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 epithelial cells results in a highly invasive phenotype, associated with increased levels of expression of the matrix metalloproteinase MMP-9. This increase was at the transcriptional level as determined by MMP-9 promoter-CAT reporter assays. Mutations in the two AP-1 binding sites within the MMP-9 promoter completely inhibited the reporter activity. We have previously shown that ILK inhibits glycogen synthase kinase-3 (GSK-3) activity. Transient transfection of wild-type GSK-3beta in ILK-overexpressing cells decreased MMP-9 promoter activity and AP-1 activity, indicating that ILK can stimulate MMP-9 expression via GSK-3beta and AP-1 transcription factor. A small molecule inhibitor of the ILK kinase reduced the in vitro invasiveness of ILK-overexpressing cells as well as the invasiveness of several human brain tumor cell lines. Furthermore, both MMP-9 promoter and AP-1 activities were inhibited by the ILK inhibitor. Invasiveness of ILK-overexpressing cells was also reduced by inhibition of MMP-9. These data demonstrate that ILK can induce an invasive phenotype via AP-1-dependent upregulation of MMP-9.
Troussard
A A
AA
BC Cancer Agency and Vancouver Hospital, Jack Bell Research Centre, Canada.
Costello
P
P
Yoganathan
T N
TN
Kumagai
S
S
Roskelley
C D
CD
Dedhar
S
S
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D015971:Gene Expression Regulation, Enzymologic; D005909:Glioblastoma / Q000201:enzymology; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D010641:Phenotype; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D015854:Up-Regulation / Q000502:physiology; D000099200:Scaffold Protein ILK
D020780:Matrix Metalloproteinase 9; D017346:Protein Serine-Threonine Kinases; D018808:Transcription Factor AP-1; D000099200:Scaffold Protein ILK