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J. Biol. Chem., Vol. 282, Issue 42, 30485-30496, October 19, 2007

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Nerve Growth Factor Induces Endothelial Cell Invasion and Cord Formation by Promoting Matrix Metalloproteinase-2 Expression through the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway and AP-2 Transcription Factor^*

Myung-Jin Park¹, Hee-Jin Kwak¹, Hyung-Chahn Lee, Doo-Hyun Yoo, In-Chul Park, Mi-Suk Kim, Seung-Hoon Lee, Chang Hun Rhee^¶, and Seok-Il Hong^||2

From the Laboratory of Functional Genomics, ^¶Department of Neurosurgery, and ^||Laboratory of Medicine and Clinical Pathology, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-706 and Research Institute and Hospital, National Cancer Center, 809 Madu-dong, Ilsan-gu, Goyang, Gyeonggi 411-764, Korea

Nerve growth factor (NGF) is a well characterized neurotrophic agonist in the nervous system that triggers angiogenesis. In this study, we investigated the signaling mechanisms involved in NGF-induced angiogenesis. NGF stimulated endothelial cell invasion and cord formation on Matrigel in vitro but had marginal effect on proliferation and migration of these cells. NGF stimulated matrix metalloproteinase (MMP)-2 mRNA expression and protein secretion in human umbilical vein endothelial cells. Using synthetic and endogenous inhibitors of MMP-2 and MMP-2 small interfering RNA suppressed NGF-induced invasion and cord formation. We demonstrated that NGF-induced MMP-2 secretion, invasion, and cord formation are regulated via activation of the NGF receptor, TrkA, phosphatidylinositol 3-kinase (PI3K), and Akt using various pharmacological inhibitors. Specifically, NGF enhanced TrkA phosphorylation, PI3K activity, and Akt phosphorylation. Introduction of NGF-neutralizing antibodies, dominant-negative Akt, or wild-type PTEN effectively inhibited NGF-induced MMP-2 secretion and cord formation. Deletion and site-directed mutagenesis analysis of the MMP-2 promoter demonstrated that the AP-2-binding site is critical for NGF-induced MMP-2 promoter activity. NGF increased the DNA binding activity of AP-2, which was suppressed by inhibitors of TrkA and PI3K. Furthermore, transfection of AP-2 small interfering RNA effectively blocked NGF-induced MMP-2 secretion and cord formation. Finally, NGF promoted neovessel formation in Matrigel plugs in vivo, which was significantly inhibited by K252a and LY294002, but it failed to promote angiogenesis using MMP-2 knock-out mice. Our data collectively suggest that NGF stimulates endothelial cell invasion and cord formation by augmenting MMP-2 via the PI3K/Akt signaling pathway and AP-2 transcription factor, which may be responsible for triggering angiogenesis.

Received for publication, February 5, 2007 , and in revised form, July 6, 2007.

^* This work was supported by the National Nuclear R&D Program of Ministry of Science and Technology, Seoul, Korea. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–3.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 82-2-970-1260; Fax: 82-2-970-2402; E-mail: hongsicp{at}kcch.re.kr.

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