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Article: FGF receptor-4 (FGFR4) polymorphism acts as an activity switch of a membrane type 1 matrix metalloproteinase - FGFR4 complex

TitleFGF receptor-4 (FGFR4) polymorphism acts as an activity switch of a membrane type 1 matrix metalloproteinase - FGFR4 complex
Authors
KeywordsECM
Invasion
MMP14
Proteolysis
Signaling
Issue Date2010
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings Of The National Academy Of Sciences Of The United States Of America, 2010, v. 107 n. 36, p. 15786-15791 How to Cite?
AbstractTumor cells use membrane type 1 matrix metalloproteinase (MT1-MMP) for invasion and metastasis. However, the signaling mechanisms that underlie MT1-MMP regulation in cancer have remained unclear. Using a systematic gain-of-function kinome screen for MT1-MMP activity, we have here identified kinases that significantly enhance MT1-MMP activity in tumor cells. Inparticular, we discovered an MT1-MMP/FGF receptor-4 (FGFR4) membrane complex that either stimulates or suppresses MT1-MMP and FGFR4 activities, depending on a tumor progression-associated polymorphism in FGFR4. The FGFR4-R388 allele, linked to poor cancer prognosis, increased collagen invasion by decreasing lysosomal MT1-MMP degradation. FGFR4-R388 induced MT1-MMP phosphorylation and endosomal stabilization, and surprisingly, the increased MT1-MMP in return enhanced FGFR4-R388 autophosphorylation. A phosphorylation-defective MT1-MMP was stabilized on the cell surface, where it induced simultaneous FGFR4-R388 internalization and dissociation of cell-cell junctions. In contrast, the alternative FGFR4-G388 variant down-regulated MT1-MMP, and the overexpression of MT1-MMP and particularly its phosphorylation-defective mutant vice versa induced FGFR4-G388 degradation. These results provide a mechanistic basis for FGFR4-R388 function in cancer invasion.
Persistent Identifierhttp://hdl.handle.net/10722/129110
ISSN
2015 Impact Factor: 9.423
2015 SCImago Journal Rankings: 6.883
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Academy of Finland
University of Helsinki Foundations
Sigrid Juselius Foundation
Association for International Cancer Research
Finnish Cancer Institute
Helsinki University Hospital
Finnish Cancer Foundation
Biocentrum Helsinki
Finnish Graduate School of Musculoskeletal Disorders and Biomaterials
Graduate School in Biotechnology and Molecular Biology
Helsinki Biomedical Graduate School
Novo Nordisk Foundation
Paulo Foundation
Finnish Cultural Foundation
Emil Aaltonen Foundation
Biomedicum Helsinki Foundation
Research Grant Council of Hong KongHKU781808M
HKU7513/03M
Funding Information:

We thank Sami Starast and Anne Remes for excellent technical assistance; Dr. Stephen J. Weiss (University of Michigan, Ann Arbor, MI) for HA-tagged MT1-MMP plasmid; and the Biomedicum Molecular Imaging Unit for imaging facilities. This work was supported by the Academy of Finland, University of Helsinki Foundations, Sigrid Juselius Foundation, Association for International Cancer Research, Finnish Cancer Institute, Helsinki University Hospital Fund, Finnish Cancer Foundation, Biocentrum Helsinki, Finnish Graduate School of Musculoskeletal Disorders and Biomaterials (N.S.) and Graduate School in Biotechnology and Molecular Biology (M. V.), Helsinki Biomedical Graduate School (P. M.), Novo Nordisk Foundation, Paulo Foundation, Finnish Cultural Foundation, Emil Aaltonen Foundation, Biomedicum Helsinki Foundation, and Research Grant Council of Hong Kong (HKU781808M and HKU7513/03M to Z.Z.).

