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. 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. Controlled degradation of extracellular matrix (ECM) 1The abbreviations used are: ECM, extracellular matrix; PLA2, phospholipase A2; sPLA2, secretory phospholipase A2; sPLA2R, secretory phospholipase A2 receptor; MMP, matrix metalloproteinase; PI3K, phosphatidylinositol 3-kinase; TIMP-2, tissue inhibitor of metalloproteinase-2; MT1, membrane type 1; Ab, antibody; ELISA, enzyme-linked immunosorbent assay; FCS, fetal calf serum; dec, decanoyl; cmk, chloromethyl ketone; ERK, extracellular signal-regulated kinase; DN, dominant negative; MAPK, mitogen-activated protein kinase.1The abbreviations used are: ECM, extracellular matrix; PLA2, phospholipase A2; sPLA2, secretory phospholipase A2; sPLA2R, secretory phospholipase A2 receptor; MMP, matrix metalloproteinase; PI3K, phosphatidylinositol 3-kinase; TIMP-2, tissue inhibitor of metalloproteinase-2; MT1, membrane type 1; Ab, antibody; ELISA, enzyme-linked immunosorbent assay; FCS, fetal calf serum; dec, decanoyl; cmk, chloromethyl ketone; ERK, extracellular signal-regulated kinase; DN, dominant negative; MAPK, mitogen-activated protein kinase. is essential in physiologic situations involving connective tissue remodeling. Nevertheless, excessive breakdown of connective tissue plays an important role in pathogenesis, e.g. chronic inflammatory processes and malignancy (1Birkedal-Hansen H. Curr. Opin. Cell Biol. 1995; 7: 728-735Crossref PubMed Scopus (973) Google Scholar, 2Chang C. Werb Z. Trends Cell Biol. 2001; 11: 37-43Abstract Full Text Full Text PDF PubMed Scopus (620) Google Scholar). The regulation of matrix metalloproteinases (MMPs) occurs on different levels, including gene expression, processing of the inactive proenzymes, and by inhibition of the active enzymes by their endogenous inhibitors delineated as tissue inhibitors of metalloproteinases (TIMPs). MMPs are important breakdown enzymes of ECM components such as collagen. These enzymes consist of gelatinases, collagenases, stromelysins, and membrane-type MMPs. MMPs are synthesized as preproenzymes, and most of them are secreted from the cells as proenzymes. Among them, MMP-2 is thought to be one of the key enzymes for degrading collagen, which is a major component of basement membranes (3McCawley L.J. Matrisian L.M. Mol. Med. Today. 2000; 6: 149-156Abstract Full Text Full Text PDF PubMed Scopus (575) Google Scholar, 4Sternlicht M.D. Werb Z. Annu. Rev. Cell Dev. Biol. 2001; 17: 463-516Crossref PubMed Scopus (3170) Google Scholar). MMP-2 is abundantly expressed in various tissues and cell types including fibroblasts (5Brooks P.C. Stromblad S. Sanders L.C. von Schalscha T.L. Aimes R.T. Stetler-Stevenson W.G. Quigley J.P. Cheresh D.A. Cell. 1996; 85: 683-693Abstract Full Text Full Text PDF PubMed Scopus (1418) Google Scholar). Transient fibroblast activation is probably regulated by a variety of mediators produced by infiltrating platelets, monocytes, and other inflammatory cells (6Ihn H. Tamaki K.J. J. Immunol. 2000; 165: 2149-2155Crossref PubMed Scopus (63) Google Scholar, 7Ihn H. Yamane K. Asano Y. Kubo M. Tamaki K. J. Immunol. 2002; 168: 1895-1902Crossref PubMed Scopus (84) Google Scholar). Numerous in vitro and in vivo studies have suggested that some cytokines and growth factors regulate fibroblast proliferation and ECM deposition (6Ihn H. Tamaki K.J. J. Immunol. 2000; 165: 2149-2155Crossref PubMed Scopus (63) Google Scholar, 7Ihn H. Yamane K. Asano Y. Kubo M. Tamaki K. J. Immunol. 2002; 168: 1895-1902Crossref PubMed Scopus (84) Google Scholar, 8Medrano E.E. Oncogene. 2003; 22: 3123-3129Crossref PubMed Scopus (74) Google Scholar). Phospholipase A2 (PLA2) catalyzes the hydrolysis of the sn-2 ester bond in phospholipids as they generate free fatty acids, such as arachidonic acid (9Balsinde J. Winstead M.V. Dennis E.A. FEBS Lett. 2002; 531: 2-6Crossref PubMed Scopus (398) Google Scholar, 10Murakami M. Nakatani Y. Atsumi G. Inoue K. Kudo I. Crit. Rev. Immunol. 