Axl promotes cell invasion by inducing MMP-9 activity through activation of NF-kappaB and Brg-1.

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.

• 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)

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

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