References

 

DC FieldValueLanguage
dc.contributor.authorSugiyama, Nen_HK
dc.contributor.authorVarjosalo, Men_HK
dc.contributor.authorMeller, Pen_HK
dc.contributor.authorLohi, Jen_HK
dc.contributor.authorChan, KMen_HK
dc.contributor.authorZhou, Zen_HK
dc.contributor.authorAlitalo, Ken_HK
dc.contributor.authorTaipale, Jen_HK
dc.contributor.authorKeskiOja, Jen_HK
dc.contributor.authorLehti, Ken_HK
dc.date.accessioned2010-12-23T08:32:36Z-
dc.date.available2010-12-23T08:32:36Z-
dc.date.issued2010en_HK
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2010, v. 107 n. 36, p. 15786-15791en_HK
dc.identifier.issn0027-8424en_HK
dc.identifier.urihttp://hdl.handle.net/10722/129110-
dc.description.abstractTumor cells use membrane type 1 matrix metalloproteinase (MT1-MMP) for invasion and metastasis. However, the signaling mechanisms that underlie MT1-MMP regulation in cancer have remained unclear. Using a systematic gain-of-function kinome screen for MT1-MMP activity, we have here identified kinases that significantly enhance MT1-MMP activity in tumor cells. Inparticular, we discovered an MT1-MMP/FGF receptor-4 (FGFR4) membrane complex that either stimulates or suppresses MT1-MMP and FGFR4 activities, depending on a tumor progression-associated polymorphism in FGFR4. The FGFR4-R388 allele, linked to poor cancer prognosis, increased collagen invasion by decreasing lysosomal MT1-MMP degradation. FGFR4-R388 induced MT1-MMP phosphorylation and endosomal stabilization, and surprisingly, the increased MT1-MMP in return enhanced FGFR4-R388 autophosphorylation. A phosphorylation-defective MT1-MMP was stabilized on the cell surface, where it induced simultaneous FGFR4-R388 internalization and dissociation of cell-cell junctions. In contrast, the alternative FGFR4-G388 variant down-regulated MT1-MMP, and the overexpression of MT1-MMP and particularly its phosphorylation-defective mutant vice versa induced FGFR4-G388 degradation. These results provide a mechanistic basis for FGFR4-R388 function in cancer invasion.en_HK
dc.languageengen_US
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_HK
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_HK
dc.rightsProceedings of the National Academy of Sciences. Copyright © National Academy of Sciences.-
dc.subjectECMen_HK
dc.subjectInvasionen_HK
dc.subjectMMP14en_HK
dc.subjectProteolysisen_HK
dc.subjectSignalingen_HK
dc.titleFGF receptor-4 (FGFR4) polymorphism acts as an activity switch of a membrane type 1 matrix metalloproteinase - FGFR4 complexen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0027-8424&volume=107&issue=36&spage=15786&epage=15791&date=2010&atitle=FGF+receptor-4+(FGFR4)+polymorphism+acts+as+an+activity+switch+of+a+membrane+type+1+matrix+metalloproteinase+-+FGFR4+complex-
dc.identifier.emailChan, KM: ming616@graduate.hku.hken_HK
dc.identifier.emailZhou, Z: zhongjun@hkucc.hku.hken_HK
dc.identifier.authorityChan, KM=rp01757en_HK
dc.identifier.authorityZhou, Z=rp00503en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1073/pnas.0914459107en_HK
dc.identifier.pmid20798051-
dc.identifier.pmcidPMC2936587-
dc.identifier.scopuseid_2-s2.0-77957686550en_HK
dc.identifier.hkuros178649en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77957686550&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume107en_HK
dc.identifier.issue36en_HK
dc.identifier.spage15786en_HK
dc.identifier.epage15791en_HK
dc.identifier.isiWOS:000281637800031-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridSugiyama, N=36931617800en_HK
dc.identifier.scopusauthoridVarjosalo, M=12140326100en_HK
dc.identifier.scopusauthoridMeller, P=36542615000en_HK
dc.identifier.scopusauthoridLohi, J=7004276649en_HK
dc.identifier.scopusauthoridChan, KM=8631854500en_HK
dc.identifier.scopusauthoridZhou, Z=8631856300en_HK
dc.identifier.scopusauthoridAlitalo, K=35448502300en_HK
dc.identifier.scopusauthoridTaipale, J=6701557728en_HK
dc.identifier.scopusauthoridKeskiOja, J=7005572715en_HK
dc.identifier.scopusauthoridLehti, K=6603777855en_HK
dc.identifier.citeulike7749115-

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