Angiopoietin 2 induces glioma cell invasion by stimulating matrix metalloprotease 2 expression through the alphavbeta1 integrin and focal adhesion kinase signaling pathway.
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.
Hu
Bo
B
University of Pittsburgh Cancer Institute, Research Pavilion at the Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA. hub@upmc.edu
Jarzynka
Michael J
MJ
Guo
Ping
P
Imanishi
Yorihisha
Y
Schlaepfer
David D
DD
Cheng
Shi-Yuan
SY
D042702:Angiopoietin-2 / Q000502:physiology*; D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology*; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000502:physiology; D005910:Glioma / Q000473:pathology*; D006801:Humans; D016023:Integrins / Q000502:physiology*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D019030:Receptors, Vitronectin / Q000502:physiology*; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D015854:Up-Regulation
D042702:Angiopoietin-2; D050719:Crk-Associated Substrate Protein; D016023:Integrins; D019030:Receptors, Vitronectin; C094340:integrin alphavbeta1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020778:Matrix Metalloproteinase 2