title: FGF receptor-4 (FGFR4) polymorphism acts as an activity switch of a membrane type 1 matrix metalloproteinase-FGFR4 complex.
abstract: 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.
authors.affiliation: Department of Pathology, Haartman Institute, University of Helsinki, Helsinki University Central Hospital, Finland.
authors.forename: Nami
authors.initials: N
authors.lastname: Sugiyama
authors.forename: Markku
authors.initials: M
authors.lastname: Varjosalo
authors.forename: Pipsa
authors.initials: P
authors.lastname: Meller
authors.forename: Jouko
authors.initials: J
authors.lastname: Lohi
authors.forename: Kui Ming
authors.initials: KM
authors.lastname: Chan
authors.forename: Zhongjun
authors.initials: Z
authors.lastname: Zhou
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Jussi
authors.initials: J
authors.lastname: Taipale
authors.forename: Jorma
authors.initials: J
authors.lastname: Keski-Oja
authors.forename: Kaisa
authors.initials: K
authors.lastname: Lehti
mesh_terms: D011992:Endosomes / Q000201:enzymology; D004795:Enzyme Stability; D006801:Humans; D008247:Lysosomes / Q000201:enzymology; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D010766:Phosphorylation; D011110:Polymorphism, Genetic; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics*; D015398:Signal Transduction
chemical_list: C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4; D053511:Matrix Metalloproteinase 14
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