The Interplay between MT1-MMP and ADAMs in Vascular Development

Abstract

Membrane Type 1-Matrix Metalloproteinase (MT1-MMP), also called as MMP14, is a membrane tethered enzyme essential for tissue remodeling and signaling transducing events ranging from growth and development to cancer progression and metastasis. Mmp14-/- mice exhibit severe craniofacial abnormalities similar to those of FGF signaling mutant mice. We found that cranial defects occurred as early as 15.5 dpc. in Mmp14-/- embryos, resulting from compromised FGF signaling that is a consequence of increased FGFR2 shedding mediated by ADAM9. MT1-MMP forms a complex with ADAM9 and FGFR2. Through this complex formation, MT1-MMP proteolytically inactivates ADAM9 to protect FGFR2 from ectodomain shedding. Interestingly, targeted deletion of ADAM9 significantly rescued cranial defects of Mmp14-/- mice in a FGF signaling-dependent manner. These findings reveal a novel paradigm for the regulation of FGF signaling (Chan et al., 2012). In addition, MT1-MMP can regulate another ADAM family member, ADAM15. MT1-MMP physically interacts with and cleaves ADAM15 to promote its degradation (Wong et al., 2012). Disturbance of this regulatory loop, such as depletion of ADAM15 in Mmp14-/- mice, leads to aberrant neovascularization. These results suggest that the regulation of ADAM15 by MT1-MMP is essential for the maintenance of vascular homeostasis. These findings also highlight the importance of the functional crosstalk between MMP and ADAM families in physiological development and probably other pathological conditions.