Authors: Hoi Leong Xavier Wong, Renhai Cao, Guoxiang Jin, Kui Ming Chan, Yihai Cao and Zhongjun Zhou

Hoi Leong Xavier Wong

Shenzhen Institute of Research and Innovation; The University of Hong Kong; Shenzhen, China; Department of Biochemistry; Li Ka Shing Faculty of Medicine; The University of Hong Kong; Hong Kong, China

Renhai Cao

Department of Microbiology and Tumor Center; Karolinska Institute; Stockholm, Sweden

Guoxiang Jin

Shenzhen Institute of Research and Innovation; The University of Hong Kong; Shenzhen, China; Department of Biochemistry; Li Ka Shing Faculty of Medicine; The University of Hong Kong; Hong Kong, China

Kui Ming Chan

Shenzhen Institute of Research and Innovation; The University of Hong Kong; Shenzhen, China; Department of Biochemistry; Li Ka Shing Faculty of Medicine; The University of Hong Kong; Hong Kong, China

Yihai Cao

Department of Microbiology and Tumor Center; Karolinska Institute; Stockholm, Sweden

Zhongjun Zhou

Corresponding author: zhongjun@hkucc.hku.hk
Shenzhen Institute of Research and Innovation; The University of Hong Kong; Shenzhen, China; Department of Biochemistry; Li Ka Shing Faculty of Medicine; The University of Hong Kong; Hong Kong, China

Abstract:
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.

Received: May 25, 2012; Accepted: May 30, 2012

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