Soluble membrane-type 3 matrix metalloprioteinase causes changes in gene expression and increased gelatinase activity...

Matrix metalloproteinases (MMPs) are a family of endopeptidases that cleave and remodel the extracellular matrix (ECM). Membrane-type 3 MMP (MT3-MMP) is a membrane-anchored MMP, which has recently been shown to 'shed' from the cell surface in a soluble form upon proteolytic cleavage. Shed MT-MMPs can activate gelatinase-A in vitro and have been directly linked to the metastatic potential of many cancers. Here we examined the effect of ectopic expression of full-length tethered and shed (soluble) forms of MT3-MMP during Xenopus laevis development. Injection of mRNA coding for full-length tethered MT3-MMP resulted in the delayed onset of gastrulation and subsequent defects. Phenotype severity and the frequency of embryo death were dose-dependent. Dose-dependent defects were also observed with the injection of mRNA of the soluble form, but the phenotypes and frequencies of death were greater. Histological analysis of injected embryos demonstrated defects in the organization of axial structures, such as the neural tube and somites. Embryos injected with full-length MT3-MMP mRNA showed no significant changes in expression levels of the tissue specific genes endodermin, chordin and muscle actin when examined by semi-quantitative RT-PCR. In contrast, embryos injected with the soluble form of MT3-MMP exhibited decreased expression of these same marker genes. In addition, while full-length tethered MT3-MMP failed to alter gelatinase activity, a 50% increase was measured in response to injection of the soluble form, suggesting that the two forms of this protein could play distinct roles during embryogenesis.