Journal of Biological Chemistry
Volume 279, Issue 35, 27 August 2004, Pages 36579-36585
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Mechanisms of Signal Transduction
Group IB Secretory Phospholipase A2 Promotes Matrix Metalloproteinase-2-mediated Cell Migration via the Phosphatidylinositol 3-Kinase and Akt Pathway*

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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 p85α 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.

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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.