When MT1-MMP meets ADAMs.
MT1-MMP is a membrane-tethered enzyme capable of remodeling extracellular matrix. MT1-MMP-deficient mice exhibit systematic defects during development, especially in craniofacial development characterized by retarded calvarial bone formation. Recently, we identified MT1-MMP as a critical positive modulator of FGF signaling during intramembranous ossification. MT1-MMP cleaves ADAM9 to protect FGFR2 from ectodomain shedding. Depletion of ADAM9 in MT1-MMP-deficient mice significantly rescued the calvarial defects via restoring FGF signaling. Interestingly, this regulatory mechanism seems to be highly tissue-specific, as defective FGF2-induced corneal angiogenesis in Mmp14-/- mice could not be rescued by removal of ADAM9. In addition, MT1-MMP also cleaves another ADAM family member, ADAM15. Our current findings not only present a novel regulatory mechanism for FGF signaling but also reveal a functional crosstalk between MMP and ADAM families. Better understanding of the interplay between ADAMs and MT1-MMP and its consequences for signaling pathways will provide new insights into therapeutic approaches for the management of developmental disorders and various diseases, such as cancer.
Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China.
Hoi Leong Xavier
HL
Wong
Renhai
R
Cao
Guoxiang
G
Jin
Kui Ming
KM
Chan
Yihai
Y
Cao
Zhongjun
Z
Zhou
D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology; D016510:Corneal Neovascularization; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D010012:Osteogenesis; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism*; D015398:Signal Transduction
D008565:Membrane Proteins; C507096:Mmp14 protein, mouse; D005346:Fibroblast Growth Factors; C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; C490902:Adam15 protein, mouse; C498316:Adam9 protein, mouse; D053511:Matrix Metalloproteinase 14; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse