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J. Biol. Chem., Vol. 279, Issue 35, 36579-36585, August 27, 2004

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Group IB Secretory Phospholipase A₂ Promotes Matrix Metalloproteinase-2-mediated Cell Migration via the Phosphatidylinositol 3-Kinase and Akt Pathway^*

Young-Ae Choi, Hyung-Kyu Lim, Jae-Ryong Kim, Chu-Hee Lee, Young-Jo Kim¶, Shin-Sung Kang, and Suk-Hwan Baek||

From the Department of Biochemistry and Molecular Biology, the ^¶Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu 705-717 and the Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu 702-701, South Korea

Secretory phospholipase A₂ (sPLA₂), abundantly expressed in various cells including fibroblasts, is able to promote proliferation and migration. Degradation of collagenous extracellular matrix by matrix metalloproteinase (MMP) plays a role in the pathogenesis of various destructive disorders, such as rheumatoid arthritis, tumor invasion, and metastasis. Here we show that group IB PLA₂ increased pro-MMP-2 activation in NIH3T3 fibroblasts. MMP-2 activity was stimulated by group IB PLA₂ in a dose- and time-dependent manner. Consistent with MMP-2 activation, sPLA₂ decreased expression of type IV collagen. These effects are due to the reduction of tissue inhibitor of metalloproteinase-2 (TIMP-2) and the activation of the membrane type1-MMP (MT1-MMP). The decrease of TIMP-2 levels in conditioned media and the increase of MT1-MMP levels in plasma membrane were observed. In addition, treatment of cells with decanoyl Arg-Val-Lys-Arg-chloromethyl ketone, an inhibitor of pro-MT1-MMP, suppressed sPLA₂-mediated MMP-2 activation, whereas treatment with bafilomycin A1, an inhibitor of H⁺-ATPase, sustained MMP-2 activation by sPLA₂. The involvement of phosphatidylinositol 3-kinase (PI3K) and Akt in the regulation of MMP-2 activity was further suggested by the findings that PI3K and Akt were phosphorylated by sPLA₂. Expression of p85 and Akt mutants, or pretreatment of cells with LY294002, a PI3K inhibitor, attenuated sPLA₂-induced MMP-2 activation and migration. Taken together, these results suggest that sPLA₂ increases the pro-MMP-2 activation and migration of fibroblasts via the PI3K and Akt-dependent pathway. Because MMP-2 is an important factor directly involved in the control of cell migration and the turnover of extracellular matrix, our study may provide a mechanism for sPLA₂-promoted fibroblasts migration.

Received for publication, December 29, 2003 , and in revised form, June 18, 2004.

^* This work was supported by Korea Research Foundation Grant KRF-2002-041-C00232. 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.

^|| To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, 317-1 Daemyung 5-Dong, Nam-Gu, Daegu 705-717, South Korea. Tel.: 82-53-620-3981; Fax: 82-53-623-8032; E-mail: sbaek{at}med.yu.ac.kr.

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