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

Oncogene. 2008 Jul 3;27(29):4044-55. doi: 10.1038/onc.2008.57. Epub 2008 Mar 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Active Transport, Cell Nucleus / genetics
  • Cell Line, Tumor
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • DNA Helicases / genetics
  • DNA Helicases / metabolism*
  • Enzyme Induction / drug effects
  • Enzyme Induction / genetics
  • Enzyme Inhibitors / pharmacology
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • MAP Kinase Kinase 1 / antagonists & inhibitors
  • MAP Kinase Kinase 1 / genetics
  • MAP Kinase Kinase 1 / metabolism
  • MAP Kinase Kinase 2 / antagonists & inhibitors
  • MAP Kinase Kinase 2 / genetics
  • MAP Kinase Kinase 2 / metabolism
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / genetics
  • Matrix Metalloproteinase 9 / biosynthesis*
  • Matrix Metalloproteinase 9 / genetics
  • Mutation
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Neoplasm Invasiveness
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Binding / drug effects
  • Protein Binding / genetics
  • Proto-Oncogene Proteins
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic* / drug effects
  • Transcription, Genetic* / genetics

Substances

  • 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
  • axl receptor tyrosine kinase
  • I-kappa B Kinase
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • MAP2K1 protein, human
  • Matrix Metalloproteinase 9
  • SMARCA4 protein, human
  • DNA Helicases