Regulation of membrane type-1 matrix metalloproteinase activation by proprotein convertases

Membrane type-1 matrix metalloproteinase (MT1-MMP) is the prototypical memb er of a subgroup of membrane-anchored proteinases that belong to the matrix metalloproteinase family. Although synthesized as a zymogen, MT1-MMP plays an essential role in extracellular matrix remodeling after an undefined pr ocess that unmasks its catalytic domain. We now report the existence of a p roprotein convertase-MT1-MMP axis that regulates the processing and functio nal activity of the metalloproteinase. Two sets of basic motifs in the prop eptide region of MT1-MMP are identified that potentially can be recognized by the proprotein convertase family of subtilisin-like proteases. Processin g of proMT1-MMP as well as the expression of its proteolytic activity were blocked by mutating these recognition motifs or by inhibiting the proprotei n convertases furin and PC6 with the serpin-based inhibitor alpha(1) antitr ypsin Portland. Furthermore, both furin-dependent and furin-independent MT1 -MMP processing pathways are identified that require tethering of the metal loproteinase to the cell surface. These findings demonstrate the existence of a proprotein convertase-MT1-MMP axis that can regulate extracellular mat rix remodeling.