Unidos