期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 36, 页码 15786-15791出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0914459107
关键词
proteolysis; signaling; MMP14; ECM; invasion
资金
- 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 Kong [HKU781808M, HKU7513/03M]
Tumor 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. In particular, 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.
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