Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production.
The Akt/protein kinase B (PKB) serine/threonine kinase is well known as an important mediator of many cell survival signaling pathways. Here, we demonstrate for the first time a major role of Akt/PKB in the cell invasion properties of the highly metastatic cell line HT1080. Using confocal microscopic analyses of live samples, we found Akt/PKB to be localized in the leading edge membrane area of migrating HT1080 cells. This localization was dependent on phosphoinositide 3-kinase and required the lipid binding ability of the phosphoinositide binding pleckstrin homology domain of Akt/PKB. We examined the possible function of Akt/PKB in HT1080 invasion. Surprisingly, Akt/PKB potently promoted HT1080 invasion, by increasing cell motility and matrix metalloproteinase-9 (MMP-9) production, in a manner highly dependent on its kinase activity and membrane-translocating ability. The increase in MMP-9 production was mediated by activation of nuclear factor-kappaB transcriptional activity by Akt/PKB. However, Akt/PKB did not affect the cell-cell or cell-matrix adhesion properties of HT1080. Our findings thus establish Akt/PKB as a major factor in the invasive abilities of cancer cells.
Kim
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National Creative Research Initiative Center for Cell Growth Regulation, Korea Advanced Institute of Science and Technology, 373-1 Kusong-Dong, Yusong, Taejon 305-701, Korea.
Kim
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Koh
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Yoon
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Chung
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Cho
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KS
Chung
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J
D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D004789:Enzyme Activation; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D020780:Matrix Metalloproteinase 9; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020830:rac1 GTP-Binding Protein; C494918:AKT1 protein, human