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Article: MT1-MMP Inactivates ADAM9 to Regulate FGFR2 Signaling and Calvarial Osteogenesis

TitleMT1-MMP Inactivates ADAM9 to Regulate FGFR2 Signaling and Calvarial Osteogenesis
Authors
Issue Date2012
PublisherCell Press. The Journal's web site is located at http://www.elsevier.com/locate/devcel
Citation
Developmental Cell, 2012, v. 22 n. 6, p. 1176-1190 How to Cite?
AbstractMMP14 encodes a membrane-tethered metalloproteinase MT1-MMP, capable of remodeling the extracellular matrix and modulating receptors on the cell surface. Loss of MT1-MMP results in craniofacial abnormalities. Here we show that MT1-MMP forms a complex with FGFR2 and ADAM9 in osteoblasts and proteolytically inactivates ADAM9, hence protecting FGFR2 from ADAM9-mediated ectodomain shedding on the cell surface. In Mmp14 -/- osteoblasts, FGF-induced proliferation and downstream signaling are specifically compromised, in conjunction with ADAM9 upregulation and FGFR2 shedding. The retarded parietal growth in Mmp14 -/- embryos starts at 15.5 dpc, attributable to the impaired FGFR2 signaling due to increased shedding mediated by ADAM9. Adam9 depletion completely rescues the defective FGFR2 signaling and largely restores calvarial bone growth in Mmp14 -/- embryos. These data reveal a regulatory paradigm for FGRF2 signaling and identify MT1-MMP as a critical negative modulator of ADAM9 activity to maintain FGFR2 signaling in calvarial osteogenesis. Mice lacking the membrane-tethered metalloproteinase MTI-MMP exhibit FGF signaling-related developmental defects, including calvarial defects. Chan et al. now show that MT1-MMP maintains FGF signaling during calvarial osteogenesis by proteolytically inactivating the metalloproteinase ADAM9, thereby protecting FGFR2 from cleavage and ectodomain shedding. © 2012 Elsevier Inc.
Persistent Identifierhttp://hdl.handle.net/10722/166965
ISSN
2015 Impact Factor: 9.338
2015 SCImago Journal Rankings: 7.338
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorChan, KMen_HK
dc.contributor.authorWong, HLXen_HK
dc.contributor.authorJin, Gen_HK
dc.contributor.authorLiu, Ben_HK
dc.contributor.authorCao, Ren_HK
dc.contributor.authorCao, Yen_HK
dc.contributor.authorLehti, Ken_HK
dc.contributor.authorTryggvason, Ken_HK
dc.contributor.authorZhou, Zen_HK
dc.date.accessioned2012-09-21T04:13:39Z-
dc.date.available2012-09-21T04:13:39Z-
dc.date.issued2012en_HK
dc.identifier.citationDevelopmental Cell, 2012, v. 22 n. 6, p. 1176-1190en_HK
dc.identifier.issn1534-5807en_HK
dc.identifier.urihttp://hdl.handle.net/10722/166965-
dc.description.abstractMMP14 encodes a membrane-tethered metalloproteinase MT1-MMP, capable of remodeling the extracellular matrix and modulating receptors on the cell surface. Loss of MT1-MMP results in craniofacial abnormalities. Here we show that MT1-MMP forms a complex with FGFR2 and ADAM9 in osteoblasts and proteolytically inactivates ADAM9, hence protecting FGFR2 from ADAM9-mediated ectodomain shedding on the cell surface. In Mmp14 -/- osteoblasts, FGF-induced proliferation and downstream signaling are specifically compromised, in conjunction with ADAM9 upregulation and FGFR2 shedding. The retarded parietal growth in Mmp14 -/- embryos starts at 15.5 dpc, attributable to the impaired FGFR2 signaling due to increased shedding mediated by ADAM9. Adam9 depletion completely rescues the defective FGFR2 signaling and largely restores calvarial bone growth in Mmp14 -/- embryos. These data reveal a regulatory paradigm for FGRF2 signaling and identify MT1-MMP as a critical negative modulator of ADAM9 activity to maintain FGFR2 signaling in calvarial osteogenesis. Mice lacking the membrane-tethered metalloproteinase MTI-MMP exhibit FGF signaling-related developmental defects, including calvarial defects. Chan et al. now show that MT1-MMP maintains FGF signaling during calvarial osteogenesis by proteolytically inactivating the metalloproteinase ADAM9, thereby protecting FGFR2 from cleavage and ectodomain shedding. © 2012 Elsevier Inc.en_HK
dc.languageeng-
dc.publisherCell Press. The Journal's web site is located at http://www.elsevier.com/locate/devcelen_HK
dc.relation.ispartofDevelopmental Cellen_HK
dc.subject.meshADAM Proteins - metabolism - physiology-
dc.subject.meshMatrix Metalloproteinase 14 - metabolism - physiology-
dc.subject.meshMembrane Proteins - metabolism - physiology-
dc.subject.meshOsteogenesis - physiology-
dc.subject.meshReceptor, Fibroblast Growth Factor, Type 2 - metabolism - physiology-
dc.titleMT1-MMP Inactivates ADAM9 to Regulate FGFR2 Signaling and Calvarial Osteogenesisen_HK
dc.typeArticleen_HK
dc.identifier.emailChan, KM: ming616@graduate.hku.hken_HK
dc.identifier.emailLiu, B: ppliew@hku.hken_HK
dc.identifier.emailZhou, Z: zhongjun@hkucc.hku.hken_HK
dc.identifier.authorityChan, KM=rp01757en_HK
dc.identifier.authorityLiu, B=rp01485en_HK
dc.identifier.authorityZhou, Z=rp00503en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1016/j.devcel.2012.04.014en_HK
dc.identifier.pmid22632802-
dc.identifier.scopuseid_2-s2.0-84862120224en_HK
dc.identifier.hkuros207820-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84862120224&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume22en_HK
dc.identifier.issue6en_HK
dc.identifier.spage1176en_HK
dc.identifier.epage1190en_HK
dc.identifier.eissn1878-1551-
dc.identifier.isiWOS:000305498200009-
dc.publisher.placeUnited Statesen_HK
dc.identifier.f1000716697807-
dc.identifier.scopusauthoridChan, KM=8631854500en_HK
dc.identifier.scopusauthoridWong, HLX=55248144900en_HK
dc.identifier.scopusauthoridJin, G=55224723000en_HK
dc.identifier.scopusauthoridLiu, B=7408693394en_HK
dc.identifier.scopusauthoridCao, R=7103341338en_HK
dc.identifier.scopusauthoridCao, Y=7404524342en_HK
dc.identifier.scopusauthoridLehti, K=6603777855en_HK
dc.identifier.scopusauthoridTryggvason, K=7102025185en_HK
dc.identifier.scopusauthoridZhou, Z=8631856300en_HK
dc.identifier.citeulike10703113-

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