1997; 17: 225-283Crossref PubMed Google Scholar). Arachidonic acid is the key substrate for the synthesis of potent lipid mediators of inflammation. Several mammalian secretory PLA2s (sPLA2s) have been characterized and classified into different families (11Hurt-Camejo E. Camejo G. Peilot H. Oorni K. Kovanen P. Circ. Res. 2001; 89: 298-304Crossref PubMed Scopus (198) Google Scholar). At present, 12 distinct sPLA2s have been identified in mammals and classified into different groups, depending on their primary structures as characterized by the number and position of cysteine residues. Initially, sPLA2s were thought to carry out digestive functions. However, the recent reports of a class of high affinity cell surface PLA2 receptors and the delineation of novel receptor-mediated biological effects have changed this notion (12Lambeau G. Lazdunski M. Trends Pharmacol. Sci. 1999; 20: 162-170Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar, 13Cupillard L. Mulherkar R. Gomez N. Kadam S. Valentin E. Lazdunski M. Lambeau G. J. Biol. Chem. 1999; 274: 7043-7051Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar). PLA2 has been implicated in a wide range of cellular responses, including cell proliferation, signal transduction, host defense, chemokinesis, and membrane remodeling (14Kundu G.C. Mukherjee A.B. J. Biol. Chem. 1997; 272: 2346-2353Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 15Yuan C.J. Mandal A.K. Zhang Z. Mukherjee A.B. Cancer Res. 2000; 60: 1084-1091PubMed Google Scholar, 16Attiga F.A. Fernandez P.M. Weeraratna A.T. Manyak M.J. Patierno S.R. Cancer Res. 2000; 60: 4629-4637PubMed Google Scholar). In addition to an extensive understanding of its action in phospholipid hydrolysis, a role for sPLA2 has been suggested in the remodeling of ECM, although little evidence for such involvement has yet been published (14Kundu G.C. Mukherjee A.B. J. Biol. Chem. 1997; 272: 2346-2353Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). A previous study reported that porcine pancreatic PLA2 promotes cell migration and ECM invasion via its high affinity receptor (14Kundu G.C. Mukherjee A.B. J. Biol. Chem. 1997; 272: 2346-2353Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). Attiga et al. (16Attiga F.A. Fernandez P.M. Weeraratna A.T. Manyak M.J. Patierno S.R. Cancer Res. 2000; 60: 4629-4637PubMed Google Scholar) showed that the sPLA2 inhibitor p-bromophenacyl bromide could reduce the pro-MMP-2 and active MMP-2 from prostate cancer cells. All these results support the possible role of sPLA2 as a factor in MMP activation. However, the mechanism for this MMP-2 activation, including related TIMP in fibroblast, is not clear. Moreover, the intracellular signaling pathway that regulates MMP-2 expression has not been characterized. To investigate the role of group IB PLA2 on MMP-2 activation in fibroblasts, we established an MMP-2 activation profile by using the mouse fibroblast cell line NIH3T3. In this study, we found that group IB PLA2 increases the activity of MMP-2 in cell conditioned medium and that this increase is the result of a decreased level of TIMP-2 protein and an increased level of MT1-MMP activity. Moreover, the sPLA2 regulation of MMP-2 seems to be mediated by PI3K and Akt. Because group IB PLA2 is involved in promoting NIH3T3 migration, our results suggest that sPLA2-promoted cell migration is mediated by MMP-2. Materials—Group IB PLA2, gelatin, and bafilomycin A1 were purchased from Sigma; the ECL reagent was from PerkinElmer Life Sciences; RPMI 1640, LipofectAMINE 2000, and Opti-MEM were from Invitrogen; the MMP-2 ELISA kit was from R & D Systems (Minneapolis, MN); FCS was from Hyclone (Logan, UT); mouse polyclonal MMP-2, TIMP-2, type IV collagen, p85α subunit antibodies, and the horseradish peroxidase-conjugated secondary were from the MT1-MMP was from the was from the inhibitor decanoyl Arg-Val-Lys-Arg-chloromethyl was from and was from The was in to to the cell The were or and these on cell Cell NIH3T3 mouse fibroblast cell line was from the were in medium with and The cells were in and were were in a and stimulated in the of group IB PLA2, with or for various from a to activity was by using as a The conditioned medium was with in the of and in the were with in and in a in and The were for with in acid and and for using an of and of activity as PI3K and Akt cells were in and they were for and with or group IB PLA2 for the were in and inhibitor PI3K of protein was with for and with protein for in the were by and to for by using PI3K Akt was using for the of Akt. of Akt and were into the mammalian expression type and of p85α of were by LipofectAMINE reagent was used to PI3K or Akt into NIH3T3 to the of the was with