The integrin linked kinase (ILK) induces an invasive phenotype via AP-1 transcription factor-dependent upregulation of matrix metalloproteinase 9 (MMP-9)

Overexpression of Integrin Linked Kinase (ILK) in intestinal and mammary ep ithelial cells results in a highly invasive phenotype, associated with incr eased levels of expression of the matrix metalloproteinase MMP-9. This incr ease was at the transcriptional level as determined by MMP-9 promoter-CAT r eporter assays. Mutations in the two AP-1 binding sites within the MMP-9 pr omoter completely inhibited the reporter activity. We have previously shown that ILK inhibits glycogen synthase kinase-3 (GSK-3) activity, Transient t ransfection of wild-type GSK-3 beta in ILK-overexpressing cells decreased M MP-9 promoter activity and AP-I activity, indicating that ILK can stimulate MMP-9 expression via GSK-3 beta and AP-1 transcription factor, A small mol ecule inhibitor of the ILK kinase reduced the in vitro invasiveness of ILK- overexpressing cells as well as the invasiveness of several human brain tum or cell lines. Furthermore, both MMP-9 promoter and AP-1 activities mere in hibited by the ILK inhibitor. Invasiveness of ILK-overexpressing cells was also reduced by inhibition of MMP-9. These data demonstrate that ILK can in duce an invasive phenotype via AP-1-dependent upregulation of MMP-9.