Angiopoietin 2 induces glioma cell invasion by stimulating matrix metalloprotease 2 expression through the αvβ1 integrin and focal adhesion kinase signaling pathway

Bo Hu*, Michael J. Jarzynka, Ping Guo, Yorihisha Imanishi, David D. Schlaepfer, Shi Yuan Cheng

*Corresponding author for this work

Research output: Contribution to journalArticle

128 Scopus citations

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 αvβ1 integrin in Tie2-deficient human glioma cells, activating focal adhesion kinase (FAK), p130Cas, extracellular signal-regulated protein kinase (ERK) 1/2, and c-jun NH2-terminal kinase (JNK) and substantially enhancing MMP-2 expression and secretion. The Ang2/ αvβ1 integrin signaling pathway was attenuated by functional inhibition of β1 and αv integrins, FAK, p130Cas, 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 αvβ1 integrin and glioma cell invasion through the FAK/ p130Cas/ERK1/2 and JNK-mediated signaling pathway.

Original languageEnglish (US)
Pages (from-to)775-783
Number of pages9
JournalCancer Research
Volume66
Issue number2
DOIs
StatePublished - Jan 15 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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