Angiopoietin 2 induces glioma cell invasion by stimulating matrix metalloprotease 2 expression through the alphavbeta1 integrin and focal adhesion kinase signaling pathway.

Abstract

Accumulating evidence reveals a significant correlation between angiopoietin 2 (Ang2) expression and tumor invasion and metastasis in various human cancers, but the major focus of recent studies has been on the angiogenic effects of Ang2. We recently reported that Ang2-stimulated glioma cell invasion results from the up-regulation and activation of matrix metalloprotease 2 (MMP-2) in tumor cells. In this study, we identify a novel mechanism by which Ang2 stimulates MMP-2 expression leading to glioma cell invasion. We show that Ang2 interacts with alpha(v)beta(1) integrin in Tie2-deficient human glioma cells, activating focal adhesion kinase (FAK), p130(Cas), extracellular signal-regulated protein kinase (ERK) 1/2, and c-jun NH(2)-terminal kinase (JNK) and substantially enhancing MMP-2 expression and secretion. The Ang2/alpha(v)beta(1) integrin signaling pathway was attenuated by functional inhibition of beta(1) and alpha(v) integrins, FAK, p130(Cas), ERK1/2, and JNK. Furthermore, expression of a negative regulator of FAK, FAK-related nonkinase, by U87MG/Ang2-expressing glioma xenografts suppressed Ang2-induced MMP-2 expression and glioma cell infiltration in the murine brain. These data establish a functional link between Ang2 interaction with alpha(v)beta(1) integrin and glioma cell invasion through the FAK/p130(Cas)/ERK1/2 and JNK-mediated signaling pathway.

• Authors: Bo Hu, Michael J Jarzynka, Ping Guo, Yorihisha Imanishi, David D Schlaepfer, Shi-Yuan Cheng
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 2 Pg. 775-83 (Jan 15 2006) ISSN: 0008-5472 [Print] United States
• PMID: 16424009 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiopoietin-2
• Crk-Associated Substrate Protein
• Integrins
• Receptors, Vitronectin
• integrin alphavbeta1
• Focal Adhesion Protein-Tyrosine Kinases
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Matrix Metalloproteinase 2

Topics

• Angiopoietin-2 (physiology)
• Animals
• Brain Neoplasms (pathology)
• Crk-Associated Substrate Protein (metabolism)
• Focal Adhesion Protein-Tyrosine Kinases (physiology)
• Glioma (pathology)
• Humans
• Integrins (physiology)
• Matrix Metalloproteinase 2 (biosynthesis)
• Mice
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Neoplasm Invasiveness
• Receptors, Vitronectin (physiology)
• Signal Transduction
• Transplantation, Heterologous
• Up-Regulation