of LipofectAMINE in of Opti-MEM medium for and to the which to in the for the medium was with To the cells with the were by in a medium in a The was for and a were and the expression was by using its protein as by of of plasma the cells were and in inhibitor and to of in were for and the and were from the by The was for The membrane was in and inhibitor for were by for and to for MT1-MMP cells were with group IB PLA2 for the and The cells were with and Cell were in and inhibitor and the was by and the was as a The protein was by and in and to a which was with in and and with the for The membrane was and for with secondary to horseradish and using an ECL Cell of sPLA2 on cell migration was by using a cell C. M. C. G. C. L. P. P. J. Cell Sci. 2001; PubMed Google Scholar). NIH3T3 cells were and in a a The cells were with media and for an 12 was and the media were to medium group IB In the sPLA2 of migration was by the PI3K inhibitor To the the was 12 for the and the of cells a line was of MMP-2 by IB PLA2 in NIH3T3 we to the of group IB PLA2 on MMP and activation in fibroblasts. MMP activity was in the conditioned medium by using To investigate the effects of sPLA2 on the of MMP-2 and activation, was with mouse fibroblast NIH3T3 cells. The results a to the treatment and sPLA2 stimulated MMP-2 activity in a by and further was with of further the protein levels of MMP-2 and found that was of MMP-2 protein by ELISA of the was by in these However, was not these and further studies on were To the MMP-2 activity was with expression, were by using an type IV collagen. The expression was out by the NIH3T3 cells with sPLA2. the of expression as a of cell treatment with of sPLA2. The decrease of expression by sPLA2 is and an sPLA2 of of TIMP-2 and MT1-MMP in the sPLA2-induced MMP-2 that the sPLA2-mediated MMP-2 activation in cells may be the regulation of TIMP and The was has been that TIMP-2 a with pro-MMP-2 their M. Z. H. S. S. R. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). To this we TIMP-2 The conditioned medium from NIH3T3 cells stimulated by sPLA2 was by with TIMP-2 protein was expressed this protein level was decreased by sPLA2 in a the of TIMP-2 on the activation of pro-MMP-2 by sPLA2. were with sPLA2 and TIMP-2 of pro-MMP-2 by sPLA2 was not in the of TIMP-2 MT1-MMP is a MMP to and pro-MMP-2 the cell surface M. Curr. Opin. Cell Biol. 2002; PubMed Scopus Google Scholar). To the of MT1-MMP activation in sPLA2 we plasma membrane treatment of sPLA2, and we The active of MT1-MMP protein was increased by sPLA2 treatment in a To investigate the involvement of MT1-MMP in pro-MMP-2 activation, cells were with a inhibitor which has been to activation of M. Curr. Opin. Cell Biol. 2002; PubMed Scopus Google Scholar, M. N. Y. Sci. 1999; PubMed Scopus Google Scholar, E.A. M.J. Cancer Res. 2003; Google Scholar). of cells with sPLA2-mediated MMP-2 activation, MT1-MMP in the sPLA2-induced pro-MMP-2 activation A previous E. K. J. 2003; PubMed Scopus Google Scholar) showed that the activity of MT1-MMP on the cell surface is regulated a degradation To or not the sPLA2-induced MMP-2 activation MT1-MMP activation, the inhibitor bafilomycin A1 was were in sPLA2 for in various of bafilomycin A1, and the conditioned media were and for MMP-2 activity by and in bafilomycin A1 the sPLA2-induced pro-MMP-2 pro-MMP-2 activation the cells were with the of sPLA2 for The plasma membranes were from and to with MT1-MMP The are of the cells were on to and with sPLA2 with the of the cells were and for an with sPLA2 with the of bafilomycin The conditioned media were and for MMP activity by was with The are of MMP-2 by sPLA2 the PI3K and Akt the has been suggested that PI3K plays a role in activation and cell migration in various cells K. Rev. Immunol. 