Uncovering functional differences between kindlin-1 and kindlin-2 in keratinocytes

Abstract

Integrin β1-null keratinocytes can adhere to fibronectin via αvβ6, but form large peripheral focal adhesions and exhibit defective cell spreading. Here we report that, in addition to the reduced avidity of αvβ6 to fibronectin, the inability of integrin β6 to efficiently bind and recruit kindlin-2 to focal adhesions directly contributes to these phenotypes. Kindlins regulate integrins through direct interactions with the integrin β cytoplasmic tail and keratinocytes express kindlin-1 and kindlin-2. Notably, while both localize to focal adhesions in wild-type cells, only kindlin-1 localizes to the β6-rich adhesions of β1-null cells. Rescue of β1-null cells with wild-type and chimeric integrin constructs revealed a correlation between kindlin-2 recruitment and cell spreading. Furthermore, despite the presence of kindlin-1, kindlin-2 knockdown in wild-type keratinocytes impaired cell spreading. Our data reveal unexpected functional consequences of differences in the association of two homologous kindlin isoforms with two closely related integrins and suggest that despite their similarities different kindlins are likely to have specific unique functions.