Abstract
Matrix metalloproteinases (MMPs) are extracellular proteases that can cleave extracellular matrix and alter signaling pathways. They have been implicated in many disease states, but it has been difficult to understand the contribution of individual MMPs, as there are over 20 MMPs in vertebrates. The vertebrate MMPs have overlapping substrates, they exhibit genetic redundancy and compensation, and pharmacological inhibitors are non-specific. In contrast, there are only two MMP genes in Drosophila, DmMmp1 and DmMmp2, which makes Drosophila an attractive system to analyze the basis of MMP specificity. Previously, Drosophila MMPs have been categorized by their pericellular localization, as Mmp1 appeared to be secreted and Mmp2 appeared to be membrane-anchored, suggesting that protein localization was the critical distinction in this small MMP family. We report here that products of both genes are found at the cell surface and released into media. Additionally, we show that products of both genes contain GPI-anchors, and unexpectedly, that GPI-anchored MMPs promote cell adhesion when they are rendered inactive. Finally, by using new reagents and assays, we show that the two MMPs cleave different substrates, suggesting that this is the important distinction within this smallest MMP family.
Highlights
Matrix metalloproteinases (MMPs) are extracellular proteases that can cleave extracellular matrix and alter signaling pathways
With only two MMP genes, Drosophila has the fewest MMPs of any known animal model, as C. elegans has six MMPs, mice have 23, zebrafish have 2526,39
The simplicity of fly MMPs offers an unparalleled opportunity to understand the nature of redundancy, specificity, and diversity in the MMP family
Summary
Matrix metalloproteinases (MMPs) are extracellular proteases that can cleave extracellular matrix and alter signaling pathways. The MMP domain structure is conserved across multicellular eukaryotes, including plants like Arabidopsis, and animals from Hydra to Drosophila to humans Because they are proteases, most MMP functions are understood to reside in the catalytic domain, which contains an active-site zinc ion. There is clear evidence of recent gene duplications within the MMP family, and redundancy and compensation have been observed between MMP family members in knockout mice[12,13,14,15] These complications make it difficult to interpret the mild phenotypes of some MMP mutants. Recent genome annotation has identified an Mmp[1] cDNA that encodes a GPI-anchor domain[25], casting doubt on cellular localization as an evolutionary rationale for multiple MMP genes
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