Abstract
Acquisition of matrix metalloproteinase-2 (MMP-2) activity is temporally associated with increased migration and invasiveness of cancer cells. ProMMP-2 activation requires multimolecular complex assembly involving proMMP-2, membrane type 1-MMP (MT1-MMP, MMP-14), and tissue inhibitor of metalloproteinases-2 (TIMP-2). Because transforming growth factor-beta1 (TGF-beta1) promotes tumor invasion in advanced squamous cell carcinomas, the role of TGF-beta1 in the regulation of MMP activity in a cellular model of invasive oral squamous cell carcinoma was examined. Treatment of oral squamous cell carcinoma cells with TGF-beta1 promoted MMP-dependent cell scattering and collagen invasion, increased expression of MMP-2 and MT1-MMP, and enhanced MMP-2 activation. TGF-beta1 induced concomitant activation of ERK1/2 and p38 MAPK, and kinase inhibition studies revealed a negative regulatory role for ERK1/2 in modulating acquisition of MMP-2 activity. Thus, a reciprocal effect on proMMP-2 activation was observed whereupon blocking ERK1/2 phosphorylation promoted proMMP-2 activation and MT1-MMP activity, whereas inhibiting p38 MAPK activity decreased proteolytic potential. The cellular mechanism for the control of MT1-MMP catalytic activity involved concurrent reciprocal modulation of TIMP-2 expression by ERK1/2 and p38 MAPKs, such that inhibition of ERK1/2 phosphorylation decreased TIMP-2 production, and down-regulation of p38 MAPK activity enhanced TIMP-2 synthesis. Further, p38 MAPK inhibition promoted ERK1/2 phosphorylation, providing additional evidence for cross-talk between MAPK pathways. These observations demonstrate the complex reciprocal effects of ERK1/2 and p38 MAPK in the regulation of MMP activity, which could complicate the use of MAPK-specific inhibitors as therapeutic agents to down-regulate the biologic effects of TGF-beta1 on pericellular collagen degradation and tumor invasion.
Highlights
Acquisition of matrix metalloproteinase-2 (MMP-2) activity is temporally associated with increased migration and invasiveness of cancer cells
We have examined the role of transforming growth factor-1 (TGF-1) in the regulation of MMP activity in a cellular model of invasive oral squamous cell carcinoma (OSCC) and have evaluated the contribution of mitogen-activated protein kinases (MAPKs) signaling to TGF-1-induced MMP activity
TGF-1 Promotes MMP-mediated Cell Scattering and Type I Collagen Invasion—Because TGF-1 expression is correlated with invasive behavior in advanced squamous cell cancers [13,14,15], the effects of TGF-1 on cell scattering and collagen invasion were examined in a cellular model of invasive OSCC
Summary
Vol 279, No 37, Issue of September 10, pp. 39042–39050, 2004 Printed in U.S.A. Differential Regulation of Membrane Type 1-Matrix Metalloproteinase Activity by ERK 1/2- and p38 MAPK-modulated Tissue Inhibitor of Metalloproteinases 2 Expression Controls Transforming Growth Factor-1-induced Pericellular Collagenolysis*. P38 MAPK inhibition promoted ERK1/2 phosphorylation, providing additional evidence for cross-talk between MAPK pathways These observations demonstrate the complex reciprocal effects of ERK1/2 and p38 MAPK in the regulation of MMP activity, which could complicate the use of MAPK-specific inhibitors as therapeutic agents to down-regulate the biologic effects of TGF-1 on pericellular collagen degradation and tumor invasion. P38 MAPK inhibition promoted ERK1/2 activation, providing evidence for cross-talk between TGF-1-activated MAPK pathways These observations highlight the complex reciprocal effects of ERK1/2 and p38 MAPK in the regulation of MT1-MMP activity, which could complicate the use of MAPK-specific inhibitors as therapeutic approaches to down-regulate the biologic effects of TGF-1 on pericellular collagen degradation and tumor invasion in OSCC
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