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 language | English (US) |
|---|---|
| Pages (from-to) | 775-783 |
| Number of pages | 9 |
| Journal | Cancer Research |
| Volume | 66 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jan 15 2006 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
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Angiopoietin 2 induces glioma cell invasion by stimulating matrix metalloprotease 2 expression through the αvβ1 integrin and focal adhesion kinase signaling pathway. / Hu, Bo; Jarzynka, Michael J.; Guo, Ping; Imanishi, Yorihisha; Schlaepfer, David D.; Cheng, Shi Yuan.
In: Cancer Research, Vol. 66, No. 2, 15.01.2006, p. 775-783.Research output: Contribution to journal › Article
TY - JOUR
T1 - Angiopoietin 2 induces glioma cell invasion by stimulating matrix metalloprotease 2 expression through the αvβ1 integrin and focal adhesion kinase signaling pathway
AU - Hu, Bo
AU - Jarzynka, Michael J.
AU - Guo, Ping
AU - Imanishi, Yorihisha
AU - Schlaepfer, David D.
AU - Cheng, Shi Yuan
PY - 2006/1/15
Y1 - 2006/1/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=31544447172&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=31544447172&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-05-1149
DO - 10.1158/0008-5472.CAN-05-1149
M3 - Article
C2 - 16424009
AN - SCOPUS:31544447172
VL - 66
SP - 775
EP - 783
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 2
ER -