2003; PubMed Scopus Google Scholar). To investigate the role of in MMP-2 cells were for activation of PI3K and Akt. cells were to sPLA2 for different and protein were by with for PI3K activity or by with for Akt activity. of PI3K by sPLA2 whereas that of Akt to and and to the level A and To into the mechanism of to pro-MMP-2 activation, cells were to sPLA2 or in with the PI3K inhibitor in suppressed the sPLA2-induced pro-MMP-2 activation. To the sPLA2 signal was on PI3K, cells were with type p85α or the of p85α NIH3T3 cells with type p85α or were to sPLA2, and conditioned medium from these cells was in to MMP-2 activity. of type p85α and was by of in of sPLA2 Moreover, the of type p85α in an increase of MMP-2 activity by sPLA2 we the of expression of type or on the MMP-2 activation by sPLA2. The of the was to sPLA2-induced MMP-2 activation, whereas the of type Akt sPLA2-induced MMP-2 activation and Akt are to sPLA2-induced pro-MMP-2 activation. cells were and for an with sPLA2 with the of The conditioned media were and for MMP activity by and cells were with a control type or were with a control type or were stimulated with sPLA2 for and were was by using or Akt The conditioned media were and for MMP activity by The are of Because the activation of extracellular signal-regulated is to sPLA2-induced cell proliferation, we were in the role of in the of pro-MMP-2 activity. cells were to sPLA2 for different and protein were by with of and and In addition, sPLA2 stimulated of a to the of the activation To into the mechanism of sPLA2 signaling to pro-MMP-2 activation, cells were to sPLA2 or in with The results of that of them on the sPLA2-induced MMP activation These results suggested that sPLA2 the the to sPLA2 Cell via a and Akt-dependent of fibroblasts is their migration into of and remodeling. migration, fibroblasts the basement in type IV M. Cancer Res. 2001; Google Scholar, Cancer Res. Google which is the substrate for MMP-2. To the of sPLA2-induced MMP-2 activation, the of sPLA2 on NIH3T3 cell migration was was by using an in vitro cell in which cells are high in a in the of a and to sPLA2 Cell migration was increased in a dose- and time-dependent results have suggested that active MMP-2 cell migration (14Kundu G.C. Mukherjee A.B. J. Biol. Chem. 1997; 272: 2346-2353Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). our results have to that PI3K and Akt are able to regulate the of migration MMP-2, and we to investigate the that PI3K could the of cell migration. To migration was PI3K and the inhibitor was which cell migration To the cell migration was on PI3K and cells were with type or dominant of p85α and Akt. of the or was to sPLA2-induced cell migration, whereas of type p85α or Akt sPLA2-induced cell migration These suggest that the PI3K and Akt pathway is able to regulate the of MMP-2 and fibroblast migration. IB PLA2 has been identified as a for fibroblasts, and cells N. Werb Z. J. Cell Sci. 2002; PubMed Scopus Google Scholar). The effects of sPLA2 are in a variety including NIH3T3 cells K. H. J. Biol. Chem. Full Text PDF PubMed Google Scholar). In addition, a previous study showed that fibroblast cell proliferation and migration were stimulated by group IB PLA2 treatment (14Kundu G.C. Mukherjee A.B. J. Biol. Chem. 1997; 272: 2346-2353Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, L. M. Circ. Res. 2002; PubMed Scopus Google and the suggested the role of sPLA2 in MMP However, the biological of sPLA2 is not clear. In the study, we that the of the active of MMP-2 group IB PLA2 treatment is in with the reduction of TIMP-2 and we that of the MMP-2 activity not the increased of the The of in the MMP-2 protein that these not to the processing of pro-MMP-2 sPLA2 pro-MMP-2 activation was with an MT1-MMP and TIMP-2 showed that sPLA2 a of TIMP-2 levels in A has been reported in other or MMP-2 activation in or cells is with TIMP-2 expression J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). found that MT1-MMP is to the activation of pro-MMP-2 by MT1-MMP activation or and bafilomycin A1 MT1-MMP activity is regulated by is by I. Mol. Biol. Cell. 2003; 7: Scholar, E. E. C. G. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). MT1-MMP be by the TIMP-2 is the major inhibitor of MT1-MMP I. Mol. Biol. Cell. 2003; 7: in the activation of MMP-2 by the of pro-MMP-2 to MT1-MMP the of a S. M. M. Y. R. