Group IB Secretory Phospholipase A2 Promotes Matrix Metalloproteinase-2-mediated Cell Migration via the Phosphatidylinositol 3-Kinase and Akt Pathway
Secretory phospholipase A 2 (sPLA 2 ), 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, suc...
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Published in | The Journal of biological chemistry Vol. 279; no. 35; pp. 36579 - 36585 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Biochemistry and Molecular Biology
27.08.2004
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Subjects | |
Online Access | Get full text |
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Summary: | Secretory phospholipase A 2 (sPLA 2 ), 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 PLA 2 increased pro-MMP-2 activation in NIH3T3 fibroblasts. MMP-2 activity was stimulated by group IB PLA 2 in a dose- and time-dependent manner. Consistent with MMP-2 activation, sPLA 2 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 sPLA 2 -mediated MMP-2 activation, whereas treatment with bafilomycin A1, an inhibitor of H + -ATPase, sustained MMP-2 activation by sPLA 2 . 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 sPLA 2 . Expression of p85α and Akt mutants, or pretreatment of cells with LY294002, a PI3K inhibitor, attenuated sPLA 2 -induced MMP-2 activation and migration. Taken together, these results suggest that sPLA 2 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 sPLA 2 -promoted fibroblasts migration. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M314235200 |