FGF receptor-4 (FGFR4) polymorphism acts as an activity switch of a membrane type 1 matrix metalloproteinase-FGFR4 complex.
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.
Sugiyama
Nami
N
Department of Pathology, Haartman Institute, University of Helsinki, Helsinki University Central Hospital, Finland.
Varjosalo
Markku
M
Meller
Pipsa
P
Lohi
Jouko
J
Chan
Kui Ming
KM
Zhou
Zhongjun
Z
Alitalo
Kari
K
Taipale
Jussi
J
Keski-Oja
Jorma
J
Lehti
Kaisa
K
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
C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4; D053511:Matrix Metalloproteinase 14
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