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, R. J. 2003; PubMed Scopus Google Scholar). is established that of intracellular plays an important role in membrane protein and degradation M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). is by H+-ATPase, which be by bafilomycin A1 K. Sci. S. 85: PubMed Scopus Google Scholar). A1 promotes the sPLA2-induced pro-MMP-2 activation, that inhibition of the degradation of MT1-MMP and increases its activity the cell an essential role in the and their primary to tissue ECM is in due to changed of growth factors and cytokines J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, R. I. M. G. Sci. 2003; PubMed Scopus Google Scholar, S. L.J. Cancer Res. 2002; Google Scholar). The increase of the MMP-2 which was implicated in connective tissue degradation in some signaling and a for sPLA2. found that sPLA2 increases the activation of pro-MMP-2 in NIH3T3 as as in fibroblasts. The study the sPLA2-induced of MMP-2 and TIMP-2 was the result of regulation of signaling In a number of possible signaling that the activation of was found that sPLA2 the PI3K and Akt pathway in NIH3T3 cells. Moreover, of PI3K and Akt activation in the of the MMP-2 activity by sPLA2. These results suggest that the PI3K and Akt pathway is essential for sPLA2 signaling responses, including pro-MMP-2 activation. In were not for pro-MMP-2 activation. The sPLA2s are of a of enzymes that are of active and signaling from membrane phospholipase activity has been delineated in the of and in the of other intracellular signaling (9Balsinde J. Winstead M.V. Dennis E.A. FEBS Lett. 2002; 531: 2-6Crossref PubMed Scopus (398) Google Scholar, 10Murakami M. Nakatani Y. Atsumi G. Inoue K. Kudo I. Crit. Rev. Immunol. 1997; 17: 225-283Crossref PubMed Google Scholar, J. Dennis E.A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). However, (12Lambeau G. Lazdunski M. Trends Pharmacol. Sci. 1999; 20: 162-170Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar, 13Cupillard L. Mulherkar R. Gomez N. Kadam S. Valentin E. Lazdunski M. Lambeau G. J. Biol. Chem. 1999; 274: 7043-7051Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar) have suggested that sPLA2 has a range of to phospholipase including cell proliferation, migration, and in cells. sPLA2 was for the activation of pro-MMP-2 in fibroblasts. evidence was in media from fibroblasts and not levels of sPLA2 the sPLA2 are found in the including M. Kudo I. J. 2002; PubMed Scopus Google Scholar, S. Lambeau G. K. M.J. J. M. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google that group IB PLA2 may to the effects in such In group IB PLA2 synthesis J. K. J. H. J. 1995; PubMed Scopus Google Scholar, J. K. H. J. Biol. Chem. Full Text PDF PubMed Google Scholar). to other cell group IB PLA2 was found to the expression of a number of including C.J. Mandal A.K. Zhang Z. Mukherjee A.B. Cancer Res. 2000; 60: 1084-1091PubMed Google Scholar, M. J. J. H. J. Biol. Chem. Full Text PDF PubMed Google and A.K. Zhang Z. Mukherjee A.B. J. 2001; PubMed Scopus Google Scholar). is thought to of sPLA2 to the J. K. H. J. Biol. Chem. Full Text PDF PubMed Google Scholar). The of the group IB PLA2 cellular involved in these biological effects to be NIH3T3 cells expressed sPLA2R, that these cells could be of sPLA2 L. Mulherkar R. Gomez N. Kadam S. Valentin E. Lazdunski M. Lambeau G. J. Biol. Chem. 1999; 274: 7043-7051Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar). To MMP-2 activity is to a signal sPLA2R, we the of on sPLA2-induced activation of were by as a control or by the of the mouse by using the increased the of in the cells. However, of conditioned medium showed that of not pro-MMP-2 activation by sPLA2 not These results suggest that this receptor may not be involved and that other surface may a major The of this study was to the role of cell migration in the activation of pro-MMP-2 by sPLA2 in NIH3T3 cells. that migration is in cells and that TIMP-2 The of cell migration, which we was dose- and PLA2 from migration of a cell line H. S. Y. Y. Res. 1997; PubMed Scopus Google whereas pancreatic PLA2 migration of cells K. H. Scopus Google Scholar). Moreover, N. and pancreatic PLA2 migration of cells E. M. Lambeau G. 2000; PubMed Google Scholar). previous studies have a role for group IB PLA2 as a of cell is evidence the of sPLA2-induced MMP-2 activation on cell migration. PI3K and Akt with MMP-2 activity and cell migration by that inhibition of PI3K results in decreased cell migration. that the decrease in cell migration is a result of the of MMP-2 activation. In our findings a physiologic role for sPLA2 as a of fibroblast migration. The by which sPLA2 cell to on MMP-2 activity. In addition, we identified the PI3K and Akt pathway as a key of pro-MMP-2 activation, and cell migration. These results provide important into the fibroblast migration and sPLA2 as a in a novel signaling for p85α and
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