Finding Dr. Jekyll & Catching Mr. Hyde: Revealing the molecular characters of Mmp11 paralogues in vivo in zebrafish using a novel molecular tool

Abstract

Matrix metalloproteinase 11 (Mmp11 or Stromelysin-3) plays paradoxical roles in mammalian tumours by promoting primary tumour growth but inhibiting metastasis. The zebrafish (Danio rerio) genome encodes two paralogous copies of this protease and may provide insight into the molecular mechanisms underpinning these distinctive roles.

I created epitope-tagged over-expression constructs of both paralogues for use in the epitope-mediated MMP activation assay and reveal different development dysfunction and activation kinetics associated with their ectopic expression across different developmental stages. I determined that while Mmp11α appears to be more evolutionarily conserved, the maternally provisioned Mmp11β has likely evolved critical distinct functions through different protein structure, differential susceptibility to cleavage by proteases, distinctive expression, and up-regulation in regeneration. This study provides a system for the further study of the functional specialization of these paralogues and an avenue for resolving the paradoxical functions of this protein in mammalian systems.