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

• Published in: The Journal of biological chemistry Vol. 279; no. 35; pp. 36579 - 36585
• Main Authors: Choi, Young-Ae, Lim, Hyung-Kyu, Kim, Jae-Ryong, Lee, Chu-Hee, Kim, Young-Jo, Kang, Shin-Sung, Baek, Suk-Hwan
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 27.08.2004
• Subjects: Amino Acid Chloromethyl Ketones - pharmacology; Animals; Apoptosis; Blotting, Western; Cell Membrane - metabolism; Cell Movement; DNA, Complementary - metabolism; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors - pharmacology; Fibroblasts - metabolism; Group IB Phospholipases A2; Macrolides - pharmacology; MAP Kinase Signaling System; Matrix Metalloproteinase 14; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinases, Membrane-Associated; Metalloendopeptidases - metabolism; Mice; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - metabolism; NIH 3T3 Cells; Phosphatidylinositol 3-Kinases - metabolism; Phospholipases A - metabolism; Phospholipases A - physiology; Phospholipases A2; Phosphorylation; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Time Factors; Tissue Inhibitor of Metalloproteinase-2 - metabolism; Transfection
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M314235200

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.