Abstract |
Activity of the Axl receptor tyrosine kinase is positively correlated with tumor metastasis; however, its detailed role in the mechanism of tumor invasion is still not completely understood. Here, we show that Axl enhances the expression of matrix metalloproteinase 9 (MMP-9), required for Axl-mediated invasion both in vitro and in vivo. We found that the highly selective MEK1/2 inhibitors U0126 and PD98059, and the expressed dominant-negative form of extracellular signal-regulated kinase (ERK), completely block Axl-mediated MMP-9 activation. In contrast, the phosphatidylinositol 3-kinase inhibitor LY294002 and wortmannin had little effect on activation. Interestingly, however, the Axl ligand Gas6 is not involved in Axl-mediated MMP-9 activation. Mutation of Glu59(Axl) and Thr77(Axl) dramatically reduced Gas6-Axl binding but continued to induce MMP-9 activation. In addition, overexpression of Axl-activated ERK and enhanced nuclear factor-kappaB ( NF-kappaB) transactivation and brahma-related gene-1 (Brg-1) translocation. Exposure to the NF-kappaB inhibitor silibinin, which inhibits IkappaBalpha kinase activity, or overexpression of the dominant-negative mutant IkappaB and Brg-1 strikingly inhibited Axl-mediated MMP-9 activation. These data indicate that coordination of ERK signaling and NF-kappaB and Brg-1 activation are indispensable to regulation of Axl-dependent MMP-9 gene transcription. Together with previous data, our results provide a plausible mechanism for Axl-mediated tumor invasion and establish a functional link between the Axl and MMP-9 signaling pathways.
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Authors | K-Y Tai, Y-S Shieh, C-S Lee, S-G Shiah, C-W Wu |
Journal | Oncogene
(Oncogene)
Vol. 27
Issue 29
Pg. 4044-55
(Jul 03 2008)
ISSN: 1476-5594 [Electronic] England |
PMID | 18345028
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Enzyme Inhibitors
- Intercellular Signaling Peptides and Proteins
- NF-kappa B
- Nuclear Proteins
- Oncogene Proteins
- Phosphoinositide-3 Kinase Inhibitors
- Proto-Oncogene Proteins
- Transcription Factors
- growth arrest-specific protein 6
- MAP2K2 protein, human
- Receptor Protein-Tyrosine Kinases
- I-kappa B Kinase
- MAP Kinase Kinase 1
- MAP Kinase Kinase 2
- MAP2K1 protein, human
- Matrix Metalloproteinase 9
- SMARCA4 protein, human
- DNA Helicases
- Axl Receptor Tyrosine Kinase
- AXL protein, human
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Topics |
- Active Transport, Cell Nucleus
(drug effects, genetics)
- Cell Line, Tumor
- Cell Nucleus
(genetics, metabolism)
- DNA Helicases
(genetics, metabolism)
- Enzyme Induction
(drug effects, genetics)
- Enzyme Inhibitors
(pharmacology)
- Humans
- I-kappa B Kinase
(antagonists & inhibitors, genetics, metabolism)
- Intercellular Signaling Peptides and Proteins
(genetics, metabolism)
- MAP Kinase Kinase 1
(antagonists & inhibitors, genetics, metabolism)
- MAP Kinase Kinase 2
(antagonists & inhibitors, genetics, metabolism)
- MAP Kinase Signaling System
(drug effects, genetics)
- Matrix Metalloproteinase 9
(biosynthesis, genetics)
- Mutation
- NF-kappa B
(genetics, metabolism)
- Neoplasm Invasiveness
- Nuclear Proteins
(genetics, metabolism)
- Oncogene Proteins
(genetics, metabolism)
- Phosphatidylinositol 3-Kinases
(genetics, metabolism)
- Phosphoinositide-3 Kinase Inhibitors
- Protein Binding
(drug effects, genetics)
- Proto-Oncogene Proteins
- Receptor Protein-Tyrosine Kinases
(genetics, metabolism)
- Transcription Factors
(genetics, metabolism)
- Transcription, Genetic
(drug effects, genetics)
- Axl Receptor Tyrosine Kinase
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